bluuebunny/crossref_metadata_2025 huggingface dataset:
International Consensus Recommendation Guidelines for Subcutaneous Infusions of Hydration and Medication in Adults
Authors: Broadhurst Daphne , Cooke Marie , Sriram Deepa , Barber Lauren , Caccialanza Riccardo , Danielsen Mathias Brix , Ebersold Stacie Lynne , Gorski Lisa , Hirsch David , Lynch Gerardine , Neo Shirlyn Hui-Shan , Roubaud-Baudron Claire , Gray Brenda
Published: July 2023

Infusion of fluids and medications is traditionally performed intravenously. However, venous depletion in patients has led to the quest for vessel health preservation. A safe, effective, acceptable, and efficient alternative is the subcutaneous route. A lack of organizational policies may contribute to the slow uptake of this practice. This modified e-Delphi (electronic) study aimed to derive international consensus on practice recommendations for subcutaneous infusions of fluids and medications. A panel of 11 international clinicians, with expertise in subcutaneous infusion research and/or clinical practice, rated and edited subcutaneous infusion practice recommendations from evidence, clinical practice guidelines, and clinical expertise within an Assessment, Best Practice, and Competency (ABC) domain guideline model. The ABC Model for Subcutaneous Infusion Therapy provides a systematic guideline of 42 practice recommendations for the safe delivery of subcutaneous infusions of fluids and medications in the adult population in all care settings. These consensus recommendations provide a guideline for health care providers, organizations, and policy makers to optimize use of the subcutaneous access route.
Phosphine Gas Poisoning
Authors: Moirangthem Sangita , Vidua Raghvendra , Jahan Afsar , Patnaik Mrinal , Chaurasia Jai
Published: July 2023

In agrarian countries, several pesticides are used on a large scale to preserve grains. However, oftentimes, the very people using it are not aware of their harmful effects. Some pesticides produce toxic gases, which can cause poisoning by inhalation. With no specific antidotes and limited data on the benefit of therapeutic interventions, such poisonings can lead to fatalities. This case report discusses the death of an apparently healthy, 6-year-old boy who presented with multiple episodes of vomiting and loose stools and was declared dead on arrival to the hospital. His other siblings and the parents also experienced similar symptoms but survived. Further investigation revealed that the family lived in a closed, poorly ventilated room adjacent to a granary where their landlord stored grains with pesticides for the purpose of preservation. However, during rainy season, moisture came into contact with the grains and toxic gases were released. The family was exposed to these gases through a small window in the living room, proving fatal to one member of the family. This article suggests that phosphine gas was liberated from an aluminum phosphide pesticide and emphasizes the need for improved knowledge, recognition, prevention, and management in such scenario.
Systematic Review of Procedural Skill Simulation in Health Care in Low- and Middle-Income Countries
Authors: Pollok Franziska , Lund Sarah B. , Traynor Michael D. , Alva-Ruiz Roberto , MacArthur Taleen A. , Watkins Ryan D. , Mahony Cillian R. , Woerster Malin , Yeh Vicky J-H , Matovu Alphonsus , Clarke Damian L. , Laack Torrey A. , Rivera Mariela
Published: July 2023

Summary Statement

Low- and middle-income countries (LMICs) have adopted procedural skill simulation, with researchers increasingly investigating simulation efforts in resource-strained settings. We aim to summarize the current state of procedural skill simulation research in LMICs focusing on methodology, clinical area, types of outcomes and cost, cost-effectiveness, and overall sustainability. We performed a comprehensive literature review of original articles that assessed procedural skill simulation from database inception until April 2022.

From 5371 screened articles, 262 were included in this review. All included studies were in English. Most studies were observational cohort studies (72.9%) and focused on obstetrics and neonatal medicine (32.4%). Most measured outcome was the process of task performance (56.5%). Several studies mentioned cost (38.9%) or sustainability (29.8%). However, few articles included actual monetary cost information (11.1%); only 1 article assessed cost-effectiveness. Based on our review, future research of procedural skill simulation in LMICS should focus on more rigorous research, cost assessments, and on less studied areas.
Two Affordable, High-Fidelity Central Venous Models for Ultrasound-Guided Interventional Training
Authors: Mason Matthew M. , Richardson Kenneth D. , Carino Mason Marisa R. , Swonger Ronald M. , Emami Shaheen , Anantha Sadhana , Thornton Lindsay M.
Published: July 2023

Introduction

Ultrasound-guided vascular access is an increasingly popular technique due to its reduced complication and higher success rates. Commercially bought training phantoms allow providers to develop tactile skills in a low-risk setting, but are also expensive and poorly accessible. This study analyzes the efficacy of homemade, low-cost, gelatin-based central line vascular models to teach vascular anatomy and intravascular access techniques in training physicians.

Methods

A gelatin mold was created using a mixture of unflavored gelatin, hot water, psyllium husk powder, and rubbing alcohol. Latex tubing, balloons, precooked hot dog, and tofu were inserted to simulate arteries, veins, nerves, and the sternocleidomastoid muscle, respectively. Medical students from a single institution participated in a 90-minute workshop led by interventional radiology residents. Participants completed presurveys and postsurveys that assessed knowledge acquisition and confidence levels related to acquiring central access. All images were obtained using a USB-C Butterfly iQ probe.

Results

Twenty medical students were analyzed after the workshop. There was a statistically significant increase in self-reported confidence in basic ultrasound use (adjusting gain, depth, probe manipulation), localizing major anatomical structures, using ultrasound for vessel access, and reported ease in identifying muscle, nerves, and major blood vessels under ultrasound. There was also a significant increase in correctly identified anatomical landmarks after the workshop, including the sternocleidomastoid muscle, internal jugular vein, carotid artery, femoral nerve, femoral artery, and femoral vein.

Conclusions

Our findings suggest that our homemade, low-cost, gelatin-based models were effective in teaching vascular anatomy and ultrasound-guided vascular access techniques to training physicians.
Vessel Density Features of Optical Coherence Tomography Angiography for Classification of Optic Neuropathies Using Machine Learning
Authors: Jalili Jalil , Nadimi Mohadeseh , Jafari Behzad , Esfandiari Amirreza , Mojarad Mohadeseh , Subramanian Prem S. , Aghsaei Fard Masoud
Published: July 2023

Background:

To evaluate the classification performance of machine learning based on the 4 vessel density features of peripapillary optical coherence tomography angiography (OCT-A) for classifying healthy, nonarteritic anterior ischemic optic neuropathy (NAION), and optic neuritis (ON) eyes.

Methods:

Forty-five eyes of 45 NAION patients, 32 eyes of 32 ON patients, and 76 eyes of 76 healthy individuals with optic nerve head OCT-A were included. Four vessel density features of OCT-A images were developed using a threshold-based segmentation method and were integrated in 3 models of machine learning classifiers. Classification performances of support vector machine (SVM), random forest, and Gaussian Naive Bayes (GNB) models were evaluated with the area under the receiver-operating-characteristic curve (AUC) and accuracy.

Results:

We divided 121 images into a 70% training set and 30% test set. For ON-NAION classification, best results were achieved with 50% threshold, in which 3 classifiers (SVM, RF, and GNB) discriminated ON from NAION with an AUC of 1 and accuracy of 1. For ON-Normal classification, with 100% threshold, SVM and RF classifiers were able to discriminate normal from ON with AUCs of 1 and accuracies of 1. For NAION-normal classification, with 50% threshold, the SVM and RF classified the NAION from normal with AUC and accuracy of 1.

Conclusions:

ML based on the combined peripapillary vessel density features of total vessels and capillaries in the whole image and ring image could provide excellent performance for NAION and ON distinction.
Occipital Nocardia Abscess Presenting With Positive Visual Phenomenon and Quadrantanopsia
Authors: Fein Alexander S. , Kelly Sean M. , Louie Eddie , Young Matthew G. , Jain Rajan , William Christopher M. , Galetta Steven L. , Grossman Scott N.
Published: July 2023

A 74-year-old man with chronic obstructive pulmonary disease, glaucoma, and Stage IIIB squamous cell lung cancer experienced several minutes of flashing lights in his right visual hemifield, followed by onset of a right visual field defect. On examination, the patient had a right homonymous hemianopsia that was most dense inferiorly by confrontation testing. Emergent CT scan of the head revealed a 2.5 × 3 cm hypodensity in the left occipital lobe, which was interpreted as an acute stroke. Continuous EEG monitoring captured left posterior quadrant seizures that were temporally correlated to the positive visual phenomena. Subsequent MRI of the brain with and without contrast revealed a conglomerate of centrally necrotic and peripherally enhancing mass lesions. On biopsy, a thick purulent material was drained and Gram stain of the sample revealed gram-positive beaded rods, which speciated to Nocardia farcinica. The patient was treated with a six-week course of intravenous meropenem and a one-year course of oral trimethroprim–sulfamethoxazole. On follow-up, the patient experienced resolution of the right visual field deficit.
Emerging Gene Therapy Technologies for Retinal Ganglion Cell Neuroprotection
Authors: Camacho David K. , Go Cammille C. , Chaqour Brahim , Shindler Kenneth S. , Ross Ahmara G.
Published: July 2023

Optic neuropathies encompass a breadth of diseases that ultimately result in dysfunction and/or loss of retinal ganglion cells (RGCs). Although visual impairment from optic neuropathies is common, there is a lack of effective clinical treatments. Addressing a critical need for novel interventions, preclinical studies have been generating a growing body of evidence that identify promising new drug-based and cell-based therapies. Gene therapy is another emerging therapeutic field that offers the potential of specifically and robustly increasing long-term RGC survival in optic neuropathies. Gene therapy offers additional benefits of driving improvements following a single treatment administration, and it can be designed to target a variety of pathways that may be involved in individual optic neuropathies or across multiple etiologies. This review explores the history of gene therapy, the fundamentals of its application, and the emerging development of gene therapy technology as it relates to treatment of optic neuropathies.
Inclusive dementia care for ethnically diverse families
Authors: Brijnath Bianca , Antoniades Josefine , Cavuoto Marina
Published: July 2023

Purpose of review

With population ageing and global migration, rates of dementia are set to rapidly increase in ethnically diverse populations. This narrative review examines recent evidence on what constitutes culturally appropriate models of care.

Recent findings

Barriers to inclusive care continue to prevail, amplifying dementia disparities in ethnically diverse communities. Cultural models that can address these include ensuring health and aged care staff are culturally competent, language supports are available, and cultural practices are integrated into daily care routines. Fundamentally, systems must be reformed to ensure they meet the needs of diverse end-users. More inclusive and widespread ethno-specific services are needed, and governments need to be mindful of demographic transitions in their populations and plan accordingly to meet future demand. Digital media and new technologies offer promising new ways to deliver culturally appropriate care to ethnically diverse groups, but its full potential is yet to be realised.

Persistent dementia disparities in ethnically diverse communities can be overcome by operationalising cultural models of care, leveraging the promise of digital media, and systems redesign.
Genomic epidemiology of human candidaemia isolates in a tertiary hospital
Authors: Chew Ka Lip , Achik Rosemini , Osman Nurul Hudaa , Octavia Sophie , Teo Jeanette W. P.
Published: July 2023

Invasive candida infections are significant infections that may occur in vulnerable patients with high rates of mortality or morbidity. Drug-resistance rates also appear to be on the rise which further complicate treatment options and outcomes. The aims of this study were to describe the prevalence, molecular epidemiology, and genetic features of Candida bloodstream isolates in a hospital setting. The resistance mechanisms towards the two most commonly administered antifungals, fluconazole and anidulafungin, were determined. Blood culture isolates between 1 January 2018 and 30 June 2021 positive for Candida spp. were included. Susceptibility testing was performed using Etest. Whole-genome-sequencing was performed using Illumina NovaSeq with bioinformatics analysis performed. A total of 203 isolates were sequenced: 56 C. glabrata, 53 C. tropicalis, 44 C. albicans, 36 C. parapsilosis complex (consisting of C. parapsilosis, C. orthopsilosis, and C. metapsilosis), six C. krusei, five C. dubliniensis, and three C. auris. A single cluster of azole-resistant C. tropicalis, and four clusters of C. parapsilosis isolates were observed, suggesting possible transmission occurring over several years. We found 11.3%, and 52.7 % of C. tropicalis and C. parapsilosis, respectively, clustered with other isolates, suggesting exogenous sources may play a significant role of transmission, particularly for C. parapsilosis. The clusters spanned over several years suggesting the possibility of environmental reservoirs contributing to the spread. Limited clonality was seen for C. albicans. Several sequence types appeared to be dominant for C. glabrata, however the SNP differences varied widely, indicating absence of sustained transmission.
Quality testing of mifepristone and misoprostol in 11 countries
Authors: Bower Jason , Chinery Lester , Fleurent Alessandra , Gülmezoglu A. Metin , Im-Amornphong Wallada , Kilfedder Catherine , Procter Petra , Tomazzini Alessandra
Published: July 2023

Objective

Previous studies have demonstrated quality concerns with misoprostol. Mifepristone, however, has not been extensively assessed for quality. Between 2020 and 2021, Concept Foundation and the International Planned Parenthood Federation conducted a study to determine the quality of these medical abortion drugs in low– and middle-income countries (LMIC).

Methods

Collection of batch samples of misoprostol and mifepristone was carried out by trained sampling agents in selected LMIC. Single drug packs and combipacks were sampled. A World Health Organization prequalified laboratory conducted testing method verifications and subsequent sample analysis. Tests included identification, assay, related substances, and content uniformity for misoprostol, and identification, assay, related substances, and dissolution for mifepristone.

Results

Samples were collected from Burkina Faso, Cambodia, Democratic Republic of Congo, India, Kyrgyzstan, Moldova, Nepal, Nigeria, Pakistan, Uganda and Vietnam. Sixty-four pooled batch samples were tested, consisting of 31 combipacks, 26 misoprostol-only and 7 mifepristone-only products. Overall, 54.7% of samples were non-compliant with one or more of the specifications, representing 51.6% of combipack products, 57.1% of misoprostol tablets analyzed and 23.7% of mifepristone tablets. One falsified misoprostol-only product was found.

Conclusion

This study confirms that a significant problem still exists in relation to the quality of medical abortion drugs in low– and middle-income countries. For misoprostol, our findings suggest that historical concerns around primary packaging may have been largely resolved but that manufacturing processes for both finished product and active pharmaceutical ingredient need to be improved. This study also provides evidence of mifepristone quality issues.
Taxane-based Chemotherapy is Effective in Metastatic Appendiceal Adenocarcinoma
Authors: Dansby Julia , More Aditya , Zeineddine Mohammad , Yousef Abdelrahman , Bent Alisha , Dayyani Farshid , Wolff Robert , Overman Michael , Shen John Paul
Published: July 2023

Appendiceal cancer is a rare, orphan disease with no therapies currently approved by the FDA for its treatment. Given the limited data regarding drug efficacy, these tumors have historically been treated with chemotherapy designed for colon cancer. However, an overwhelming body of molecular data has demonstrated that appendiceal adenocarcinoma is a distinct entity with key molecular differences from colon cancer, notably rareAPCmutation. Recognizing that APC loss-of-function is thought to contribute to taxane resistance, and that taxanes are effective in the treatment of other gastrointestinal tumors including gastric, esophageal, and small bowel adenocarcinoma, we completed a single-center retrospective study to assess efficacy. In a cohort of 13 patients with metastatic appendiceal adenocarcinoma, treated with taxane chemotherapy the median overall survival was 8.3 months. Of 10 evaluable patients we observed 3 responses, 4 patients with stable disease, and 3 with progression (30% response rate, 70% disease control rate). The results of this study showing activity of taxane-based chemotherapy in appendiceal adenocarcinoma support further clinical investigation of taxane therapy in this orphan disease.
Low and Borderline Ankle Brachial Index is Associated with Intracranial Aneurysms – A Retrospective Cohort Study
Authors: Laukka Dan , Kangas Essi , Kuusela Aino , Hirvonen Jussi , Rissanen Tiia , Rahi Melissa , Kivelev Juri , Rantasalo Ville , Rinne Jaakko , Hakovirta Harri
Published: July 2023

Background and Aims

A low ankle-brachial index (ABI) is associated with a higher risk of cardiovascular diseases, stroke, and systemic inflammation. Intracranial aneurysms (IAs) share similar risk factors with other cardiovascular diseases. However, the association between low ABI and IAs lacks sufficient investigation.

Methods

This retrospective study reviewed 2751 patients who had ABI measurements at a tertiary hospital from January 2011 to December 2013. Patients with available cerebrovascular imaging or a diagnosis of ruptured IA were included in the study (n=776) to examine the association between ABI and saccular IAs. The patients were classified into four groups: low ABI (≤0.9, n=464), borderline ABI (0.91-0.99; n=47), high ABI (>1.4, n=57), and normal ABI (1.00-1.40; n=208).

Results

The prevalence of IAs was 20.3% (18.1% unruptured IAs) in the low ABI group, 14.9% (12.8% unruptured IAs) in the borderline ABI group, 7.0 % (5.3% unruptured IAs) in the high ABI group, and 2.4% (1.9% unruptured IAs) in the normal ABI group (p<0.001). Sex- and age-adjusted multinomial regression, including clinically relevant variables, revealed that low ABI (odds ratio [OR], 11.33; 95% confidence interval [CI], 4.08-31.51;p<0.001) and borderline ABI (0.91-0.99) (OR, 7.13; 95% CI, 1.91-26.63;p=0.004) were the only variables significantly associated with unruptured IAs.

Conclusions

The prevalence of unruptured IAs was 9-fold higher in the low ABI group and nearly 7-fold higher in the borderline ABI group when compared to the normal ABI group. ABI measurements could be clinically relevant for identifying individuals at higher risk of IAs and may help guide screening and preventive strategies.
Acidic nanoparticles restore lysosomal acidification and rescue metabolic dysfunction in pancreatic β-cells under lipotoxic condition
Authors: Lo Chih Hung , O’Connor Lance M. , Loi Gavin Wen Zhao , Saipuljumri Eka Norfaishanty , Indajang Jonathan , Lopes Kaitlynn M. , Shirihai Orian S. , Grinstaff Mark W. , Zeng Jialiu
Published: July 2023

Type 2 diabetes (T2D), a prevalent metabolic disorder lacking effective treatments, is associated with lysosomal acidification dysfunction as well as autophagic and mitochondrial impairments. Here, we report a series of biodegradable poly(butylene tetrafluorosuccinate-co-succinate) (PBFSU) polyesters, comprising an 1,4-butanediol linker and varying ratios of tetrafluorosuccinic acid (TFSA) and succinic acid as components, to engineer new lysosome acidifying nanoparticles (NPs). Notably, TFSA NPs, which composed entirely of TFSA, exhibit the strongest degradation capability and superior acidifying property. We further reveal significant downregulation of lysosomal vacuolar (H+)-ATPase (V-ATPase) subunits, which are responsible for maintaining lysosomal acidification, in human T2D pancreatic islets and INS-1 β-cells under lipotoxic condition. Treatment of TFSA NPs counteracts lipotoxicity in INS-1 β-cells by restoring lysosomal acidification, autophagic function, and mitochondrial activity, along with promoting glucose-stimulated insulin secretion. Administration of TFSA NPs to high-fat diet T2D mice improves glucose clearance and reduces insulin resistance. These findings highlight the therapeutic potential of lysosome acidifying TFSA NPs for T2D.

Graphical Table of Contents
Predictions and errors are distinctly represented across V1 layers
Authors: Thomas Emily R , Haarsma Joost , Nicholson Jessica , Yon Daniel , Kok Peter , Press Clare
Published: July 2023

‘Predictive processing’ frameworks of cortical functioning propose that neural populations in different cortical layers serve distinct roles in representing the world. There are distinct testable theories within this framework that we examined with a 7T fMRI study, where we contrasted responses in primary visual cortex (V1) to expected (75% likely) and unexpected (25%) Gabor orientations. Multivariate decoding analyses revealed an interaction between expectation and layer, such that expected events could be decoded with comparable accuracy across layers, while unexpected events could only be decoded in superficial laminae. These results are in line with predictive processing accounts where expected virtual input is injected into deep layers, while superficial layers process the ‘error’ with respect to expected signals. While this account of cortical processing has been popular for decades, such distinctions have not previously been demonstrated in the human sensory brain. We discuss how both prediction and error processes may operate together to shape our unitary perceptual experiences.
Natural transformation specific DprA coordinate DNA double strand break repair pathways in heavily irradiatedD. radiodurans
Authors: Sharma Dhirendra Kumar , Soni Ishu , Misra Hari S. , Rajpurohit Yogendra Singh
Published: July 2023

Deinococcus radioduransexhibits remarkable survival under extreme conditions, including ionizing radiation, desiccation, and various DNA-damaging agents. It employs unique repair mechanisms, such as single-strand annealing (SSA) and extended synthesis-dependent strand annealing (ESDSA), to efficiently restore damaged DNA fragments. In this study, we investigate the regulatory role of the NT-specific protein DprA in DNA repair pathways following acute gamma radiation exposure. Our findings demonstrate that the absence of DprA leads to rapid repair of gamma radiation-induced DNA double-strand breaks (DSBs), with diminished involvement of the ESDSA pathway. Furthermore, our data suggest that the SSA pathway becomes the primary mechanism for DNA DSB repair in the absence of DprA. Overall, our results highlight the regulatory function of DprA in modulating the choice between SSA and ESDSA pathways for DNA repair in the radiation-resistant bacteriumD. radioduransx.
Orthogonal analysis of mitochondrial function in Parkinson’s disease patients
Authors: Barnhoorn Sander , Milanese Chiara , Li Tracy , Dons Lieke , Ghazvini Mehrnaz , Farina Stefania , Sproviero Daisy , Gomez Cesar Payan , Mastroberardino Pier G.
Published: July 2023

The etiopathology of Parkinson’s disease has been associated with mitochondrial defects at genetic, laboratory, epidemiological, and clinical level. These converging lines of evidence suggest that mitochondrial defects are systemic and causative factors in the pathophysiology of PD, rather than being mere correlates. Understanding mitochondrial biology in PD at granular level is therefore crucial from both basic science and translational perspectives.

In a recent study, we investigated mitochondrial alterations in fibroblasts obtained from PD patients assessing mitochondrial function in relation to clinical measures. Our findings demonstrated that the magnitude of mitochondrial alterations parallels disease severity. In this study, we extend these investigations to blood cells and dopamine neurons derived from induced pluripotent stem cells reprogrammed from PD patients. To overcome the inherent metabolic heterogeneity of blood cells, we focused our analyses on metabolically homogeneous, accessible, and expandable erythroblasts. Our results confirm the presence of mitochondrial anomalies in erythroblasts and induced dopamine neurons. Consistent with our previous findings in fibroblasts, we observed that mitochondrial alterations are reversible, as evidenced by enhanced mitochondrial respiration when PD erythroblasts were cultured in a galactose medium that restricts glycolysis. This observation indicates that suppression of mitochondrial respiration may constitute a protective, adaptive response in PD pathogenesis. Notably, this effect was not observed in induced dopamine neurons, suggesting their distinct bioenergetic behavior.

In summary, we provide additional evidence for the involvement of mitochondria in the disease process by demonstrating mitochondrial abnormalities in additional cell types relevant to PD. These findings contribute to our understanding of PD pathophysiology and may have implications for the development of novel biomarkers and therapeutic strategies.
Understanding woody plant encroachment: a plant functional trait approach
Authors: de Jonge Inger K. , Olff Han , Mayemba Emilian P. , Berger Stijn J. , Veldhuis Michiel P.
Published: July 2023

The increase in the density of woody plants threatens the integrity of grassy ecosystems. It remains unclear if such encroachment can be explained mostly by direct effects of soil conditions and hydrology on woody plant growth or by indirect effects on fire regime and herbivory imposing tree recruitment limitation. Here, we investigate whether woody plant functional traits provide a mechanistic understanding of the complex relationships between these direct and indirect effects. We first assess the role of rainfall, soil fertility, texture, and geomorphology to explain variation in woody plant encroachment following anthropogenically-induced fire suppression across the Serengeti ecosystem. Second, we explore trait-environment relationships and how these mediate vegetation response to fire suppression. We find that woody plant encroachment is strongest in areas with high soil fertility, high rainfall, intermediate catenae positions, and fine soil textures. These conditions promote woody plant communities associated with small stature, small seed sizes, and high recruit densities (linked to a recruitment-stature trade-off). The positioning of species along this ‘recruitment-stature axis’ was found to be the most important predictor of recruitment limitation. Areas that support such plant communities - e.g. mid-catena position - were most sensitive to woody plant encroachment. These findings demonstrate the importance of trait-environment relationships in predicting the impact of human alterations on local vegetation change. Understanding how environmental factors directly (resources) and indirectly (legacy effects and plant traits) determine woody plant encroachment supports the development of process-based ecosystem structure and function models.
DNAGPT: A Generalized Pre-trained Tool for Multiple DNA Sequence Analysis Tasks
Authors: Zhang Daoan , Zhang Weitong , Zhao Yu , Zhang Jianguo , He Bing , Qin Chenchen , Yao Jianhua
Published: July 2023

Pre-trained large language models demonstrate potential in extracting information from DNA sequences, yet adapting to a variety of tasks and data modalities remains a challenge. To address this, we propose DNAGPT, a generalized DNA pre-training model trained on over 200 billion base pairs from all mammals. By enhancing the classic GPT model with a binary classification task (DNA sequence order), a numerical regression task (guanine-cytosine content prediction), and a comprehensive token language, DNAGPT can handle versatile DNA analysis tasks while processing both sequence and numerical data. Our evaluation of genomic signal and region recognition, mRNA abundance regression, and artificial genome generation tasks demonstrates DNAGPT’s superior performance compared to existing models designed for specific downstream tasks, benefiting from pre-training using the newly designed model structure.
Tutorial: guidelines for manual cell type annotation of single-cell multi-omics datasets using interactive software
Authors: Kim Yang-Joon , Tarashansky Alexander , Liang Karen , Urisko Meg , Dorman Leah , Borja Michael , Neff Norma , Pisco Angela Oliveira , Granados Alejandro
Published: July 2023

Assigning cell identity to clusters of single cells is an essential step towards extracting biological insights from many genomics datasets. Although annotation workflows for datasets built with asinglemodality are well established, limitations exist in annotating cell types in datasets withmultiplemodalities due to the need for a framework to exploit them jointly. While, in principle, different modalities could convey complementary information about cell identity, it is unclear to what extent they can be combined to improve the accuracy and resolution of cell type annotations.

Here, we present a conceptual framework to examine and jointly interrogate distinct modalities to identify cell types. We integrated our framework into a series of vignettes, using immune cells as a well-studied example, and demonstrate cell type annotation workflows ranging from using single-cell RNA-seq datasets alone, to using multiple modalities such as single-cell Multiome (RNA and chromatin accessibility), CITE-seq (RNA and surface proteins). In some cases, one or other single modality is superior to the other for identification of specific cell types, in others combining the two modalities improves resolution and the ability to identify finer subpopulations. Finally, we use interactive software from CZ CELLxGENE community tools to visualize and integrate histological and spatial transcriptomic data.
Platelet hyperactivity in patients of vascular dementia
Authors: Dev Priya , Ekhlak Mohammad , Yadav Ashish , Dash Debabrata , Pathak Abhishek
Published: July 2023

Background

Platelet-monocyte (PMA) and platelet-neutrophil aggregations (PNA) are critical in causing acute inflammatory reactions favoring vascular dysfunction. However, the precise pathophysiological link between Platelet-leukocyte aggregates and Vascular Dementia (VaD) remains undetermined. Our study aimed to investigate whether platelet hyperresponsiveness is independently associated with a predictor of VaD.

Methods

Platelet from 19 VaD patients and 18 age-matched healthy controls were subjected to different investigations.

Result

PMA, PNA, P-selectin externalization, and intracellular free Ca+2([Ca+2i]) flux were evaluated either in whole blood or in platelet-rich plasma. The result revealed that PMA, PNA, P-selectin, and [Ca+2]iwere found to be significantly outnumbered in the VaD group (4.1, 2.8, 2.7, and 2.5 times higher) compared to the control group with p-value <0.001, <0.001, <0.001, and 0.001 at 95% CI = 31.164 to 54.855, 8.653 to 22.793, 35.064 to 94.369 and 8747.015 to 28829.618 respectively.

Conclusion

Patients with Vascular Dementia have increased platelet leucocyte interaction, and PMA has the most significant prediction of vascular dementia than in subjects of healthy control. Thus, platelets in VaD patients switch to a ‘hyperactive’ phenotype.
WITHDRAWN: Comparative Analysis of Four Scoring Systems (APACHE II, CURB-65, Pneumonia Severity Index [PSI], and CHA2DS2-VASc) for Predicting New-Onset Cardiovascular Events, Including Atrial Fibrillation, in Critically Ill Patients with Pneumonia
Authors: Lin Yi-Tsung , Wang Tzu-Lin
Published: July 2023

Withdrawal Statement

This manuscript has been withdrawn by the authors as it was submitted and made public without the full consent of all the authors. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author (Yi-Tsung Linytlin8@vghtpe.gov.tw).
Systematic Review and Meta-Analysis of Endovascular Therapy Effectiveness for Unruptured Saccular Intracranial Aneurysms
Authors: Pineda-Castillo Sergio A. , Jones Evan R. , Laurence Keely A. , Thoendel Lauren R. , Cabaniss Tanner L. , Zhao Yan D. , Bohnstedt Bradley N. , Lee Chung-Hao
Published: July 2023

Background

Currently, endovascular treatment of intracranial aneurysms (ICAs) is limited by low complete occlusion rates. The advent of novel endovascular technology has expanded the applicability of endovascular therapy; however, the superiority of novel embolic devices over the traditional Guglielmi detachable coils (GDCs) is still debated. We performed a systematic review of literature that reported the Raymond-Roy occlusion classifications (RROC) rates of modern endovascular devices to determine their immediate and long-term occlusion effectiveness for the treatment of unruptured saccular ICAs.

Methods

A search was conducted using electronic databases (PUBMED, Cochrane,ClinicalTrials.gov, Web of Science). We retrieved studies published between 2000-2022 reporting immediate and long-term RROC rates of subjects treated with different endovascular ICA therapies. We extracted demographic information of the treated patients and their reported angiographic RROC rates.

Results

A total of 80 studies from 15 countries were included for data extraction. RROC rates determined from angiogram were obtained for 21,331 patients (72.5% females, pooled mean age: 58.2 (95% CI: 56.8-59.6), harboring 22,791 aneurysms. The most frequent aneurysm locations were the internal carotid artery (46.4%, 95% CI: 41.9%-50.9%), the anterior communicating artery (26.4%, 95% CI: 22.5%-30.8%), the middle cerebral artery (24.5%, 95% CI:19.2%-30.8%) and the basilar tip (14.4%, 95% CI:11.3%-18.3%). The RROC rates were analyzed for GDCs, the Woven EndoBridge (WEB), and flow diverters. The immediate complete occlusion (RROC-I) rate was the highest in balloon-assisted coiling (73.9%, 95% CI: 65.0%-81.2%) and the lowest in the WEB (27.8%, 95% CI:13.2%-49.2%). The long-term complete occlusion probability was homogenous in all analyzed devices.

Conclusions

We observed that the coil-based endovascular therapy provides acceptable rates of complete occlusion, where the balloon-assisted coils provide greater probability of immediate complete occlusion. Out of the analyzed devices, the WEB exhibited the shortest time to achieve >90% probability of long-term complete occlusion (∼18 months). Overall, the GDCs remain thegold standardfor endovascular treatment of unruptured saccular aneurysms.
Common infections and neuroimaging markers of dementia in three UK cohort studies
Authors: Green Rebecca E , Sudre Carole H , Warren-Gash Charlotte , Butt Julia , Waterboer Tim ,   the Insight 46 study team, Hughes Alun D , Schott Jonathan M , Richards Marcus , Chaturvedi Nish , Williams Dylan M
Published: July 2023

Introduction

We aimed to investigate associations between common infections and neuroimaging markers of dementia risk (brain volume, hippocampal volume, white matter lesions) across three population-based studies.

Methods

We tested associations between serology measures (pathogen serostatus, cumulative burden, continuous antibody responses) and outcomes using linear regression, including adjustments for total intracranial volume and scanner/clinic information (basic model), age, sex, ethnicity, education, socioeconomic position, alcohol, BMI, and smoking (fully adjusted model). Interactions between serology measures and APOE genotype were tested. Findings were meta-analysed across cohorts (Nmain=2632; NAPOE-interaction=1810).

Results

Seropositivity to JC virus associated with smaller brain volumes in basic models (ß=-3.89ml[-5.81,-1.97],padjusted<0.05); these were largely attenuated in fully adjusted models (ß=-1.59ml[-3.55,0.36], p=0.11). No other relationships were robust to multiple testing correction and sensitivity analyses, but several suggestive associations were observed.

Discussion

We did not find clear evidence for relationships between common infections and markers of dementia risk. Some suggestive findings warrant testing for replication.
AAV-mediated Delivery of Plakophilin-2a Arrests Progression of Arrhythmogenic Right Ventricular Cardiomyopathy in Murine Hearts: Preclinical Evidence Supporting Gene Therapy in Humans
Authors: van Opbergen Chantal JM , Narayanan Bitha , Sacramento Chester B , Stiles Katie M , Mishra Vartika , Frenk Esther , Ricks David , Chen Grace , Zhang Mingliang , Yarabe Paul , Schwartz Jonathan , Delmar Mario , Herzog Chris D , Cerrone Marina
Published: July 2023

Background

Pathogenic variants in plakophilin-2 (PKP2) cause arrhythmogenic right ventricular cardiomyopathy (ARVC), a disease characterized by life-threatening arrhythmias and progressive cardiomyopathy leading to heart failure. No effective medical therapy is available to prevent and/or arrest the disease. We tested the hypothesis that AAV-mediated delivery of the humanPKP2gene to an adult mammalian heart deficient in PKP2 can arrest disease progression and significantly prolong survival.

Methods

Experiments were carried out using a cardiac-specific, tamoxifen (TAM)-activated PKP2 knockout murine model (PKP2-cKO). The potential therapeutic, AAVrh.74-PKP2a (RP-A601), is a recombinant AAVrh.74 gene therapy viral vector encoding the human PKP2 variant A (PKP2a). AAVrh.74-PKP2a was delivered to adult mice by a single tail vein injection either before or after TAM-activated PKP2-cKO. PKP2 expression was confirmed by molecular and histopathologic analyses. Cardiac function and disease progression were monitored by survival analyses, echocardiography and electrocardiography.

Results

Consistent with prior findings, loss of PKP2 expression caused 100% mortality within 50 days after TAM injection. In contrast, AAVrh.74-PKP2a-mediated PKP2a expression resulted in 100% survival for more than 5 months (at study termination). Echocardiographic analysis revealed that AAVrh.74-PKP2a prevented right ventricle dilation, arrested left ventricle functional decline, and mitigated arrhythmia burden. Molecular and histological analysis showed AAVrh.74-PKP2a– mediated transgene mRNA and protein expression and appropriate PKP2 localization at the cardiomyocyte intercalated disc. Importantly, therapeutic benefit was shown in mice receiving AAVrh.74-PKP2aafterdisease onset.

Conclusion

These preclinical data demonstrate the potential for AAVrh.74-PKP2a (RP-A601) as a therapeutic for PKP2-related ARVC in both early and more advanced stages of disease.
The Integrated Stress Response effector GADD34 is repurposed by neurons to promote stimulus-induced translation
Authors: Oliveira Mauricio M. , Mohamed Muhaned , Elder Megan K. , Banegas-Morales Keylin , Mamcarz Maggie , Lu Emily H. , Golhan Ela A.N. , Navrange Nishika , Chatterjee Snehajyoti , Abel Ted , Klann Eric
Published: July 2023

Neuronal protein synthesis is required for long-lasting plasticity and long-term memory consolidation. Dephosphorylation of eukaryotic initiation factor 2α is one of the key translational control events that is required to increasede novoprotein synthesis that underlies long-lasting plasticity and memory consolidation. Here, we interrogate the molecular pathways of translational control that are triggered by stimulation of neurons with brain-derived neurotrophic factor (BDNF), which results in eIF2α dephosphorylation andde novoprotein synthesis. Primary rodent neurons exposed to BDNF displayed elevated translation, but not transcription, of GADD34, which facilitates eIF2α dephosphorylation and subsequentde novoprotein synthesis. Furthermore, GADD34 requires G-actin generated by cofilin to dephosphorylate eIF2α and enhance protein synthesis. Finally, GADD34 is required for the BDNF-induced translation of synaptic plasticity-related proteins. Overall, we provide evidence that neurons repurpose GADD34, an effector of the Integrated Stress Response, as an orchestrator of rapid increases in eIF2-dependent translation in response to plasticity-inducing stimuli.
Polo-like kinase 1 regulates immune synapse assembly and cytotoxic T cell function by driving microtubule dynamics
Authors: Zevolini Fabrizia , Onnis Anna , Khazen Roxana , Müller Sabina , Marotta Giuseppe , Valitutti Salvatore , Finetti Francesca , Baldari Cosima T
Published: July 2023

Elimination of virally infected or tumoral cells is mediated by cytotoxic T cells (CTL). Upon antigen recognition CTLs assemble a specialized signaling and secretory domain at the interface with their target, the immune synapse (IS). During IS formation CTLs acquire a transient polarity, marked by re-orientation of the centrosome and microtubule cytoskeleton toward the IS, thus directing the transport and delivery of the lytic granules to the target cell. Based on the implication of the kinase Aurora-A in CTL function we hypothesized that its substrate, the mitotic regulator Polo-like kinase 1 (PLK1), may participate in CTL IS assembly. We demonstrate that PLK1 is phosphorylated upon TCR triggering and polarizes to the IS. PLK1 silencing or inhibition results in impaired IS assembly and function, as witnessed by defective synaptic accumulation of TCRs as well as compromised centrosome and lytic granule polarization to the IS, resulting in impaired target cell killing. This function is achieved by coupling early signaling to microtubule dynamics, a function pivotal for CTL-mediated cytotoxicity. These results identify PLK1 as a new player in CTL IS assembly and function.

Summary statement

The mitotic kinase Polo-like kinase 1 promotes centrosome polarization to the immune synapse in cytotoxic T cells by coupling TCR signaling to microtubule dynamics
Extracellular vesicle-mediated release of bis(monoacylglycerol)phosphate is regulated by LRRK2 and Glucocerebrosidase activity
Authors: Meneses-Salas Elsa , Arnold Marianna , Castellá Moises , Hsieh Frank , Fernández-Santiago Ruben , Ezquerra Mario , Garrido Alicia , Martí María-José , Enric Carlos , Pfeffer Suzanne R. , Merchant Kalpana , Lu Albert
Published: July 2023

The endo-lysosomal phospholipid, bis(monoacylglycerol)phosphate (BMP), is aberrantly elevated in the urine of Parkinson’s patients with mutations in genes encoding leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GCase). Because BMP resides on and regulates the biogenesis of endo-lysosomal intralumenal membranes that become extracellular vesicles (EVs) upon release, we hypothesized that elevated urinary BMP may be driven by increased exocytosis of BMP-enriched EVs. To test this hypothesis, we analyzed BMP metabolism and EV-associated release of BMP in wild type (WT) and R1441G LRRK2-expressing mouse embryonic fibroblast (MEF) cells. Using immunofluorescence microscopy and transmission electron microscopy we detected structural alterations in endo-lysosomes and antibody-accessible BMP pool, indicating that mutant LRRK2 affects endolysosomal homeostasis. Biochemical analyses of isolated EV fractions confirmed the effect on endo-lysosomes by showing an increase in LAMP2-positive EVs in mutant cells, which was partially restored by LRRK2 kinase inhibition but further augmented by GCase inhibition. Using mass spectrometry, we detected an overall increase in total di-22:6-BMP and total di-18:1-BMP in cell lysates from mutant LRRK2 MEFs compared to WT cells. Inhibition of LRRK2 kinase partially restored cellular BMP levels, whereas inhibition of GCase further increased the BMP content. In isolated EVs from LRRK2 mutant cells, LRRK2 inhibition decreased BMP content whereas GCase inhibition tended to increase it. Using metabolic labeling experiments, we demonstrated that the increase in cellular BMP content is not due to an increase in BMP synthesis, even though we observed an increase in BMP synthesizing enzyme, CLN5, in LRRK2 mutant MEFs and patient-derived fibroblasts. Finally, pharmacological modulators of EV release confirmed that BMP release is associated with EV secretion. Together, these results establish LRRK2 as a regulator of BMP levels in cells and its release through EVs, with GCase activity further modulating this process in LRRK2 mutant cells. Mechanistic insights from these studies have implications for the potential use of BMP-positive EVs as a biomarker for Parkinson’s disease and associated treatments.
Multiscale entropy analysis of combined EEG-fNIRS measurement in preterm neonates
Authors: Semeia Lorenzo , Nourhashemi Mina , Mahmoudzadeh Mahdi , Wallois Fabrice , Sippel Katrin , Preissl Hubert
Published: July 2023

In nature, biological systems such as the human brain are characterized by complex and non-linear dynamics. One way of quantifying signal complexity is Multiscale Entropy (MSE), which is suitable for structures with long-range correlation at different time scales. In developmental neuroscience, MSE can be taken as an index of brain maturation, and can differentiate between healthy and pathological development. In our current work, we explored the developmental trends of MSE on the basis of 30 simultaneous EEG – fNIRS recordings in premature infants between 27 and 34 weeks of gestational age (wGA). To explore potential factors impacting MSE, we determined the relation between MSE and the EEG Power Spectrum Density (PSD) and Spontaneous Activity Transients (SATs). As a result, via wGA, the MSE calculated on the EEG increases, thus reflecting the maturational processes in the brain networks, whereas in the fNIRS, MSE decreases, which might indicate a maturation of the brain blood supply. Moreover, we propose that the EEG power in the beta band (13-30 Hz) might be the main contributor to MSE in the EEG. Finally, we highlight the importance of SATs in determining MSE as calculated from the fNIRS recordings.

Highlights

Biological systems show complex and non-linear dynamics. With Multiscale Entropy (MSE) we studied simultaneous EEG-fNIRS in premature infants. MSE in the EEG increases over gestational age, MSE in the fNIRS decreases. EEG power spectrum density and spontaneous activity transients contribute to MSE.
High throughput PRIME editing screens identify functional DNA variants in the human genome
Authors: Ren Xingjie , Yang Han , Nierenberg Jovia L. , Sun Yifan , Chen Jiawen , Beaman Cooper , Pham Thu , Nobuhara Mai , Takagi Maya Asami , Narayan Vivek , Li Yun , Ziv Elad , Shen Yin
Published: July 2023

Despite tremendous progress in detecting DNA variants associated with human disease, interpreting their functional impact in a high-throughput and base-pair resolution manner remains challenging. Here, we develop a novel pooled prime editing screen method, PRIME, which can be applied to characterize thousands of coding and non-coding variants in a single experiment with high reproducibility. To showcase its applications, we first identified essential nucleotides for a 716 bpMYCenhancer via PRIME-mediated saturation mutagenesis. Next, we applied PRIME to functionally characterize 1,304 non-coding variants associated with breast cancer and 3,699 variants from ClinVar. We discovered that 103 non-coding variants and 156 variants of uncertain significance are functional via affecting cell fitness. Collectively, we demonstrate PRIME capable of characterizing genetic variants at base-pair resolution and scale, advancing accurate genome annotation for disease risk prediction, diagnosis, and therapeutic target identification.