bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Different Training Methods on Daily Use of Point-of-Care Ultrasound
Authors: De Carvalho Hugo , Godiveaux Nicolas , Javaudin Francois , Le Bastard Quentin , Kuczer Vincent , Pes Philippe , Montassier Emmanuel , Le Conte Philippe
Published: September 2023

Point-of-care ultrasound (POCUS) curriculum varies among countries. However, the length of training required for physicians is still under debate. We investigated the impact of different training methods: short hands-on courses (STS), long academic training sessions (LTS), or both (mixed training [MTS]), for POCUS daily use and self-reported confidence overall and specific to specific clinical situations. This was a descriptive study conducted over a 3-month period through a Web-based survey designed to assess the influence of different methods of POCUS training among physicians and residents on their daily practice. The survey was sent to 1212 emergency physicians with prior POCUS training; 515 answers (42%) could be analyzed. Participants in the STS group performed POCUS less frequently than physicians in the LTS or MTS group. Daily use in the STS group was 51% versus 82% in the LTS group and 83% in the MTS group (P < 0.01). The overall self-reported confidence in POCUS was lower in the STS group (P < 0.01) in all studied clinical situations. There was no significant difference between LTS and MTS groups (P > 0.05). Method of POCUS training significantly influenced POCUS daily use. Physicians who underwent long training sessions used POCUS more frequently in their routine practice and were significantly more confident in their ability to perform and interpret a POCUS examination.
Oxygen Consumption as an Early Warning System in the Critically ill
Authors: Hoeyer-Nielsen Anne Kirstine , Holmberg Mathias J. , Grossestreuer Anne V. , Yankama Tuyen , Berg Katherine M. , Donnino Michael W.
Published: September 2023

Introduction

In this study, we assessed whether changes in oxygen consumption (VO2) and other metabolic parameters could be used as an early warning system for detecting clinical deterioration in mechanically ventilated patients.

Methods

This was a prospective cohort study of adult patients requiring mechanical ventilation between February 2016 and March 2019. We looked for changes in VO2, carbon dioxide production (VCO2), respiratory quotient (RQ), and end-tidal carbon dioxide (EtCO2), occurring prior to clinical deterioration. Clinical deterioration was pre-defined as a requirement of vasopressor, an increase in serum lactate by 20% where at least one value was above 3 mmol/L, or a decrease in hemoglobin by 20% in the four hours prior to clinical deterioration.

Results

A total of 141 patients were included. There were no detectable changes in VO2, VCO2, and EtCO2 within the four hours prior to any clinical deterioration. RQ increased significantly within the four hours prior to an increase in lactate as compared to no increase in lactate but there were no detectable changes prior to other clinical deteriorations.

Conclusions

RQ has the potential to be an early marker of tissue hypoperfusion or mitochondrial dysfunction. However, future studies are necessary to evaluate the use of RQ as a bedside monitor in critical care settings.
Preoperative Prediction of Postoperative Infections Using Machine Learning and Electronic Health Record Data
Authors: Zhuang Yaxu , Dyas Adam , Meguid Robert A. , Henderson William , Bronsert Michael , Madsen Helen , Colborn Kathryn
Published: September 2023

Objective:

Estimate preoperative risk of postoperative infections using structured electronic health record (EHR) data.

Summary Background Data:

Surveillance and reporting of postoperative infections is primarily done through costly, labor-intensive manual chart review on a small sample of patients. Automated methods using statistical models applied to postoperative EHR data have shown promise to augment manual review as they can cover all operations in a timely manner. However, there are no specific models for risk-adjusting infectious complication rates using EHR data.

Methods:

Preoperative EHR data from 30,639 patients (2013-2019) were linked to American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) preoperative data and postoperative infection outcomes data from five hospitals in the University of Colorado Health System. EHR data included diagnoses, procedures, operative variables, patient characteristics, and medications. Lasso and the knockoff filter was used to perform controlled variable selection. Outcomes included surgical site infection (SSI), urinary tract infection (UTI), sepsis/septic shock, and pneumonia up to 30 days post-operatively.

Results:

Among >15,000 candidate predictors, seven were chosen for the SSI model and six for each of the UTI, sepsis, and pneumonia models. Important variables included preoperative presence of the specific outcome, wound classification, comorbidities, and American Society of Anesthesiologists physical status classification (ASA Class). Area under the receiver operating characteristic curve for each model ranged from 0.73-0.89.

Conclusion:

Parsimonious preoperative models for predicting postoperative infection risk using EHR data were developed and showed comparable performance to existing ACS-NSQIP risk models that use manual chart review. These models can be used to estimate risk-adjusted postoperative infection rates applied to large volumes of EHR data in a timely manner.
TraumaICDBERT, A Natural Language Processing Algorithm to Extract Injury ICD-10 Diagnosis Code from Free Text
Authors: Choi Jeff , Chen Yifu , Sivura Alexander , Vendrow Edward B. , Wang Jenny , Spain David A.
Published: September 2023

Objective:

To develop and validate TraumaICDBERT, a natural language processing algorithm to predict injury ICD-10 diagnosis codes from trauma tertiary survey notes.

Summary Background Data:

The adoption of ICD-10 diagnosis codes in clinical settings for injury prediction is hindered by the lack of real-time availability. Existing natural language processing algorithms have limitations in accurately predicting injury ICD-10 diagnosis codes.

Methods:

Trauma tertiary survey notes from hospital encounters of adults between January 2016 and June 2021 were used to develop and validate TraumaICDBERT, an algorithm based on BioLinkBERT. The performance of TraumaICDBERT was compared to Amazon Web Services Comprehend Medical, an existing natural language processing tool.

Results:

A dataset of 3,478 tertiary survey notes with 15,762 4-character injury ICD-10 diagnosis codes was analyzed. TraumaICDBERT outperformed Amazon Web Services Comprehend Medical across all evaluated metrics. On average, each tertiary survey note was associated with 3.8 (standard deviation: 2.9) trauma registrar-extracted 4-character injury ICD-10 diagnosis codes.

Conclusions:

TraumaICDBERT demonstrates promising initial performance in predicting injury ICD-10 diagnosis codes from trauma tertiary survey notes, potentially facilitating the adoption of downstream prediction tools in clinical settings.
Healthy and pathological pallidal regulation of thalamic burst versus tonic mode firing: a computational simulation
Authors: Kumbhare Deepak , Azam Md Ali , Hadimani Ravi , Toms Jamie , Weistroffer George , Atulasimha Jayasimha , Baron Mark S.
Published: September 2023

The mechanisms by which the basal ganglia influence the pallidal-receiving thalamus remain to be adequately defined. Our prior in vivo recordings in fully alert normal and dystonic rats revealed that normally fast tonic discharging entopeduncular [EP, rodent equivalent of the globus pallidus internus (GPi)] neurons are pathologically slow, highly irregular, and bursty under dystonic conditions. This, in turn, induces pallidal-receiving thalamic movement-related neurons to change from a healthy burst predominant to a pathological tonic-predominant resting firing mode. This study aims to understand the pallidal influence on thalamic firing modes using computational simulations. We inputted various combinations of healthy and pathological (dystonic) in vivo neuronal recordings to the Rubin and Terman’s computational model of low threshold spiking pallidothalamic neurons. The input sets consist of representative tonic, burst, irregular tonic and irregular burst inputs collected from EP/GPi in our animal lab. Initial test combinations of EP/ GPi input to the model were identical to the neuronal population distributions observed in vivo. The thalamic neuron model outputted similar firing rate and mode as observed in corresponding in-vivo thalamus. Further influence of each individual patterns was also delineated. By simulating the firing properties of encountered neurons, the basal ganglia output is suggested to critically act as firing mode selector for thalamic motor relay neurons. By selecting and determining the timing and extent of opening of thalamic T-type calcium channels via GABAergic hyperpolarizing input, GPi neurons are in position to precisely orchestrate thalamocortical burst motor signaling.
Monitoring and tracking the spread of SARS-CoV-2 in Asturias, Spain
Authors: Gonzalez-Alba Jose Maria , Rojo-Alba Susana , Perez-Martinez Zulema , Boga Jose A. , Alvarez-Arguelles Marta Elena , Gomez Juan , Herrero Pablo , Costales Isabel , Alba Luz Maria , Martin-Rodriguez Gabriel , Campo Rainer , Castelló-Abietar Cristian , Sandoval Marta , Abreu-Salinas Fátima , Coto Eliecer , Rodriguez Mercedes , Rubianes Pablo , Sanchez Maria Luisa , Vazquez Fernando , Antuña Luis , Álvarez Victoria , Melón García Santiago
Published: September 2023

Mutational analysis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can quantify the relative importance of variants over time, enable dominant mutations to be identified, and facilitate near real-time detection, comparison and tracking of evolving variants. SARS-CoV-2 in Asturias, an autonomous community of Spain with a large ageing population, and high levels of migration and tourism, was monitored and tracked from the beginning of the pandemic in February 2020 until its decline and stabilization in August 2021, and samples were characterized using whole genomic sequencing and single nucleotide polymorphisms. Data held in the GISAID database were analysed to establish patterns in the appearance and persistence of SARS-CoV-2 strains. Only 138 non-synonymous mutations occurring in more than 1 % of the population with SARS-CoV-2 were found, identifying ten major variants worldwide (seven arose before January 2021), 19 regional and one local. In Asturias only 17 different variants were found. After vaccination, no further regional major variants were found. Only half of the defined variants circulated and no new variants were generated, indicating that infection control measures such as rapid diagnosis, isolation and vaccination were efficient.
An RNA foundation model enables discovery of disease mechanisms and candidate therapeutics
Authors: Celaj Albi , Gao Alice Jiexin , Lau Tammy T.Y. , Holgersen Erle M. , Lo Alston , Lodaya Varun , Cole Christopher B. , Denroche Robert E. , Spickett Carl , Wagih Omar , Pinheiro Pedro O. , Vora Parth , Mohammadi-Shemirani Pedrum , Chan Steve , Nussbaum Zach , Zhang Xi , Zhu Helen , Ramamurthy Easwaran , Kanuparthi Bhargav , Iacocca Michael , Ly Diane , Kron Ken , Verby Marta , Cheung-Ong Kahlin , Shalev Zvi , Vaz Brandon , Bhargava Sakshi , Yusuf Farhan , Samuel Sharon , Alibai Sabriyeh , Baghestani Zahra , He Xinwen , Krastel Kirsten , Oladapo Oladipo , Mohan Amrudha , Shanavas Arathi , Bugno Magdalena , Bogojeski Jovanka , Schmitges Frank , Kim Carolyn , Grant Solomon , Jayaraman Rachana , Masud Tehmina , Deshwar Amit , Gandhi Shreshth , Frey Brendan J.
Published: September 2023

Accurately modeling and predicting RNA biology has been a long-standing challenge, bearing significant clinical ramifications for variant interpretation and the formulation of tailored therapeutics. We describe a foundation model for RNA biology, “BigRNA”, which was trained on thousands of genome-matched datasets to predict tissue-specific RNA expression, splicing, microRNA sites, and RNA binding protein specificity from DNA sequence. Unlike approaches that are restricted to missense variants, BigRNA can identify pathogenic non-coding variant effects across diverse mechanisms, including polyadenylation, exon skipping and intron retention. BigRNA accurately predicted the effects of steric blocking oligonucleotides (SBOs) on increasing the expression of 4 out of 4 genes, and on splicing for 18 out of 18 exons across 14 genes, including those involved in Wilson disease and spinal muscular atrophy. We anticipate that BigRNA and foundation models like it will have widespread applications in the field of personalized RNA therapeutics.
Exploring the effects of Dasatinib, Quercetin, and Fisetin on DNA methylation clocks: a longitudinal study on senolytic interventions
Authors: Lee Edwin , Carreras-Gallo Natàlia , Lopez Leilani , Turner Logan , Lin Aaron , Mendez Tavis L. , Went Hannah , Tomusiak Alan , Verdin Eric , Corley Michael , Ndhlovu Lishomwa , Smith Ryan , Dwaraka Varun B.
Published: September 2023

Senolytics, small molecules targeting cellular senescence, have emerged as potential therapeutics to enhance health span. However, their impact on epigenetic age remains unstudied. This study aimed to assess the effects of Dasatinib and Quercetin (DQ) senolytic treatment on DNA methylation (DNAm), epigenetic age, and immune cell subsets. In a Phase I pilot study, 19 participants received DQ for 6 months, with DNAm measured at baseline, 3 months, and 6 months. Significant increases in epigenetic age acceleration were observed in first-generation epigenetic clocks and mitotic clocks at 3 and 6 months, along with a notable decrease in telomere length. However, no significant differences were observed in second and third-generation clocks. Building upon these findings, a subsequent investigation evaluated the combination of DQ with Fisetin (DQF), a well-known antioxidant and antiaging senolytic molecule. After one year, 19 participants (including 10 from the initial study) received DQF for 6 months, with DNAm assessed at baseline and 6 months. Remarkably, the addition of Fisetin to the treatment resulted in non-significant increases in epigenetic age acceleration, suggesting a potential mitigating effect of Fisetin on the impact of DQ on epigenetic aging. Furthermore, our analyses unveiled notable differences in immune cell proportions between the DQ and DQF treatment groups, providing a biological basis for the divergent patterns observed in the evolution of epigenetic clocks. These findings warrant further research to validate and comprehensively understand the implications of these combined interventions.
Quantitative Assessment of Morphological Changes in Lipid Droplets and Lipid-Mito Interactions with Aging in Brown Adipose
Authors: Crabtree Amber , Neikirk Kit , Pinette Julia , Whiteside Aaron , Shao Bryanna , McKenzie Jessica , Vue Zer , Vang Larry , Le Han , Dermici Mert , Ahmad Taseer , Owens Trinity Celeste , Oliver Ashton , Zeleke Faben , Beasley Heather K. , Lopez Edgar Garza , Scudese Estevão , Rodman Taylor , Kabugi Kinuthia , Koh Alice , Navarro Suzanne , Lam Jacob , Kirk Ben , Mungai Margaret , Sweetwyne Mariya , Koh Ho-Jin , Zaganjor Elma , Damo Steven M. , Gaddy Jennifer A. , Kirabo Annet , Murray Sandra A. , Cooper Anthonya , Williams Clintoria , McReynolds Melanie R. , Marshall Andrea G. , Hinton Antentor
Published: September 2023

The physical characteristics of brown adipose tissue (BAT) are defined by the presence of multilocular lipid droplets (LD) within the brown adipocytes and a high abundance of iron-containing mitochondria, which give it its characteristic color. Normal mitochondrial function is, in part, regulated by organelle-to-organelle contacts. Particularly, the contact sites that mediate mitochondria-LD interactions are thought to have various physiological roles, such as the synthesis and metabolism of lipids. Aging is associated with mitochondrial dysfunction, and previous studies show that there are changes in mitochondrial structure and proteins that modulate organelle contact sites. However, how mitochondria-LD interactions change with aging has yet to be fully clarified. Therefore, we sought to define age-related changes in LD morphology and mitochondria-lipid interactions in BAT. We examined the three-dimensional morphology of mitochondria and LDs in young (3-month) and aged (2-year) murine BAT using serial block face-scanning electron microscopy and the Amira program for segmentation, analysis, and quantification. Analysis showed reductions in LD volume, area, and perimeter in aged samples compared to young samples. Additionally, we observed changes in LD appearance and type in aged samples compared to young samples. Notably, we found differences in mitochondrial interactions with LDs, which could implicate that these contacts may be important for energetics in aging. Upon further investigation, we also found changes in mitochondrial and cristae structure for mitochondria interacting with LD lipids. Overall, these data define the nature of LD morphology and organelle-organelle contacts during aging and provide insight into LD contact site changes that interconnect biogerontology and mitochondrial functionality, metabolism, and bioactivity in aged BAT.

Abstract Figure

Graphical Abstract

Workflow highlighting the process of murine interscapular BAT extraction, processing and imaging serial block facing-scanning electron microscopy and using Amira software for 3D reconstruction of LDs and mitochondrial lipid contact sites to elucidate their structure across aging.
Research ethics review during the COVID-19 pandemic: An international study
Authors: Salamanca-Buentello Fabio , Katz Rachel , Silva Diego S. , Upshur Ross E.G. , Smith Maxwell J.
Published: September 2023

Research ethics review committees (ERCs) worldwide faced daunting challenges during the COVID-19 pandemic. There was a need to balance rapid turnaround with rigorous evaluation of high-risk research protocols in the context of considerable uncertainty. This study explored the experiences and performance of ERCs during the pandemic.

We conducted an anonymous, cross-sectional, global online survey of chairs (or their delegates) of ERCs who were involved in the review of COVID-19-related research protocols after March 2020. The survey ran from October 2022 to February 2023 and consisted of 50 items, with opportunities for open text responses.

Two hundred and three participants [130 from high-income countries (HICs) and 73 from low-and middle-income countries (LMICs)] completed our survey. Respondents came from diverse entities and organizations from 48 countries (19 HICs and 29 LMICs) in all World Health Organization regions. Responses show little of the increased global funding for COVID-19 research was allotted to the operation of ERCs. Few ERCs had pre-existing internal policies to address operation during public health emergencies, but almost half used existing guidelines. Most ERCs modified existing procedures or designed and implemented new ones but had not evaluated the success of these changes. Participants overwhelmingly endorsed permanently implementing several of them. Few ERCs added new members but non-member experts were consulted; quorum was generally achieved. Collaboration among ERCs was infrequent, but reviews conducted by external ERCs were recognized and validated. Review volume increased during the pandemic, with COVID-19-related studies being prioritized. Most protocol reviews were reported as taking less than three weeks. One-third of respondents reported external pressure on their ERCs from different stakeholders to approve or reject specific COVID-19-related protocols.

ERC members faced significant challenges to keep their committees functioning during the pandemic. Our findings can inform ERC approaches towards future public health emergencies. To our knowledge, this is the first international, COVID-19-related study of its kind.
How demographic factors matter for antimicrobial resistance – quantification of the patterns and impact of variation in prevalence of resistance by age and sex
Authors: Waterlow Naomi R , Cooper Ben S , Robotham Julie V , Knight Gwenan M
Published: September 2023

Background

Antibiotic usage, contact with high transmission healthcare settings as well as changes in immune system function all vary by a patient’s age and sex. Yet, most analyses of antimicrobial resistance (AMR) ignore demographic indicators and provide only country level resistance prevalence values.

In this work we use routine surveillance data on serious infections in Europe to characterise the importance of age and sex on incidence and resistance prevalence patterns for 33 different bacteria and antibiotic combinations. We fit Bayesian multilevel regression models to quantify these effects and provide estimates of country-, bacteria- and drug-family effect variation.

Results

At the European level, we find distinct patterns in resistance prevalence by age that have previously not been explored in detail. Trends often vary more within an antibiotic family than within a bacterium: clear resistance increases by age for methicillin resistantS. aureus(MRSA) contrast with a peak in resistance to several antibiotics at ∼30 years of age forP. aeruginosa.This diverges from the known, clear exponential increase in infection incidence rates by age, which are higher for males except forE. coliat ages 15-40.

At the country-level, the patterns are highly context specific with national and subnational differences accounting for a large amount of resistance variation (∼38%) and a range of associations between age and resistance prevalence. We explore our results in greater depths for two of the most clinically important bacteria–antibiotic combinations. For MRSA, age trends were mostly positive, with 72% of countries seeing an increased resistance between males aged 1 and 100 and more resistance in males. This compares to age trends for aminopenicillin resistance inE. coliwhich were mostly negative (males: 93% of countries see decreased resistance between ages 1 and 100) with more resistance in females. A change in resistance prevalence between ages 1 and 100 ranged up to ∼0.46 (95% CI 0.37 – 0.51, males) for MRSA but varied between 0.16 (95% CI 0.23-0.3, females) to -0.27 (95%CI -0.4 - - 0.15, males) across individual countries for aminopenicillin resistance inE. coli.

Conclusion

Prevalence of resistance in infection varies substantially by the age and sex of the individual revealing gaps in our understanding of AMR epidemiology. These context-specific patterns should now be exploited to improve intervention targeting as well as our understanding of AMR dynamics.
BMP signaling pathway member expression is enriched in enteric neural progenitors and required for zebrafish enteric nervous system development
Authors: Moore Joshua A. , Noah Arielle S. , Singleton Eileen W. , Uribe Rosa A.
Published: September 2023

The vertebrate enteric nervous system (ENS) consists of a series of interconnected ganglia within the gastrointestinal (GI) tract, formed during development following the migration of enteric neural crest cells (ENCCs) into the primitive gut tube. Much work has been done to unravel the complex nature of extrinsic and intrinsic factors that regulate processes that direct the migration, proliferation, and differentiation of ENCCs. However, ENS development is a complex process and we still have much to learn regarding the signaling factors that regulate ENCC development. Here in zebrafish, through transcriptomic,in situtranscript expression, immunohistochemical analysis, and chemical attenuation, we identified a time-dependent role for bone morphogenetic protein (BMP) in the maintenance of Phox2bb+enteric progenitor numbers and/or time of differentiation of the progenitor pool. In support of ourin silicotranscriptomic analysis, we identified expression of a novel ENS ligand-encoding transcript,bmp5,within developmental regions of ENCCs. Through generation of a novel mutantbmp5wmr2,we identified a functional role for BMP5 in proper GI tract colonization, wherebyphox2bb+enteric progenitor numbers were reduced. Altogether, this work has identified time-dependent roles for BMP signaling and identification of a novel extrinsic factor, BMP5, that is necessary for proper formation of vertebrate ENS.
Recruitment, Consent and DNA Sample Acquisition in a U.S. Precision Health Cohort During the COVID-19 Pandemic
Authors: Derry Allyson M. , Strong Yvette , Schioppo Davia , Cotter Joni , Wilkins Geisa M. , Siqueiros Laura I. , Ouyang Andrea , Hulseman Kathleen , Petrosino Joseph , Liang Lorrin , Stevenson Megan , Aguilera Tiffany Elianne , Soto Alexandria L. , Meurer Katherine , Herman Alison L. , Cohen Inessa , Falcone Guido J. , Longbrake Erin E. , Chaar Cassius I. Ochoa , Anastasio Kelly M. , Murray Michael F.
Published: September 2023

Aim

The Yale Generations Project (YGP) is a precision health cohort initiative that began enrollment in New Haven Connecticut USA in July 2019. In March 2020, after nine months of operation, pandemic restrictions prompted abrupt changes to staff availability as well as changes to the project’s recruitment, consenting, and sample acquisition. This manuscript describes the successful addition of remote recruitment, consenting, and DNA sampling to YGP workflows during the initial 27-months of pandemic restrictions ending June 30, 2022.

Methods

The initial YGP protocol established face-to-face workflow for recruiting, consenting and peripheral blood collection. A telemedicine consent protocol was initiated in April of 2020, and a remote saliva collection was established in October of 2020. De-identified data was extracted from YGP dataset and reported here.

Results

At the completion of YGP’s initial 36 months (9-months pre-pandemic and 27-months pandemic) YGP enrolled N=4949 volunteers. There were N=1,950 (216.7 per month) volunteers consented pre-pandemic and N=2,999 (111.1 per month) during pandemic. The peak consenting month was February 2020 with N=428. DNA sample acquisition peaked in the pre-pandemic month of February 2020 with N=291 peripheral blood draws, and in the pandemic period the peak DNA acquisition month was November 2020 with N=176 (N=68 peripheral blood draws and N=108 saliva samples).

Conclusion

The YGP successfully transitioned from pre-pandemic recruiting, consenting and sample acquisition model that was exclusively face-to-face, to pandemic model that was predominantly remote. The added value of remote recruiting, consenting, and sampling has led to plans for an optimized hybrid model post-pandemic.
Noninvasive Quantification of Radiation-Induced Lung Injury using a Targeted Molecular Imaging Probe
Authors: Abston Eric , Zhou Iris Y. , Saenger Jonathan A. , Shuvaev Sergey , Akam Eman , Esfahani Shadi A. , Hariri Lida P. , Rotile Nicholas J. , Crowley Elizabeth , Montesi Sydney B. , Humblet Valerie , Arabasz Grae , Catana Ciprian , Fintelmann Florian J. , Caravan Peter , Lanuti Michael
Published: September 2023

Rationale

Radiation-induced lung injury (RILI) is a progressive inflammatory process commonly seen following irradiation for lung cancer. The disease can be insidious, often characterized by acute pneumonitis followed by chronic fibrosis with significant associated morbidity. No therapies are approved for RILI, and accurate disease quantification is a major barrier to improved management.

Objective

To noninvasively quantify RILI, utilizing a molecular imaging probe that specifically targets type 1 collagen in mouse models and patients with confirmed RILI.

Methods

Using a murine model of lung radiation, mice were imaged with EP-3533, a type 1 collagen probe to characterize the development of RILI and to assess disease mitigation following losartan treatment. The human analog probe targeted against type 1 collagen,68Ga-CBP8, was tested on excised human lung tissue containing RILI and quantified via autoradiography. Finally,68Ga-CBP8 PET was used to assess RILIin vivoin six human subjects.

Results

Murine models demonstrated that probe signal correlated with progressive RILI severity over six-months. The probe was sensitive to mitigation of RILI by losartan. Excised human lung tissue with RILI had increased binding vs unirradiated control tissue and68Ga-CBP8 uptake correlated with collagen proportional area. Human imaging revealed significant68Ga-CBP8 uptake in areas of RILI and minimal background uptake.

Conclusions

These findings support the ability of a molecular imaging probe targeted at type 1 collagen to detect RILI in preclinical models and human disease, suggesting a role for targeted molecular imaging of collagen in the assessment of RILI.

Clinical trial registered withwww.clinicaltrials.gov(NCT04485286,NCT03535545)
Voice-Enabled Response Analysis Agent (VERAA): Leveraging Large Language Models to Map Voice Responses in SDoH Survey
Authors: Krishnamoorthy Rishivardhan , Nagarajan Vishal , Pour Hayden , Shashikumar Supreeth P. , Boussina Aaron , Farcas Emilia , Nemati Shamim , Josef Christopher S.
Published: September 2023

Social Determinants of Health (SDoH) have been shown to have profound impacts on health-related outcomes, yet this data suffers from high rates of missingness in electronic health records (EHR). Moreover, limited English proficiency in the United States can be a barrier to communication with health care providers. In this study, we have designed a multilingual conversational agent capable of conducting SDoH surveys for use in healthcare environments. The agent asks questions in the patient’s native language, translates responses into English, and subsequently maps these responses via a large language model (LLM) to structured options in a SDoH survey. This tool can be extended to a variety of survey instruments in either hospital or home settings, enabling the extraction of structured insights from free-text answers. The proposed approach heralds a shift towards more inclusive and insightful data collection, marking a significant stride in SDoH data enrichment for optimizing health outcome predictions and interventions.
An assessment of census-tract level socioeconomic position as a modifier of the relationship between PM 2.5 concentrations and cardiovascular emergency department visits in Missouri
Authors: McCann Zachary H. , Chang Howard H. , D’Souza Rohan , Scovronick Noah , Ebelt Stefanie
Published: September 2023

Ambient PM2.5 exposure elevates the risk for cardiovascular disease morbidity (CVDM). The aim of this study is to characterize which area-level measures of socioeconomic position (SEP) modify the relationship between PM2.5 exposure and CVDM in Missouri at the census-tract (CT) level. We use individual level Missouri emergency department (ED) admissions data (n = 3,284,956), modeled PM2.5 data, and yearly census tract data from 2012-2016 to conduct a two-stage analysis. Stage one uses a case-crossover approach with conditional logistic regression to establish the baseline risk of ED visits associated with interquartile range (IQR) changes in PM2.5. In the second stage, we use multivariate meta-regression to examine how census tract level SEP modifies the relationship between ambient PM2.5 exposure and CVDM. We find that overall, ambient PM2.5 exposure is associated with increased risk for CVDM. We test effect modification in statewide and urban census tracts, and in the warm-season only. Effect modification results suggest that among SEP measures, poverty is most consistently associated with increased risk for CVDM. For example, across Missouri the highest poverty CTs are at an elevated risk for CVDM [OR = 1.010 (95% CI 1.007, 1.014)] compared to the lowest poverty CTs [OR = 1.004 (95% CI 1.000, 1.008)]. Other SEP modifiers generally display an inconsistent or null effect. Overall, we find some evidence that area-level SEP modifies the relationship between ambient PM2.5 exposure and CVDM, and suggest that the relationship between air-pollution, area-level SEP, and CVDM may be sensitive to spatial scale.
Ketogenic diet reduces a neurobiological craving signature in alcohol use disorder
Authors: Wiers Corinde E. , Manza Peter , Wang Gene-Jack , Volkow Nora D.
Published: September 2023

Background and Aims

Increasing evidence suggests that a ketogenic (high-fat, low-carbohydrate) diet intervention reduces alcohol withdrawal severity and alcohol craving in individuals with alcohol use disorder (AUD) by shifting brain energetics from glucose to ketones. We hypothesized that the ketogenic diet would reduce a brain craving signature when individuals undergoing alcohol detoxification treatment were exposed to alcohol cues.

Methods

We performed a secondary analysis of functional magnetic resonance data of n=33 adults with an AUD were randomized to a ketogenic diet (n=19) or a standard American diet (n=14) and underwent three weeks of inpatient alcohol detoxification treatment. Once per week, participants performed an alcohol cue-reactivity paradigm with functional magnetic resonance imaging. We extracted brain responses to food and alcohol cues and quantified the degree to which each set of brain images shared a pattern of activation with a recently validated ‘Neurobiological Craving Signature’ (NCS). We then performed a group-by-time repeated measures ANOVA to test for differences in craving signature expression between the dietary groups over the three-week treatment period. We also correlated these expression patterns with self-reported wanting ratings for alcohol cues.

Results

For alcohol relative to food cues, there was a main effect of group, such that the ketogenic diet group showed lower NCS expression across all three weeks of treatment. The main effect of time and the group-by-time interaction were not significant. Self-reported wanting for alcohol cues reduced with KD compared to SA but did not correlate with the NCS score.

Conclusions

A ketogenic diet reduces self-reported alcohol wanting, and induced lower brain craving signatures to alcohol cues during inpatient treatment for AUD.
Developing and validating the Nepalese Abuse Assessment Screen (N-AAS) for identifying domestic violence among pregnant women in Nepal
Authors: Manandhar Pratibha , Chalise Pratibha , Rishal Poonam , Campbell Jacquelyn , Henriksen Lena , Infanti Jennifer J. , Joshi Sunil Kumar , Lukasse Mirjam , Pun Kunta Devi , Schei Berit , Swahnberg Katarina
Published: September 2023

This study culturally adapted and validated a Nepalese version of the Abuse Assessment Screen (AAS) tool for identifying domestic violence among pregnant women in Nepal, creating the Nepalese Abuse Assessment Screen (N-AAS). International and national topic experts reviewed the initial N-AAS version using the Delphi method, and pregnant women participated in cognitive interviews, providing feedback on the N-AAS as user experts. Subsequent pre-testing of a comprehensive questionnaire, which included the translated version of the N-AAS, occurred in two tertiary care hospitals using an electronic format known as Color-Coded Audio Computer-Assisted Self-Interview (C-ACASI). We assessed the content validity index, compared the concurrent validity of the N-AAS with the gold standard interview, estimated the prevalence of domestic violence from two hospitals, and calculated the Kappa coefficient. The reliability of the entire questionnaire was also evaluated through a test-retest analysis, with content validity rated as “good to excellent” by topic and user experts and high test-retest reliability (91.2–98.9%), indicating consistency across questionnaires completed at two different time points, with 12% of participants reporting any form of violence. The N-AAS demonstrated ≥91.7% specificity for all forms of abuse, accurately identifying non-abuse cases. In addition, moderate to excellent sensitivity was observed for emotional abuse (52.5%) and physical abuse since marriage (50%), while sensitivity for physical abuse in the past 12 months was 100%. Thus, the N-AAS demonstrated reliable test-retest results with a good Kappa coefficient and specificity, as well as showing excellent sensitivity for detecting recent physical abuse and moderate sensitivity for detecting emotional abuse and physical abuse since marriage. Because cultural context often leads women to normalize and tolerate abuse from spouses and family members and women are thus reluctant to report abuse, the results imply that the N-AAS can serve as a valuable screening tool for domestic abuse in antenatal care settings in Nepal.
Cladosporiumspecies detoxify multiple water micropollutants of emerging concern using diverse strategies
Authors: Leth Maria Louise , Tang Kai , Sørensen Trine , Andersen Aaron John , Hélix-Nielsen Claus , Andersen Birgitte , Frisvad Jens , Sondergaard Teis Esben , Andersen Henrik Rasmus , Hachem Maher Abou
Published: September 2023

The accumulation of micropollutants of emerging concern in aqueous systems raises safety concerns regarding biological systems and human health. Mycoremediation is a promising and green strategy to mitigate the micropollutant challenge. Hitherto, focus has mainly been on white-rot Basidiomycota and micropollutant transformation by ascomycetes remains underexplored. Here, we assayed 53 Ascomycota isolates from 10 genera for the removal of 22 micropollutants. Notably, 9 out of 22 micropollutants were removed from fungal culture supernatant at efficacies >45%. Temporal analysis of the nine top- performing strains, highlighted remarkable potency ofCladosporiumisolates in removal of multiple micropollutants. Importantly,Cladosporiumconsiderably reduced the toxicity of a micropollutant cocktail based on growth assays. Metabolomics analyses identified oxidation for 5-methyl-1H-benzotriazole and citalopram, whereas methylation and carboxylation were observed for 5-chlorobenzotriazole. No transformation products were detected for ciprofloxacin, sulfamethoxazole, and sertraline, hinting their extensive degradation. These findings suggest micropollutant transformation via diverse catalytic routes byCladosporium. Genome sequencing and proteomic analyses of the top-performing isolates were consistent with the observed transformations and tentatively identified the molecular apparatus, conferring micropollutant transformation. This unprecedented study brings novel insight into the micropollutant transformation and detoxification capabilities of the prevalentCladosporiumspecies, thereby revealing a considerable and hitherto underappreciated potential of this genus and potentially other ascomycetes in micropollutant transformation.

Importance

At present, conventional wastewater treatment plants (WWTPs) are not designed for removing micropollutants, which are released into aqueous systems. This raises concerns due to the poor insight into micropollutant long-term interplay with biological systems. Innovating biotechnological solutions to tackle micropollutant require addressing the paucity of knowledge on microbial groups and molecular pathways, which mediate micropollutant transformation. Our study highlights the considerable potential of theCladosporiumgenus that remains underexplored in the arena of micropollutant transformation. We report the first genomes sequences for threeCladosporiumspecies:C. allicinum, C. inversicolor,andC. fusiforme, which sets the stage for further analyses of micropollutant transformation, but also offers an important resource on this ecologically significant, albeit under-studied genus and related Ascomycota.
Single-cell multi-omics map of human foetal blood in Down’s Syndrome
Authors: Marderstein Andrew R. , Zuani Marco De , Xue Haoliang , Bezney Jon , Wong Shuo , Coorens Tim H. H. , Montgomery Stephen B. , Cvejic Ana
Published: September 2023

Down’s Syndrome (DS) predisposes individuals to haematological abnormalities, such as increased number of erythrocytes and leukaemia in a process that is initiated before birth and is not entirely understood. To understand dysregulated hematopoiesis in DS, we integrated single-cell transcriptomics of over 1.1 million cells with chromatin accessibility and spatial transcriptomics datasets using human foetal liver and bone marrow samples from three disomic and 15 trisomic foetuses. We found that differences in gene expression in DS were both cell type- and environment-dependent. Furthermore, we found multiple lines of evidence that DS haematopoietic stem cells (HSCs) are “primed” to differentiate. We subsequently established a DS-specific map of enhancer-gene relationships in disomic and trisomic HSCs using 10X Multiome data. By integrating this map with genetic variants associated with blood cell variation, we discovered that trisomy restructured enhancer-gene maps to dysregulate enhancer activity and gene expression critical to erythroid lineage differentiation. Further, as DS mutations display a signature of oxidative stress, we validated both increased mitochondrial mass and oxidative stress in DS, and observed that these mutations preferentially fell into regulatory regions of expressed genes in HSCs. Altogether, our single- cell, multi-omic resource provides a high-resolution molecular map of foetal haematopoiesis in Down’s Syndrome and indicates significant enhancer-gene restructuring giving rise to co- occurring haematological conditions.
HaloTag display enables quantitative single-particle characterization and functionalization of engineered extracellular vesicles
Authors: Mitrut Roxana E. , Stranford Devin M. , DiBiase Beth N. , Chan Jonathan M. , Bailey Matthew D. , Luo Minrui , Harper Clare S. , Meade Thomas J. , Wang Muzhou , Leonard Joshua N.
Published: September 2023

Extracellular vesicles (EVs) play key roles in diverse biological processes, transport biomolecules between cells, and have been engineered for therapeutic applications. A useful EV bioengineering strategy is to express engineered proteins on the EV surface to confer targeting, bioactivity, and other properties. Measuring how incorporation varies across a population of EVs is important for characterizing such materials and understanding their function, yet it remains challenging to quantitatively characterize the absolute number of engineered proteins incorporated at single-EV resolution. To address these needs, we developed a HaloTag-based characterization platform in which dyes or other synthetic species can be covalently and stoichiometrically attached to engineered proteins on the EV surface. To evaluate this system, we employed several orthogonal quantification methods, including flow cytometry and fluorescence microscopy, and found that HaloTag-mediated quantification is generally robust across EV analysis methods. We compared HaloTag-labeling to antibody-labeling of EVs using single vesicle flow cytometry, enabling us to measure the substantial degree to which antibody labeling can underestimate proteins present on an EV. Finally, we demonstrate the use of HaloTag to compare between protein designs for EV bioengineering. Overall, the HaloTag system is a useful EV characterization tool which complements and expands existing methods.
Gut microbial genomes with paired isolates from China signify probiotic and cardiometabolic effects
Authors: Huang Pan , Dong Quanbing , Wang Yifeng , Tian Yunfan , Wang Shunhe , Zhang Chengcheng , Yu Leilei , Tian Fengwei , Gao Xiaoxiang , Guo Hang , Yi Shanrong , Li Mingyang , Liu Yang , Zhang Qingsong , Lu Wenwei , Wang Gang , Yang Bo , Cui Shumao , Hua Dongxu , Wang Xiuchao , Jiao Yuwen , Liu Lu , Deng Qiufeng , Ma Beining , Wu Tingting , Zou Huayiyang ,   CGMR Consortium, Shi Jing , Zhang Haifeng , Fan Daming , Sheng Yanhui , Zhao Jianxin , Tang Liming , Zhang Hao , Sun Wei , Chen Wei , Kong Xiangqing , Chen Lianmin , Zhai Qixiao
Published: September 2023

The gut microbiome displays significant genetic differences between populations while systematic characterization of the genomic landscape of the gut microbiome in Asia populations remains limited. Here, we present the Chinese gut microbial reference (CGMR) set, comprising 101,060 high quality metagenomic assembled genomes (MAGs) of 3,707 non-redundant species paired with 1,376 live isolates from a national wide collection of 3,234 fecal samples across China. This improved reference set contains 987 novel species compared with existing resources worldwide. By associating MAGs with geographic and phenotypic characteristics, we observed regional-specific coexisting MAGs and MAGs with probiotic and cardiometabolic functionalities. We further conducted mice experiments to confirm the probiotic effects of twoFaecalibacterium intestinalisisolates in alleviating constipation, the cardiometabolic influences of threeBacteroides fragilis_Aisolates in obesity, and the functional potential of isolates from the two new species belonging to the generaParabacteroidesandLactobacillusin host lipids metabolism. Our study not only expands the current microbial genomes with paired isolates but also demonstrates their probiotic and cardiometabolic effects on hosts, contributing to the mechanistic understanding of host-microbe interactions and the translation of microbiome-based personalized therapies.
Comparing the Diagnostic Performance of qPCR, ddPCR, and NGS Liquid Biopsies for HPV-Associated Cancers
Authors: Naegele Saskia , Ruiz-Torres Daniel A. , Zhao Yan , Goss Deborah , Faden Daniel L.
Published: September 2023

HPV-associated cancers, including oropharyngeal squamous cell carcinoma(HPV+OPSCC), cervical cancer(HPV+CC), and squamous cell carcinoma of the anus(HPV+SCCA), release circulating tumor HPV DNA(ctHPVDNA) into the blood. The diagnostic performance of ctHPVDNA detection depends on the approaches utilized and the individual assay metrics. A comparison of these approaches has not been systematically performed to inform expected performance, which in turn impacts clinical interpretation. A meta-analysis was performed using Ovid MEDLINE, Embase, and Web of Science Core Collection databases to assess the diagnostic accuracy of ctHPVDNA detection across cancer anatomic sites, detection platforms, and blood components. The population included HPV+OPSCC, HPV+CC, and HPV+SCCA patients with pre-treatment samples analyzed by quantitative PCR(qPCR), digital droplet PCR(ddPCR), or next generation sequencing(NGS). 36 studies involving 2,986 patients met the inclusion criteria. The sensitivity, specificity and quality of each study were assessed and pooled for each analysis.

The sensitivity of ctHPVDNA detection was greatest with NGS, followed by ddPCR and lastly qPCR when pooling all studies, while specificity was similar(sensitivity: ddPCR>qPCR, p<0.001; NGS>ddPCR, p=0.014). ctHPVDNA from OPSCC was more easily detected compared to CC and SCCA, overall(p=0.044).

In conclusion, detection platform, anatomic site of the cancer and blood component utilized impacts ctHPVDNA detection and must be considered when interpreting results. Plasma NGS-based testing should be considered the most sensitive approach for ctHPVDNA overall.