bluuebunny/crossref_metadata_2025 huggingface dataset:
Glucagon-Like Peptide-1 Receptor–Targeted PET/CT With 68Ga-HBED-CC-Exendin-4 in Localizing Insulinoma
Authors: Li Linlin , Wang Guochang , Wang Jiarou , Ma Heng , Chen Jingci , Wang Rongxi , Pan Qingqing , Hong Haiyan , Jin Wenbin , Kung Hank F. , Zhu Lin , Luo Yaping , Zhu Zhaohui
Published: November 2024

Purpose

Modifying glucagon-like peptide-1 receptor (GLP-1R)–targeted PET agent to achieve faster renal clearance and preserved high affinity to GLP-1R is clinically relevant. The aim of this study is to assess the performance of a newly developed GLP-1R–targeted agent, 68Ga-HBED-CC-exendin-4 in localizing insulinoma, and its biodistribution, as compared with previously introduced 68Ga-NOTA-exendin-4.

Patients and Methods

Nineteen patients with endogenous hyperinsulinemic hypoglycemia were enrolled and referred for 68Ga-HBED-CC-exendin-4 PET/CT and 68Ga-NOTA-exendin-4 PET/CT within 2 consecutive days. Diagnostic performance of the 2 tracers in localizing insulinoma was evaluated, and SUV of the lesion, normal pancreas background, kidneys, and bladder were measured.

Results

68Ga-HBED-CC-exendin-4 and 68Ga-NOTA-exendin-4 PET/CT exhibited an equivalent efficacy in detection rate (both sensitivity of 100%). Although SUVmax of the tumor in 68Ga-HBED-CC-exendin-4 was significantly lower than that in 68Ga-NOTA-exendin-4 (20.01 ± 9.41 vs 31.78 ± 15.46, P < 0.001) at 50 minutes postinjection, there was no significant difference in the tumor-to-background ratio between the 2 agents (8.61 ± 3.57 vs 8.18 ± 3.38, P = 0.326), and the lesions could be visible as early as 4 minutes postinjection for both agents in patients who underwent dynamic PET/CT. In addition, 68Ga-HBED-CC-exendin-4 exhibited approximately 30% decrease of the renal accumulation compared with 68Ga-NOTA-exendin-4 (SUVmean, 42.21 ± 5.79 vs 58.58 ± 10.06 at 50 minutes, P < 0.001).

Conclusions

68Ga-HBED-CC-exendin-4 is an effective agent for localizing insulinoma showing similar detectability and tumor-to-background ratio compared with 68Ga-NOTA-exendin-4. Notably, 68Ga-HBED-CC-exendin-4 exhibits significantly lower renal uptake than 68Ga-NOTA-exendin-4, which might potentially benefit the detection of the tumors adjacent to the left kidneys.
Incretin-Based Therapies: A Promising Approach for Modulating Oxidative Stress and Insulin Resistance in Sarcopenia
Authors: Alnaser Raniah I. , Alassaf Fawaz A. , Abed Mohammed N.
Published: November 2024

Background: Recent studies have linked sarcopenia development to the hallmarks of diabetes, oxidative stress, and insulin resistance. The anti-oxidant and insulin sensitivityenhancing effects of incretin-based therapies may provide a promising option for the treatment of sarcopenia. This review aimed to unveil the role of oxidative stress and insulin resistance in the pathogenesis of sarcopenia and explore the potential benefits of incretin-based therapies in individuals with sarcopenia. Methods: PubMed, the Cochrane Library, and Google Scholar databases were searched by applying keywords relevant to the main topic, to identify articles that met our selection criteria. Results: Incretin-based therapies manifested anti-oxidant effects by increasing the anti-oxidant defense system and decreasing free radical generation or by indirectly minimizing glucotoxicity, which was mainly achieved by improving insulin signaling and glucose homeostasis. Likewise, these drugs exhibit insulin-sensitizing activities by increasing insulin secretion, transduction, and β-cell function or by reducing inflammation and lipotoxicity.Conclusions: Incretin-based therapies, as modulators of oxidation and insulin resistance, may target the main pathophysiological factors of sarcopenia, thus providing a promising strategy for the treatment of this disease.
General practice antibiotic prescriptions attributable to Respiratory Syncytial Virus by age and antibiotic class: An ecological analysis of the English population
Authors: Miller Lucy , Beaney Thomas , Hope Russel , Cunningham Mark , Robotham Julie V. , Pouwels Koen B. , Costelloe Cèire E.
Published: November 2024

Background

Respiratory syncytial virus (RSV) may contribute to a substantial volume of antibiotic prescriptions in primary care. However, data on the type of antibiotics prescribed for such infections is only available for children <5 years in the UK. Understanding the contribution of RSV to antibiotic prescribing would facilitate predicting the impact of RSV preventative measures on antibiotic use and resistance.

Objectives

To estimate the proportion of antibiotic prescriptions in English general practice attributable to RSV by age and antibiotic class.

Methods

Generalised additive models examined associations between weekly counts of general practice antibiotic prescriptions and laboratory-confirmed respiratory infections from 2015 to 2018, adjusting for temperature, practice holidays and remaining seasonal confounders. We used general practice records from the Clinical Practice Research Datalink and microbiology tests for RSV, influenza, rhinovirus, adenovirus, parainfluenza, human Metapneumovirus,Mycoplasma pneumoniaeandStreptococcus pneumoniaefrom England’s Second Generation Surveillance System.

Results

An estimated 2.1% of antibiotics were attributable to RSV, equating to an average of 640,000 prescriptions annually. Of these, adults ≥75 years contributed to the greatest volume, with an annual average of 149,078 (95% credible interval: 93,733-206,045). Infants 6-23 months had the highest average annual rate at 6,580 prescriptions per 100,000 individuals (95% credible interval: 4,522-8,651). Most RSV-attributable antibiotic prescriptions were penicillins, macrolides or tetracyclines. Adults ≥65 years had a wider range of antibiotic classes associated with RSV compared to younger age groups.

Conclusions

Interventions to reduce the burden of RSV, particularly in older adults, could complement current strategies to reduce antibiotic use in England.
Genome sequence of the medicinal plantTropaeolum majusprovides insights into flavonoid biosynthesis
Authors: Friedhoff Ronja , Wittstock Ute , Pucker Boas
Published: November 2024

Tropaeolum majusis a very popular species around the world with an enormous number of commercially available varieties displaying various flower color patterns and growth characteristics. It is rich in phytochemicals such as glucotropaeolin, hydroxycinnamic acid derivatives, and flavonol glycosides. Here, we report a highly continuous genome sequence ofT. majusand a comprehensive annotation of protein encoding genes suitable for comparative genomics. The potential for the exploration of individual gene functions in this valuable plant is demonstrated by an analysis of the flavonoid biosynthesis genes and their transcriptional regulators. Important players of the flavonol biosynthesis, including structural genes and a transcription factor, were identified that are required to produce precursors of phytomedically relevant flavonol glycosides. The genome sequence does not reveal an ortholog of the leucoanthocyanidin reductase encoding gene (LAR), which aligns with previous reports about the absence of this gene in many Brassicales species.
Genomic, phenomic, and geographic associations of leukocyte telomere length in the United States
Authors: Nakao Tetsushi , Koyama Satoshi , Truong Buu , Uddin Md Mesbah , Misra Anika , Patel Aniruddh P. , Bhatnagar Aarushi , Viscosi Victoria , Vlasschaert Caitlyn , Bick Alexander G. , Nelson Christopher P. , Codd Veryan , Samani Nilesh J. , Hornsby Whitney , Ellinor Patrick T. , Natarajan Pradeep
Published: November 2024

Leukocyte telomere length (LTL) is associated with multiple conditions, including cardiovascular diseases and neoplasms, yet their differential associations across diverse individuals are largely unknown. We estimated LTL from blood-derived whole genome sequences in theAll of UsResearch Program (n=242,494) with diverse backgrounds across the United States. LTL was associated with lifestyle, socioeconomic status, biomarkers, cardiometabolic diseases, and neoplasms with heterogeneity across genetic ancestries and sexes. Geographical analysis revealed that significantly longer LTL clustered in the West Coast and Central Midwest, while significantly shorter LTL clustered in the Southeast in the United States, accounting for age, sex, and genetic ancestry. Genome-wide association study and meta-analysis with the UK Biobank (n=679,972) found 234 non-overlapping loci, of which 36 were novel. We identified 4 novel loci unique to non-European-like populations and one specific to females. Rare variant analysis uncovered 7 novel genes, providing new functional insights. Our study highlighted previously underappreciated contextual heterogeneities of phenomic and genomic associations with LTL.
Validation of the patient reported outcome measures tool ′Catquest ′ in Odia language
Authors: SEN SASWATI , Das Matuli , AK Kavitha , Mohanty Aiswariya , Goel Anjali
Published: November 2024

Aim– To validate ′Catquest ′questionnaire in Odia speaking population of Eastern India Methodology– Prospective study was conducted on 40 patients planned for cataract surgery in a tertiary care centre in eastern India. Demographic data was collected and comprehensive ocular examination which included slit lamp examination, fundus examination, intraocular pressure measurement was done. Patients were asked to fill the ′Catquest ′ Questionnaire before and six weeks after the surgery. The English version of the questionnaire was translated and validated into Odia for use in the study. Patients filled both Odia and English questionnaires on both occasions. Statistical analysis was done to note the agreement between the answers given in both languages to validate the questionnaire in Odia Results – The ICC values for various activities such as Reading Papers, Seeing to Walk on Uneven Ground, Watching Television, and Preferred Hobby showed perfect reliability, with ICC ≈ 1 both preOP and post-OP. This indicates consistent perceptions of these activities across the two time points. Activities such as seeing prices, seeing to do needle work, reading news papers and shopping also showed good reliability. For Reading Text on Television, the ICC values were -0.0588 preOP and 0 postOP. The negative ICC preOP indicates very poor reliability or inconsistency, while the zero ICC post-OP suggests a lack of variability. Conclusion – with growing emphasis on patient reported outcomes, both clinical and subjective parameters need to be considered for the success of any procedure. The study shows good correlation between original and translated version and can be incorporated in clinical practice successfully
The Society of Radiologists in Training (SRT) 2024 Training Survey on the impact of recent changes to training and non-radiologist roles
Authors: Kilic Yakup , Colman Jordan , Kiandee Miraen , Shyamanur Bhavana , Ngu Wee Ping , Watura Emma
Published: November 2024

Introduction

In 2016, the Royal College of Radiologists (RCR) launched an initiative to address the radiology workforce crisis in the UK, focusing on increasing the number of training places. To address this, the RCR advocated for the introduction of skill mix and expanded imaging training academies. The NHS’s 2023 long-term workforce plan proposed increased integration of medical associate professions (MAPs) in radiology, although this has raised concerns regarding regulation and training quality.

Methods

We conducted an online survey targeting UK radiologists to gather insights on their perceptions of training quality, recent modifications to training, and views on non-radiologist roles. The purpose of the study was to evaluate the ways in which these elements affect their training experiences and general contentment.

Results

A total of 227 responses were collected, predominantly from residents across all UK training deaneries. 63.9% of trainees expressed satisfaction with their training although this varied, with trainees in new/hybrid academies reporting lower satisfaction. Concerns about training quality were prevalent, attributed to numerous factors such as consultants working from home and increased training numbers. Although opinions on the new curriculum were divided, many commented on the challenges of meeting the new IR competences, and the greater focus on general training was perceived more adversely. Career prospects in radiology were often bleak.

Conclusion

The survey results highlighted a multifaceted array of perceptions and concerns amongst radiology residents regarding several factors negatively impacting their training, such as changes to the curriculum and growth of non-radiologist roles.
A Multimodal Foundation Model for Discovering Genetic Associations with Brain Imaging Phenotypes
Authors: Machado Reyes Diego , Burch Myson , Parida Laxmi , Bose Aritra
Published: November 2024

Due to the intricate etiology of neurological disorders, finding interpretable associations between multi-omics features can be challenging using standard approaches. We proposeCOMICAL, a contrastive learning approach leveraging multi-omics data to generate associations between genetic markers and brain imaging-derived phenotypes.COMICALjointly learns omic representations utilizing transformer-based encoders with custom tokenizers. Our modality-agnostic approach uniquely identi-fies many-to-many associations via self-supervised learning schemes and cross-modal attention encoders.COMICALdiscovered several significant associations between genetic markers and imaging-derived phenotypes for a variety of neurological disorders in the UK Biobank as well as predicting across diseases and unseen clinical outcomes from the learned representations. Source code ofCOMICALalong with pre-trained weights, enabling transfer learning is available athttps://github.com/IBM/comical.
The open-closed mod-minimizer algorithm
Authors: Koerkamp Ragnar Groot , Liu Daniel , Pibiri Giulio Ermanno
Published: November 2024

Sampling algorithms that deterministically select a subset ofk-mers are an important building block in bioinformatics applications. For example, they are used to index large textual collections, like DNA, and to compare sequences quickly. In such applications, a sampling algorithm is required to select onek-mer out of every window ofwconsecutivek-mers. The folklore and most used scheme is therandom minimizerthat selects the smallestk-mer in the window according to some random order. This scheme is remarkably simple and versatile, and has adensity(expected fraction of selectedk-mers) of 2/(w+ 1). In practice, lower density leads to faster methods and smaller indexes, and it turns out that the random minimizer is not the best one can do. Indeed, some schemes are known to approach optimal density 1/wwhenk → ∞, like the recently introducedmod-minimizer(Groot Koerkamp and Pibiri, WABI 2024).

In this work, we study methods that achieve low density whenk ≤ w. In this small-kregime, a practical method with provably better density than the random minimizer is theminiception(Zheng et al., Bioinformatics 2021). This method can be elegantly described as sampling the smallestclosed sycnmer(Edgar, PeerJ 2021) in the window according to some random order. We show that extending the miniception to prefer samplingopensyncmers yields much better density. This new method – theopen-closedminimizer – offers improved density for smallk ≤ wwhile being as fast to compute as the random minimizer. Compared to methods based on decycling sets, that achieve very low density in the small-kregime, our method has comparable density while being computationally simpler and intuitive.

Furthermore, we extend the mod-minimizer to improve density of any scheme that works well for smallkto also work well whenk > wis large. We hence obtain theopen-closed mod-minimizer, a practical method that improves over the mod-minimizer for allk.
Biobank-scale characterization of Alzheimer’s disease and related dementias identifies potential disease-causing variants, risk factors, and genetic modifiers across diverse ancestries
Authors: Khani Marzieh , Akçimen Fulya , Grant Spencer M. , Akerman S. Can , Lee Paul Suhwan , Faghri Faraz , Leonard Hampton , Kim Jonggeol Jeffrey , Makarious Mary B. , Koretsky Mathew J. , Rothstein Jeffrey D , Blauwendraat Cornelis , Nalls Mike A. , Singleton Andrew , Bandres-Ciga Sara
Published: November 2024

Alzheimer’s disease and related dementias (AD/ADRDs) pose a significant global public health challenge, underscored by the intricate interplay of genetic and environmental factors that differ across ancestries. To effectively implement equitable, personalized therapeutic interventions on a global scale, it is essential to identify disease-causing mutations and genetic risk and resilience factors across diverse ancestral backgrounds. Exploring genetic-phenotypic correlations across the globe enhances the generalizability of research findings, contributing to a more inclusive and universal understanding of disease. This study leveraged biobank-scale data to conduct the largest multi-ancestry whole-genome sequencing characterization of AD/ADRDs. We aimed to build a valuable catalog of potential disease-causing, genetic risk and resilience variants impacting the etiology of these conditions. We thoroughly characterized genetic variants from key genes associated with AD/ADRDs across 11 genetic ancestries, utilizing data from All of Us, UK Biobank, 100,000 Genomes Project, Alzheimer’s Disease Sequencing Project, and the Accelerating Medicines Partnership in Parkinson’s Disease, including a total of 25,001 cases and 93,542 controls. We prioritized 116 variants possibly linked to disease, including 18 known pathogenic and 98 novel variants. We detected previously described disease-causing variants among controls, leading us to question their pathogenicity. Notably, we showed a higher frequency ofAPOEε4/ε4 carriers among individuals of African and African Admixed ancestry compared to other ancestries, confirming ancestry-driven modulation ofAPOE-associated AD/ADRDs. A thorough assessment ofAPOErevealed a disease-modifying effect conferred by theTOMM40:rs11556505,APOE:rs449647,19q13.31:rs10423769,NOCT:rs13116075,CASS4:rs6024870, andLRRC37A:rs2732703 variants amongAPOEε4 carriers across different ancestries. In summary, we compiled the most extensive catalog of established and novel genetic variants in known genes increasing risk or conferring resistance to AD/ADRDs across diverse ancestries, providing clinical insights into their genetic-phenotypic correlations. The findings from this investigation hold significant implications for potential clinical trials and therapeutic interventions on a global scale. Finally, we present an accessible and user-friendly platform for the AD/ADRDs research community to help inform and support basic, translational, and clinical research on these debilitating conditions (https://niacard.shinyapps.io/MAMBARD_browser/).
Obsessive-compulsive disorder is characterised by metacognitive deficits resistant to subthalamic stimulation
Authors: Kist Audrey , Pereira Michael , Msheik Ramla , Goueytes Dorian , Pouchon Arnaud , Chabardès Stephan , Bastin Julien , Polosan Mircea , Faivre Nathan
Published: November 2024

Most human studies on perceptual decision-making are correlational, and few addressed the causal role of the neural markers they identify. Here, we took the opportunity offered by deep brain stimulation to study the causal role of subthalamo-cortical networks on perceptual decision-making and perceptual monitoring. To this end, we asked participants with obsessive-compulsive disorder (OCD) treated with subthalamic stimulation to detect visual stimuli and provide confidence reports while we recorded scalp electroencephalography. Following a preregistered plan, we compared behavioural and neural results between patients off-stimulation and matched healthy controls and among patients on and off-stimulation to identify the effect of subthalamic stimulation on perceptual choices and metacognitive judgments. Our results indicate that patients off-stimulation detected visual stimuli similarly to matched healthy controls but provided poorer confidence judgments indicative of a metacognitive deficit. Moreover, chronic subthalamic stimulation significantly reduced clinical symptoms, but acute stimulation changes did not impact visual detection, confidence, or corresponding event-related potentials at the scalp level. We conclude that acute changes in subthalamic stimulation are insufficient to alleviate metacognitive deficits observed in OCD.
Machine learning predicts liver cancer risk from routine clinical data: a large population-based multicentric study
Authors: Clusmann Jan , Koop Paul-Henry , Zhang David Y. , van Haag Felix , El Nahhas Omar S. M. , Seibel Tobias , Žigutytė Laura , Kaewdech Apichat , Calderaro Julien , Tacke Frank , Luedde Tom , Truhn Daniel , Bruns Tony , Schneider Kai Markus , Kather Jakob N. , Schneider Carolin V.
Published: November 2024

Background and aims

Hepatocellular carcinoma (HCC) is a highly fatal tumor, for which early detection and risk stratification is crucial, yet remains challenging. We aimed to develop an interpretable machine-learning framework for HCC risk stratification based on routinely collected clinical data.

Methods

We leverage data obtained from over 900,000 individuals and 983 cases of HCC across two large-scale population-based cohorts: the UK Biobank study and the “All Of Us Research Program”. For all of these patients, clinical data from timepoints years before diagnosis of HCC was available. We integrate data modalities including demographics, electronic health records, lifestyle, routine blood tests, genomics and metabolomics to offer a unique, multi-modal perspective on HCC risk.

Results

Our random-forest-based model significantly outperforms all publicly available state-of-the-art risk-scores, with an AUROC of 0.88 both for internal and external test sets. We demonstrate robustness of our model across ethnic subgroups, a major advance over previous models with variable performance by ethnicity. Further, we perform extensive feature-importance analysis, showcasing our approach as an interpretable framework. We provide all model weights and an open-source web calculator to facili-tate further validation of our model.

Conclusion

Our study presents a robust and interpretable machine-learning framework for HCC risk stratification, which offers the potential to improve early detection and could ultimately reduce disease burden through targeted interventions.

Lay summary

Finding liver cancer early is crucial for successful treatment. Therefore, screening with abdominal ultra-sound can be performed. However, it is not clear who should receive ultrasound screening, as with the current standard of screening only patients with liver cirrhosis, a severe liver disease, many patients are diagnosed with liver cancer in late stages. Therefore, we trained a machine learning model, acting like many decision trees at the same time, to detect patients with high risk of liver cancer by looking at patterns of almost 1000 cases of liver cancer in a population of 900.000 individuals. In a separate set of patients, which the model has not seen during training, our model worked better than all available models. Additionally, we investigated 1. how the model comes to its prediction, 2. whether it works in males and females alike and 3. which data is most relevant for the model. Like this, our model can help sort patients into categories like “high-risk”, “medium-risk” and “low-risk”, via which screening strategies can then be decided, to help improve early detection of liver cancer.
Involvement of the Posterior Visual Pathway Correlates with Higher-Order Visual Impairment in Childhood Stroke Patients detected by Virtual Reality/Eye Tracking Paradigm
Authors: Da Cruz Emily , Tambala Diana , Lynch Anna , Manley Claire , Bambery Melissa , Kelly Daniel , Chui Carrie , Alhadid Kenda , Sullivan Alyssa W. , Grieco Julie , Ondeck Benjamin , Lauer Arne , Merabet Lotfi B. , Musolino Patricia L.
Published: November 2024

Background/Objective

Cerebral injury due to stroke in childhood increases the risk of higher-order visual processing (HOVP) deficits, like cerebral visual impairment (CVI), which can lead to severe behavioral and learning disabilities if left untreated. Using a virtual reality-based search task and structural Magnetic Resonance Imaging analysis, we assess the extent of functional vision deficits in childhood stroke patients and potential anatomical correlates.

Methods

20 childhood stroke patients and 38 healthy controls completed a dynamic visual search task using a virtual reality/eye-tracking (VR/ET) paradigm to quantify functional vision abilities between 2021 to 2024 (average 7.34 years after stroke). Virtual reality assessment measures, stroke imaging characteristics (visual pathway involvement) and neuropsychological outcomes were analyzed between cohorts using statistical comparison methods and linear regression model.

Results

All childhood stroke patients could complete the VR/ET task, whose metrics were associated with neuropsychological testing measures of visual attention and processing speed, as demonstrated by success rates and task compliance in equal measure to controls. However, less accurate search and slower fixation rates together with less sensitivity to changes in task load and greater impairment in initiating a response to a target were observed in our patient cohort. On MRI lesion analysis injury involving the posterior visual pathways, specifically the optic radiations, inferior longitudinal fasciculus, or superior longitudinal fasciculus, correlated with slower reaction time to fixation on a target when controlling for age at time of VR testing.

Conclusions

Bedside VR/ET assessment in children affected by stroke can detect signs of HOVP deficits as confirmed by neuropsychological testing. Imaging demonstrating involvement of the posterior visual pathway at the time of diagnosis is strongly correlated with development of impaired visual tracking abilities later in life. While detection of HOVP deficits relies on current standard clinical and neuropsychological evaluations between 3 to 6 years of age, our study demonstrates that injury pattern on imaging at stroke onset can help identify children at risk of HOVP deficits. This may enable early monitoring and timely accommodations facilitating functional vision development, critical to learning and skill acquisition.
Antagonizingcis-regulatory elements of a conserved flowering gene mediate developmental robustness
Authors: Lanctot Amy , Hendelman Anat , Udilovich Peter , Robitaille Gina M. , Lippman Zachary B.
Published: November 2024

Developmental transitions require precise temporal and spatial control of gene expression. In plants, such regulation is critical for flower formation, which involves the progressive differentiation of stem cell populations within floral meristems followed by rapid sequential development of floral organs. Across plant taxa, these transitions are orchestrated by the F-box transcriptional co-factor geneUNUSUAL FLORAL ORGANS(UFO). The conserved and pleiotropic functions ofUFOoffer a useful framework for investigating how evolutionary processes have shaped the intricatecis-regulation of key developmental genes. By pinpointing a conserved promoter sequence in an accessible chromatin region of the tomato ortholog ofUFO, we engineeredin vivoa series ofcis-regulatory alleles that caused both loss- and gain-of-function floral defects. These mutant phenotypes were linked to disruptions in predicted transcription factor binding sites for known transcriptional activators and repressors. Allelic combinations revealed dosage-dependent interactions between opposing alleles, influencing the penetrance and expressivity of gain-of-function phenotypes. These phenotypic differences support that robustness in tomato flower development requires precise temporal control ofUFOexpression dosage. Bridging our analysis toArabidopsis, we found that although homologous sequences to the tomato regulatory region are dispersed within theUFOpromoter, they maintain similar control over floral development. However, phenotypes from disrupting these sequences differ due to the differing expression patterns ofUFO. Our study underscores the complexcis-regulatory control of dynamic developmental genes and demonstrates that critical short stretches of regulatory sequences that recruit both activating and repressing machinery are conserved to maintain developmental robustness.
Self-organization of spermatogenic wave coordinates sustained sperm production in the mouse testis
Authors: Sato Toshiyuki , Li Yuting I. , Jörg David J. , Komeya Mitsuru , Yamanaka Hiroyuki , Nakamura Hiroko , Hirano Kodai , Kondo Yohei , Aoki Kazuhiro , Takahashi Masahide , Nakata Hiroki , Kimura Hiroshi , Ogawa Takehiko , Simons Benjamin D. , Yoshida Shosei
Published: November 2024

Spermatogenesis takes place in the testis, relying on the ordered turnover of differentiating cells supplied from stem cells. Classic histological analyses have revealed that this process shows hierarchical spatiotemporal patterning known as the spermatogenic cycle, wave, and descent of segmental order, indicative of currently underexplored mechanisms of tissue- and organ-scale homeostasis. Here, using mice, we conducted high-resolution, wide-field, and ‘ultra’ long-term live imaging studiesin vivoandex vivo, combined with whole-organ mapping of differentiation stages. Such trans-scale measures demonstrate how stereotypic local cell turnover is coordinated into characteristic phase waves propagating along the seminiferous tubules, further organized into organ-scale patterning over the tubule loops. Minimal mathematical modeling shows that such higher-order dynamics can emerge from the local coupling of autonomous oscillators, which are rooted in delayed feedback interplay between stem and differentiating cells via retinoic acid signaling. These findings highlight a self-organization mechanism underpinning organ-scale homeostasis and constant sperm production.
Quantifying the population-level impact of expanded antibiotic treatment for cholera outbreak management
Authors: Ahmed Sharia M. , LaPrete Cormac R. , Ciglenecki Iza , Azman Andrew S. , Leung Daniel T. , Keegan Lindsay T.
Published: November 2024

Background

Since 2021, there has been a resurgence in the number of cholera cases, countries affected, and the case fatality risk. Partly due to concerns about antibiotic resistance, current cholera treatment guidelines reserve antibiotics for severely symptomatic cases, recommending only supportive care (e.g., oral rehydration) for non-severe cases. However, it has been suggested that the reduction in transmissibility from antibiotic treatment may result in circumstances under which treating mild or moderate cases with antibiotics may have population-level benefits. We developed a compartmental model of cholera transmission in a non-endemic setting to quantify the potential impact of expanded antibiotic treatment on disease burden and antibiotic use. Through simulations, we evaluated different outbreak scenarios, by varying the reproductive number, care-seeking behavior, and proportion of non-severe cases receiving antibiotics. We found that expanding antibiotic treatment could significantly reduce the final outbreak size under certain outbreak characteristics. Under these different transmission scenarios, treating non-severe symptomatic infections with antibiotics decreased cholera transmission and, in some cases, the total number of antibiotic doses used. In high transmission settings, the benefits of expanded treatment are less pronounced and the strategy may lead to increased antibiotic use, potentially increasing the risk of antibiotic resistance. We show that the effectiveness of expanded antibiotic treatment is highly dependent on achieving high care-seeking rates among non-severely symptomatic infections and tailoring the approach to specific outbreak conditions. While expanding antibiotic eligibility could enhance outbreak control in some settings, careful consideration of antibiotic resistance risks is necessary in high-transmission contexts.
Hospital-wide, dynamic, individualized prediction of central line-associated bloodstream infections - development and temporal evaluation of six prediction models
Authors: Albu Elena , Gao Shan , Stijnen Pieter , Rademakers Frank E. , Janssens Christel , Cossey Veerle , Debaveye Yves , Wynants Laure , Van Calster Ben
Published: November 2024

Background

Central line-associated bloodstream infections (CLABSI) are preventable hospital-acquired infections. Predicting CLABSI helps improve early intervention strategies and enhance patient safety.

Aim

To develop and temporally evaluate dynamic prediction models for continuous CLABSI risk monitoring.

Methods

Data from hospitalized patients with central catheter(s) admitted to University Hospitals Leuven between 2014 and 2017 were used to develop five dynamic models (a cause-specific landmark supermodel, two random forest models, and two XGBoost models) to predict 7-day CLABSI risk, accounting for competing events (death, discharge, and catheter removal). The models’ predictions were then combined using a superlearner model. All models were temporally evaluated on data from the same hospital from 2018 to 2020 using performance metrics for discrimination, calibration, and clinical utility.

Findings

Among 61629 catheter episodes in the training set, 1930 (3.1%) resulted in CLABSI, while in the test set of 44544 catheter episodes, 1059 (2.4%) experienced CLABSI.

Among individual models, one XGBoost model reached an AUROC of 0.748. Calibration was good for predicted risks up to 5%, while the cause-specific and XGBoost models overestimated higher predicted risks. The superlearner displayed a modest improvement in discrimination (AUROC up to 0.751) and better calibration than the cause-specific and XGBoost models, but worse than the random forest models. The models showed clinical utility to support standard care interventions (at risk thresholds between 0.5-4%), but not to support advanced interventions (at thresholds 15-25%). A deterioration in model performance over time was observed on temporal evaluation.

Conclusion

Hospital-wide CLABSI prediction models offer clinical utility, though temporal evaluation revealed dataset shift.
MRI-based surrogates of brain clearance in narcolepsy type 1
Authors: van Heese Eva M. , Gool Jari K. , Lammers Gert Jan , van der Werf Ysbrand D. , van Osch Matthias J.P. , Fronczek Rolf , Hirschler Lydiane
Published: November 2024

Brain clearance involves the drainage of waste molecules from the brain, a process that is suggested to be amplified during sleep. Recently proposed MRI-based methods attempt to approximate human brain clearance with surrogate measures. The current study aimed to explore whether two brain clearance surrogates are altered in narcolepsy. We processed diffusion-weighted and functional resting-state images to extract two surrogates: Diffusion Tensor Imaging Along the Perivascular Space (DTI-ALPS index), and dBOLD-CSF coupling. Both measures were analysed in 12 drug-free, awake people with narcolepsy type 1 and 11 age- and sex-matched controls, as well as in relation to clinical features. We also assessed the correlation between the DTI-ALPS index and dBOLD-CSF coupling. The DTI-ALPS index and dBOLD-CSF coupling amplitude identified were similar to previous research and did not show significant differences between narcolepsy and controls, nor significant relations with severity of excessive daytime sleepiness. We found a significant correlation between the DTI-ALPS index and dBOLD-CSF coupling amplitude. The hypothesis of altered brain clearance in narcolepsy type 1 is not supported by evidence from the current study. The two surrogates correlated with each other, suggesting that both offer different perspectives from the same underlying physiology. Yet, the suitability of the surrogates as brain clearance markers remains debatable. Whereas DTI is not exclusively sensitive to perivascular fluid, dBOLD-CSF coupling is reflecting large-scale CSF motion. Future work should explore other surrogate markers, preferably during sleep, to better understand the possible role of altered brain clearance in narcolepsy type 1 symptomatology.
Reference values and determinants of fractional exhaled nitric oxide in a representative adult population in Western Sweden
Authors: Abohalaka Reshed , Ercan Selin , Lehtimäki Lauri , Özuygur Ermis Saliha Selin , Lisik Daniil , Awad Bashir Muwada Bashir , Jadhav Radhika , Ekerljung Linda , Wennergren Göran , Lötvall Jan , Pullerits Teet , Backman Helena , Rådinger Madeleine , Nwaru Bright Ibeabughichi , Kankaanranta Hannu
Published: November 2024

Background

Fractional exhaled nitric oxide (FeNO) is used to differentiate asthma inflammatory phenotypes and guide its management. However, data on FeNO reference values in a representative adult population is limited.

Objective

To derive reference values and determinants of FeNO in a representative adult population.

Methods

The West Sweden Asthma Study is a clinical-epidemiological population- representative study of randomly selected adults in Western Sweden. From this cohort, 943 subjects participated in comprehensive clinical investigations, including skin prick testing (SPT), specific immunoglobulin E (sIgE) analysis, and FeNO measurement. Clinical allergy was defined as co-occurrence of atopy (positivity to SPT or sIgE) and self-reported allergic symptoms to the same allergen family. FeNO levels were analysed in relation to the presence or absence of clinical allergy, asthma, and other factors.

Results

The 95thpercentile of FeNO ranged from 34 to 52 parts per billion (ppb) in the entire sample (N=943), and from 26 to 37 ppb among individuals without clinical allergy, asthma, or chronic obstructive pulmonary disease (COPD) (n=587), depending on age. Sex, smoking, clinical allergy, atopy, asthma, and hypertension influenced FeNO levels, meanwhile, age, asthma, clinical allergy, and reversibility- related variables were significant determinants of FeNO levels.

Conclusion

The 95thpercentile (upper normal limit) for FeNO ranges from 34 to 52 ppb overall, and from 26 to 37 ppb in those without clinical allergy, asthma, or COPD, depending on age. These findings provide a guide for interpreting FeNO in the general population and in asthma and COPD clinics.
Unsupervised cardiac MRI phenotyping with 3D diffusion autoencoders reveals novel genetic insights
Authors: Ometto Sara , Chatterjee Soumick , Vergani Andrea Mario , Landini Arianna , Sharapov Sodbo , Giacopuzzi Edoardo , Visconti Alessia , Bianchi Emanuele , Santonastaso Federica , Soda Emanuel M. , Cisternino Francesco , Ieva Francesca , Di Angelantonio Emanuele , Pirastu Nicola , Glastonbury Craig A.
Published: November 2024

Biobank-scale imaging provides a unique opportunity to characterise structural and functional cardiac phenotypes and how they relate to disease outcomes. However, deriving specific phenotypes from MRI data requires time-consuming expert annotation, limiting scalability and does not exploit how information dense such image acquisitions are. In this study, we applied a 3D diffusion autoencoder to temporally resolved cardiac Magnetic Resonance Imaging (MRI) data from 71,021 UK Biobank participants to derive latent phenotypes representing the human heart in motion. These phenotypes were reproducible, heritable (h2= [4 - 18%]), and significantly associated with cardiometabolic traits and outcomes, including atrial fibrillation (P= 8.5×10−29) and myocardial infarction (P= 3.7×10−12). By using latent space manipulation techniques, we directly interpreted and visualised what specific latent phenotypes were capturing in a given MRI. To establish the genetic basis of such traits, we performed a genome-wide association study, identifying 89 significant common variants (P <2.3×10−9) across 42 loci, including seven novel loci. Extensive multi-trait colocalisation analyses (PP.H4>0.8) linked these variants to various cardiac traits and diseases, revealing a shared genetic architecture spanning phenotypic scales. Polygenic Risk Scores (PRS) derived from latent phenotypes demonstrated predictive power for a range of cardiometabolic diseases and high risk individuals had substantially increased cumulative hazard rates across a range of diseases. This study showcases the use of diffusion autoencoding methods as powerful tools for unsupervised phenotyping, genetic discovery and disease risk prediction using cardiac MRI imaging data.
Accurate Machine Learning Model for Human Embryo Morphokinetic Stage Detection
Authors: Misaghi H , Cree L , Knowlton N
Published: November 2024

Purpose

The ability to detect, monitor, and precisely time the morphokinetic stages of human embryos plays a critical role in assessing their viability and potential for successful implantation. In this context, the development and utilization of accurate and accessible tools for analysing embryo development are needed. This work introduces a highly accurate, machine learning model designed to predict 16 morphokinetic stages of pre-implantation human development, which is a significant improvement over existing models. This provides a robust tool for researchers and clinicians to use to automate the prediction of morphokinetic stage, allowing standardisation and reducing subjectivity between clinics.

Method

A computer vision model was built on a public dataset for embryo Morphokinetic stage detection containing approximately 273,438 labelled images based on Embryoscope/+© embryo images. The dataset was split 70/10/20 into training/validation/test sets. Two different deep learning architectures were trained and tested, one using efficient net V2 and the other using efficient-net V2 with the addition of post-fertilization time as input. A new postprocessing algorithm was developed to reduce the noise in predictions of the deep learning model and detect the exact time of each morphokinetic stage change.

Results

The proposed model reached an overall test accuracy of 87% across 17 morphokinetic stages on an independent test set. If only considering plus or minus one developmental stage, the accuracy rises to 97.1%.

Conclusion

The proposed model shows state-of-the-art performance (17% accuracy improvement compared to the best models on the same dataset) to detect morphokinetic stages in static embryo images as well as detecting the exact moment of stage change in a complete time-lapse video.
Suppression of Huntington’s Disease Somatic Instability by Transcriptional Repression and Direct CAG Repeat Binding
Authors: Mathews Ella W. , Coffey Sydney R. , Gärtner Annette , Belgrad Jillian , Bragg Robert M. , O’Reilly Daniel , Cantle Jeffrey P. , McHugh Cassandra , Summers Ashley , Fentz Joachim , Schwagarus Tom , Cornelius Antje , Lingos Ioannis , Burch Zoe , Kovalenko Marina , Andrew Marissa A , Bennett Frank C. , Kordasiewicz Holly B. , Marchionini Deanna M. , Wilkinson Hilary , Vogt Thomas F. , Pinto Ricardo M. , Khvorova Anastasia , Howland David , Wheeler Vanessa C. , Carroll Jeffrey B.
Published: November 2024

Huntington’s disease (HD) arises from a CAG expansion in thehuntingtin(HTT) gene beyond a critical threshold. A major thrust of current HD therapeutic development is lowering levels of mutantHTTmRNA (mHTT) and protein (mHTT) with the aim of reducing the toxicity of these product(s). Human genetic data also support a key role for somatic instability (SI) inHTT’s CAG repeat – whereby it lengthens with age in specific somatic cell types – as a key driver of age of motor dysfunction onset. Thus, an attractive HD therapy would address both mHTT toxicity and SI, but to date the relationship between SI and HTT lowering remains unexplored. Here, we investigated multiple therapeutically-relevant HTT-lowering modalities to establish the relationship between HTT lowering and SI in HD knock-in mice. We find that repressing transcription of mutantHtt(mHtt) provides robust protection from SI, using diverse genetic and pharmacological approaches (antisense oligonucleotides, CRISPR-Cas9 genome editing, theLacrepressor, and virally delivered zinc finger transcriptional repressor proteins, ZFPs). However, we find that small interfering RNA (siRNA), a potent HTT-lowering treatment, lowers HTT levels without influencing SI and that SI is also normal in mice lacking 50% of total HTT levels, suggesting HTT levels,per se, do not modulate SI intrans. Remarkably, modified ZFPs that bind the mHttlocus, but lack a repressive domain, robustly protect from SI, despite not reducing HTT mRNA or protein levels. These results have important therapeutic implications in HD, as they suggest that DNA-targeted HTT-lowering treatments may have significant advantages compared to other HTT-lowering approaches, and that interaction of a DNA-binding protein andHTT’s CAG repeats may provide protection from SI while sparing HTT expression.
Three positively charged binding sites on the eastern equine encephalitis virus E2 glycoprotein coordinate heparan sulfate- and protein receptor-dependent infection
Authors: Alcorn Maria D.H. , Sun Chengqun , Gilliland Theron C. , Lukash Tetyana , Crasto Christine M. , Raju Saravanan , Diamond Michael S. , Weaver Scott C. , Klimstra William B.
Published: November 2024

Naturally circulating strains of eastern equine encephalitis virus (EEEV) bind heparan sulfate (HS) receptors and this interaction has been linked to its neurovirulence. Previous studies associated EEEV-HS interactions with three positively charged amino acid clusters on the E2 glycoprotein. One of these sites has recently been reported to be critical for binding EEEV to very-low-density lipoprotein receptor (VLDLR), an EEEV receptor protein. The proteins apolipoprotein E receptor 2 (ApoER2) isoforms 1 and 2, and LDLR have also been shown to function as EEEV receptors. Herein, we investigate the individual contribution of each HS interaction site to EEEV HS- and protein receptor-dependent infectionin vitroand EEEV replication in animals. We show that each site contributes to both EEEV-HS and EEEV-protein receptor interactions, providing evidence that altering these interactions can affect disease in mice and eliminate mosquito infectivity. Thus, multiple HS-binding sites exist in EEEV E2, and these sites overlap functionally with protein receptor interaction sites, with each type of interaction contributing to tissue infectivity and disease phenotypes.