bluuebunny/crossref_metadata_2025 huggingface dataset:
An Observational Study to Determine the Prevalence of COVID-19 Among Hospitalized Patients With Multidrug-Resistant Enterobacterales Infections and Clinical Outcomes, 10 US Sites, 2020­–2022
Authors: Grass Julian E , Bulens Sandra N , Ansari Uzma A , Duffy Nadezhda , Jacob Jesse T , Smith Gillian , Rebolledo Paulina A , Restrepo Ana Mesa , Vaeth Elisabeth , Dumyati Ghinwa , Tsay Rebecca , Looi Hsioa Che , Phipps Erin , Flores Kristina G , Wilson Christopher , Muleta Daniel , Czaja Christopher A , Driscoll Jennifer , Johnston Helen , Lynfield Ruth , O’Malley Sean , Maloney Meghan , Stabach Nicole , Nadle Joelle , Pierce Rebecca , Hertzel Heather , Guh Alice Y
Published: December 2024

Background

We investigated hospitalized carbapenem-resistant Enterobacterales (CRE) and extended-spectrum β-lactamase–producing Enterobacterales (ESBL-E) cases with and without COVID-19, as identified through Emerging Infections Program surveillance in 10 sites from 2020 to 2022.

Methods

We defined a CRE case as the first isolation of Escherichia coli, Enterobacter cloacae complex, Klebsiella aerogenes, K oxytoca, K pneumoniae, or K variicola resistant to any carbapenem. We defined an ESBL-E case as the first isolation of E coli, K pneumoniae, or K oxytoca resistant to any third-generation cephalosporin and nonresistant to all carbapenems tested. Specimens were drawn from a normally sterile site or urine among hospitalized residents of the surveillance area in a 30-day period. We defined COVID-19 as a positive SARS-CoV-2 test result (SC2+) within 14 days before CRE or ESBL-E specimen collection and performed multivariable logistic regression analyses.

Results

Of 1595 CRE and 1866 ESBL-E hospitalized cases, 38 (2.4%) and 60 (3.2%), respectively, had a SC2+. Among these cases, a SC2+ was associated with intensive care unit admission (adjusted odds ratio [aOR], 1.69 [95% CI, 1.14–2.50]; aOR, 1.48 [95% CI, 1.03–2.12]) and 30-day mortality (aOR, 1.79 [95% CI, 1.22–2.64]; aOR, 1.94 [95% CI, 1.39–2.70]).

Conclusions

CRE and ESBL-E infections among hospitalized patients with preceding COVID-19 were uncommon but had worse outcomes when compared with cases without COVID-19. COVID-19 prevention in patients at risk of CRE and ESBL-E infections is needed, as well as continued infection control measures and antibiotic stewardship for patients with COVID-19.
COMPOSIT study: evaluating osimertinib combination with targeted therapies in EGFR-mutated non-small cell lung cancer
Authors: Mehlman Camille , Swalduz Aurelie , Monnet Isabelle , Morin Clara , Wislez Marie , Guisier Florian , Curcio Hubert , Du Rusquec Pauline , Cortot Alexis B , Gounant Valerie , Abbar Baptiste , Duchemann Boris , Giroux-Leprieur Etienne , Pierret Thomas , Quilot Fleur-Marie , Cadranel Jacques , Fallet Vincent
Published: December 2024

Introduction

The emergence of diverse resistance mechanisms after osimertinib therapy, including on-target epidermal growth factor receptor (EGFR) mutations and off-target alterations, warrants investigation of novel therapeutics to overcome these challenges and improve patient outcomes.

Methods

COMPOSIT was a French, retrospective, multicenter, cohort study of the effectiveness and tolerability of osimertinib in combination with other targeted therapies in patients with advanced EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC) who harbored other oncogenic drivers as primary or acquired resistance mechanisms. Real-world progression-free survival (rwPFS), overall survival (OS), and objective response rate (ORR) were the primary endpoints.

Results

The study included 61 patients (63.9% women; median age, 61 years). Chemotherapy was administered to 26 patients (42.6%) before the combinations. The most frequently targeted resistance mechanisms were MET amplification (n = 40) and BRAF alterations (n = 11). Sixteen combinations of osimertinib with other targeted therapies were reported. Overall (except for 10 patients in clinical trials), median rwPFS and OS were 3.9 (95% CI, 2.9-5.2) and 9.8 months (95% CI, 6.8-14.8). Best ORR (n = 54) was 50% (95% CI, 33.0-72.8). In patients with MET amplification (n = 29), median rwPFS and OS were 4.9 (95% CI, 2.9-7.2) and 8.6 months (95% CI, 5.3-21.6). Grade ≥3 adverse events occurred in 15 patients (24.6%). No deaths were related to treatment.

Conclusions

Combinations of osimertinib with other targeted therapies appeared to be feasible and safe and may offer clinical benefit to overcome resistance to osimertinib in EGFRm NSCLC, especially in patients with MET amplification.
Physiologic and structural characterization of desisobutyryl-ciclesonide, a selective glucocorticoid receptor modulator in newborn rats
Authors: Jaumotte Juliann D , El Khoury Nathalie , Min Charles K , Wang Jiefei , Madigan Caroline , Jano Antalya , Russo Kobylski Robin J , Solt Laura A , Dhavan Rutu S , Short Kelly L , Lei Tianhua , Chandran Uma , Cole Timothy J , Monaghan-Nichols Ann Paula , Sampath Venkatesh , Houtman René , Nettles Kendall W , DeFranco Donald B
Published: December 2024

Bronchopulmonary dysplasia, the most prevalent chronic lung disease of prematurity, is often treated with glucocorticoids (GCs) such as dexamethasone (DEX), but their use is encumbered with several adverse somatic, metabolic, and neurologic effects. We previously reported that systemic delivery of the GC prodrug ciclesonide (CIC) in neonatal rats activated glucocorticoid receptor (GR) transcriptional responses in lung but did not trigger multiple adverse effects caused by DEX. To determine whether limited systemic metabolism of CIC was solely responsible for its enhanced safety profile, we treated neonatal rats with its active metabolite desisobutyryl-ciclesonide (Des-CIC). DEX but not Des-CIC caused a reduction in body weight as well as reduced insulin-like growth factor-1 serum levels and chronic hyperglycemia in neonatal rats. However, Des-CIC was as effective as DEX in reducing the expression of various bleomycin-induced proinflammatory cytokine mRNAs. In vitro studies with various cell types demonstrate the potent GR transactivation and transrepression activity of Des-CIC, although genome-wide transcriptomic analyses reveal differences in DEX vs. Des-CIC responses in neonatal rat lung and liver tissue. Des-CIC is a GR super-agonist as revealed by an in vitro coregulator peptide binding assay. In addition, molecular dynamics simulations revealed unique Des-CIC-dependent allosteric signaling pathways between specific residues in the GR ligand-binding domain and receptor surfaces interacting with coregulator peptides. Thus, Des-CIC is a potential novel selective GR modulator that could impart a favorable therapeutic index for CIC use for even modest durations of GC exposure which could have long-lasting adverse somatic, metabolic, or neurologic effects.
A new strategy for drug delivery systems in oral diseases using stem cell-derived extracellular vesicles: review and new perspectives
Authors: Xia Ruyang , Li Maojiao , Huang Bo
Published: December 2024

Extracellular vesicles (EVs) are membrane vesicles derived from cells and serve as an endogenous mechanism for intercellular communication. Since the discovery of their capacity to effectively transfer biological information, their potential as drug delivery vehicles has garnered significant scientific interest. Particularly, EVs derived from mesenchymal cells (MSC-EVs) have emerged as a highly promising method for drug delivery. They can transport bioactive molecules, such as nucleic acids, lipids, and proteins, and possess the ability to modulate immune responses, transmit information, and target specific cells. EVs offer several advantages over conventional drug delivery systems, including their capacity to traverse natural barriers, inherent cell targeting capabilities, and stability in circulation. Compared to their parent cells, EVs exhibit low immunogenicity, ease of storage and transport, and a reduced risk of tumorigenesis. The diagnosis and treatment of oral diseases often involve invasive measures, and MSC-EVs have demonstrated initial efficacy in oral disease treatment. This review explores the application of MSC-EVs in maxillofacial tissue regeneration, periodontitis, temporomandibular joint osteoarthritis, Sjögren’s Syndrome, oral cancer, and other oral diseases. Additionally, it outlines potential future directions for the development of MSC-EVs. This review aims to provide a comprehensive understanding of MSC-EVs in oral disease treatment and to stimulate interest in their applications for targeted drug delivery.
Genetic diversity of Moniliophthora roreri from cacao trees growing in the Soconusco area, Chiapas, Mexico
Authors: Rodríguez-Velázquez Nadia Denisse , Fernández Pavía Sylvia Patricia , Pineda-Vaca Daniela , Tlacuilo Cano Juan Daniel , López Guillén Guillermo , Chávez Ramírez Belén , Estrada de los Santos Paulina
Published: December 2024

Moniliophthora roreri (Cif.) Evans et al. is the causal agent of frosty pod rot or cacao moniliasis. This disease represents the main phytosanitary problem that cacao production faces in Latin America. The vastly destructive capacity of frosty pod rot conveys high economic losses. This study aimed to determine the genetic diversity of M. roreri associated with cacao trees growing around the Soconusco area in Chiapas, México, through the Inter-Simple Sequence Repeat analysis or ISSR. The study consisted of 145 strains of M. roreri isolated from 17 sites belonging to 12 regions in the Soconusco area, from Suchiate in the south, near the Guatemala border, to Acapetahua in the north of Chiapas. According to the analysis, two genetic groups were identified; the first one was located in the north of the Soconusco area, and the second in the south. The AMOVA analysis indicated high variability in the populations (59.64%), meaning among sampling sites that within them (40.35%), and together with the Mantel analysis (p = 0.034), it indicates that the gene flow of M. roreri is affected by landscape features, e.g., mountains, roads, and rivers.
An Analysis of School-Based Mental Health Models and Policies
Authors: Kemp Caroline M.
Published: December 2024

The youth mental health crisis in the United States was exacerbated by the COVID-19 pandemic, as well as in part by widespread, frequent use of the internet and social media. Schools provide an opportune setting for delivering prompt preventative interventions to actively mitigate this crisis. The purpose of this project was to identify policy recommendations for improving school-based mental health services and reducing inequities in care, as well as to produce guidelines on how to advocate for better policies for school mental health services. School policies were analyzed in 3 states at 3 different levels: the state level, district level, and school level. To augment the policy reviews, unstructured interviews were conducted with 5 school nurses from the 3 states. Recommendations for just and sustainable policies for school-based mental health care and strategies on how to advocate for such policies are outlined. This project exemplifies the need for strong policies to support school mental health, with a focus on the role of the school nurse.
A Mother's Cry
Authors: Arroyo Elizabeth
Published: December 2024

A nurse reflects on a profound and precious human connection.
Extended High-Frequency Audiometry Using the Wireless Automated Hearing Test System Compared to Manual Audiometry in Children and Adolescents
Authors: Blankenship Chelsea M. , Hickson Lindsey M. , Quigley Tera , Larsen Erik , Lin Li , Hunter Lisa L.
Published: December 2024

Objectives:

Valid wireless automated Békésy-like audiometry (ABA) outside a sound booth that includes extended high frequencies (EHF) would increase access to monitoring programs for individuals at risk for hearing loss, particularly those at risk for ototoxicity. The purpose of the study was to compare thresholds obtained with (1) manual audiometry using an Interacoustics Equinox and modified Hughson–Westlake 5 dB threshold technique to automated audiometry using the Wireless Automated Hearing Test System (WAHTS) and a Békésy-like 2 dB threshold technique inside a sound booth, and (2) ABA measured in the sound booth to ABA measured outside the sound booth.

Design:

Cross-sectional study including 28 typically developing children and adolescents (mean = 14.5 years; range = 10 to 18 years). Audiometric thresholds were measured from 0.25 to 16 kHz with manual audiometry inside the sound booth and with ABA measured both inside and outside the sound booth in counterbalanced order.

Results:

ABA thresholds measured inside the sound booth were overall about 5 dB better compared with manual thresholds in the conventional frequencies (0.25 to 8 kHz). In the EHFs (10 to 16 kHz), a larger threshold difference was observed, where ABA thresholds were overall about 14 dB better compared with manual thresholds. The majority of ABA thresholds measured outside the sound booth were within ±10 dB of ABA thresholds measured inside the sound booth (conventional: 86%; EHF: 80%). However, only 69% of ABA thresholds measured inside the sound booth were within ±10 dB of manual thresholds in the conventional frequencies and only 32% of ABA thresholds measured inside the sound booth were within ±10 dB of manual thresholds in the EHFs.

Conclusions:

These results indicate that WAHTS ABA results in better thresholds in conventional frequencies than manual audiometry in children and adolescents, consistent with previous studies in adults. Hearing thresholds for the EHF were better when measured with WAHTS ABA compared with manual audiometry, likely due to different transducer-related calibration values that are not age-adjusted. Additional studies of WAHTS automated Békésy-like EHF thresholds that include healthy pediatric participants are needed to establish age-appropriate normative thresholds for clinical application in monitoring programs for noise-induced hearing loss and/or ototoxicity.
Temporal Changes in PROMs Improvement and Recovery Kinetics Following Transforaminal Endoscopic Lumbar Discectomy
Authors: Zhao Eric , Ehrlich Adin , Omurzakov Arsen , Asada Tomoyuki , Singleton Quante , Colon Luis , Owusu-Sarpong Stephane , Musharbash Farah , Halayqeh Sereen , Lui Adrian , Pezzi Andrea , Araghi Kasra , Subramanian Tejas , Mai Eric , Heuer Annika , Singh Nishtha , Tuma Olivia C. , Durbas Atahan , Harhash Tarek , Qureshi Sheeraz , Iyer Sravisht
Published: December 2024

Study Design.

Retrospective cohort study

Objective.

to analyze trends in PROMs improvement and recovery kinetics following transforaminal endoscopic lumbar discectomy and foraminotomy (TELD)

Summary of Background Data.

As TELDs become an increasingly common alternative to fusions for lateral disc herniations, it is important to understand patients’ postoperative recovery timelines to manage patient expectations. Although studies have shown improvement after TELD compared to preoperative baseline, there is a paucity of information regarding rate of postoperative improvement.

Methods.

Patients who underwent primary one- or two-level TELD for far lateral disc herniations with a minimum of 6-month follow-up were included. Outcomes included: patient reported outcome measures (PROMs), including Oswestry Disability Index (ODI), 12-Item Short Form Survey Physical Component Score (SF-12 PCS), and Visual Analog Scale (VAS) for back and leg; PROMs minimally clinically important difference (MCID); global rating of change (GRC); and return to activities. Timepoints included were preoperative, 2 weeks, 6 weeks, 12 weeks, 6 months. Trends in improvement were plotted on graphs and with P values displayed in tables.

Results.

51 patients were included. Mean operative time was 68.4±23.0 minutes and mean length of stay was 9.6±10.5 hours. There were statistically significant improvements in VAS back and leg at 2 weeks and 6 weeks, with a plateau after 6 weeks. ODI and SF-12 PCS did not experience statistically significant improvement until 6 weeks, which was also the point of plateau. VAS leg MCID and GRC peaked at 6 weeks. All patients returned to driving and discontinued opioids, and most patients returned to work. Median days to return to driving, work, and discontinue opioids were 8, 35, and 1, respectively.

Conclusion.

Patients can expect the majority of postoperative improvement to occur within 6 weeks, after which improvements tend to plateau. Around 75% of patients feel better compared to preoperative at 6 months. TELD may therefore spare some patients of a more invasive fusion initially.

Level of Evidence.

3
Combination of bacteriophage and antibiotic therapy to control antimicrobial drug resistance bacterial infections: the evolutionary trade-off mechanism
Authors: van Leeuwen Willem B. , Razavi Erfan Darban , Kazemi Sima , Aghaee Bahareh Lashtoo
Published: December 2024

Antimicrobial resistance (AMR) is a global health threat because of the emergence of infections with multidrug-resistant (MDR) bacterial strains. Combination therapy, involving both phages and antibiotics, is being explored to approach this burden. This combination therapy offers a promising solution by overcoming resistance, enhancing treatment efficacy, and serving as an alternative to combat bacterial infections. However, challenges like phage resistance and the need for extensive clinical trials must be addressed. Nevertheless, the synergistic action of phages in combination with antibiotics, provides hope in effectively combating AMR and safeguarding public health. Understanding the evolutionary trade-off and optimizing this approach, researchers aim to pave the way for more successful treatments in the future.
A System to Explore the Adaptive Dynamics of Multicopy Plasmids: The Role of Copy Number and Mutation Rate in Evolutionary Outcomes
Authors: Pisera Alexander (Olek) , Liu Chang C.
Published: December 2024

Multicopy plasmids are widespread in nature and compose a common strategy for spreading beneficial traits across microbes. However, the role of plasmids in supporting the evolution of encoded genes remains underexplored due to challenges in experimentally manipulating key parameters such as plasmid copy number and mutation rate. In this work, we developed a strategy for controlling copy number in the plasmid-based continuous evolution system, OrthoRep, and used our resulting capabilities to investigate the evolution of a conditionally essential gene under varying CN and mutation rate conditions. Our results show that low CN facilitates the faster enrichment of beneficial alleles while high CN promotes robustness through the maintenance of allelic diversity. High CN also slows the removal of deleterious mutations and increased the fraction of non-functional alleles that could hitchhike during evolution. This study highlights the nuanced relationships between plasmid CN, mutation rate, and evolutionary outcomes, providing insights into the adaptive dynamics of genes encoded on multicopy plasmids and nominating OrthoRep as a versatile tool for studying plasmid evolution.
Mutations inampDcause hyperproduction of AmpC and CphA beta-lactamases and high resistance to beta-lactam antibiotics inChromobacterium violaceum
Authors: Laranjeiro Luís G. , Neme Carlos E. M. , Previato-Mello Maristela , Batista Bianca B. , Henriques Isabel , da Silva Neto José F.
Published: December 2024

Bacterial resistance to beta-lactam antibiotics mediated by beta-lactamase enzymes is widespread worldwide.Chromobacterium violaceum, an environmental Gram-negative bacteria pathogen, is intrinsically resistant to some beta-lactam antibiotics. In this work, we found that mutations in anampDgene, encoding a peptidoglycan-recycling amidase, cause hyperproduction of two chromosomal beta-lactamases (AmpC and CphA), conferring high beta-lactam resistance inC. violaceum. Susceptibility tests using ΔampC, ΔcphA, andΔampCΔcphAmutant strains revealed specific susceptibility profiles to penicillin, cephalosporin, and carbapenem beta-lactams, suggesting that AmpC is a broad-spectrum beta-lactamase (penicillinase and cephalosporinase), while CphA is a narrow-spectrum metallo-carbapenemase. Beta-galactosidase assays indicate that the expression ofampCandcphAincreased in response to beta-lactams. We isolatedC. violaceumspontaneous mutants resistant to the antibiotic ceftazidime and found that most mutants were also resistant to several other beta-lactams and overexpressedampCandcphA. DNA sequencing of the three paralog genes encoding theC. violaceumAmpD amidases revealed mutations of different types in AmpD1 (CV_0566) in most of the spontaneous mutants, but no mutation was found in AmpD2 or AmpD3. Analysis of single and combined null amidase mutants revealed overexpression of both beta-lactamases and increased resistance to beta-lactams only in mutants with deletedampD1. When introduced intoampD1null or spontaneous mutants, theampD1gene rescued the antibiotic-related phenotypes. The AmpD1 amidase fromC. violaceumhas a unique architecture with an N-terminal acetyltransferase domain. Our work offers new insights into the mechanisms of beta-lactamase-mediated antibiotic resistance and open perspectives to improve the treatment ofC. violaceuminfections.
Development of a cognitive behavioral therapy intervention in Pujehun District, Sierra Leone among pregnant women
Authors: Lee Ashleen , Koroma Aminata , Duncan Joshua A , Bah Abdulai Jawo , Kleban Eliza , Kohlmann Kristin , Lopez-Arteaga Jumeika , Stephenson Kevin , Manary Mark J
Published: December 2024

This report outlines the development of a novel therapeutic intervention to address perinatal depression (PND) in Pujehun District, a rural area in Sierra Leone marked by high illiteracy rates and socio-economic challenges. PND poses significant health risks for both mothers and their children yet remains largely unaddressed due to stigma and limited resources.

In collaboration with the Mental Health Coalition – Sierra Leone, Project Peanut Butter established the first cognitive behavioral therapy (CBT) service in the district for women with PND. This process began with the creation of the first mental health counseling service in the district for women with postnatal depression, along with the selection and training of female counselors. A culturally adapted CBT curriculum was developed, designed to empower participants to reintegrate into their communities. Additionally, a novel screening tool was introduced to effectively diagnose PND in pregnant women in low-literacy settings.

This model serves as a replicable framework for similar initiatives in high illiteracy contexts, with the goal of improving maternal mental health and ultimately infant development.
Characterization of Dynamic Adaptation to Stressors using Multi-System Stimulus-Response Data: The Study of Physical Resilience in Aging Pilot
Authors: Bandeen-Roche Karen , Zhu Jiafeng , Xue Qian-Li , Buta Brian , Laskow Thomas , Walston Jeremy D. , Varadhan Ravi
Published: December 2024

Resilience to stressors has emerged as a major gerontological concept aiming to promote more positive outcomes for older adults. Achieving this aim relies on determining mechanisms underlying capacity to respond resiliently. This paper seeks proof of principle for the hypothesis that physical aspects of said capacity are rooted in the fitness of one’s physiology governing stress response, conceptualized as a dynamical system.

The Study of Physical Resilience in Aging (“SPRING”) leveraged stimulus-response experiments to characterize physiological fitness in older adults scheduled for one of three major stressors: Total knee replacement, incident hemodialysis, or bone marrow transplant in hematological cancer. Here we analyze Holter monitor time series, cortisol responses to adrenocorticotropic hormone (ACTH) stimulation, and repeated diurnal salivary cortisol assessment in the SPRING pilot (n=79). Principal components analysis was applied anticipating steady-state and “adaptation” mechanisms underlying the repeated physiological measures. Analytic features evidenced these mechanisms, supporting construct validity. Component scores were analyzed by major stressor, hypothesized surrogate physiologic measures (physical frailty phenotype, self-report of health), and demographic, health and behavioral characteristics. Scores differed substantially by stressor type and the surrogate physiologic measures, evidencing criterion validity.

Our data support that HRV, ACTH and salivary cortisol stimulus-response data jointly assess adaptation capacity across a variety of major stressors. We believe that SPRING is the first study in humans to concurrently query multiple physiologic systems using stimulus-response tests. Our findings lay groundwork for future validation with further data and to better forecast resilience of older adults to clinical stressors.
Patient safety education in undergraduate medical curricula: a concept analysis and scoping review protocol
Authors: Bowman-Newmark Jonathan , Brock Evangeline , Vosper Helen
Published: December 2024

Objective

This study aims to establish how the phenomenon of patient safety education manifests within undergraduate medical curricula. The specific objectives are to conduct a concept analysis, in order to make explicit the concept of patient safety education and inform its operational definition. Thereafter, to conduct a scoping review, in order to systematically map what educational content is taught, who is taught that content, and how that content is taught.

Introduction

Preliminary searches identified four extant systematic reviews, published between 2010 and 2022, which investigated different aspects of how patient safety education manifested within undergraduate medical curricula. Notwithstanding, those findings do not provide a sufficiently robust basis to inform contemporaneous discourse.

Eligibility criteria

The participants, concept, and context framework will be used to determine the evidence sources eligible for inclusion in the scoping review. Eligible participants will include learners matriculated on undergraduate medical programmes, and the educators that teach learners on those programmes. The concept will be patient safety education, according to an operational definition that will be established. Eligible contexts will include the taught curricula of undergraduate programmes in medicine.

Methods

An exploratory and descriptive study that will sequentially implement the Walker and Avant framework for concept analysis and the updated JBI methodology for scoping reviews. Eight electronic databases and one internet search engine will be utilised to identify sources published between 1 May 2014 and 30 November 2024. Pre-defined eligibility criteria will be used to select sources. Data will be extracted and analysed, and findings will be presented.
Community Threat, Positive Parenting, and Accelerated Epigenetic Aging: Longitudinal Links from Childhood to Adolescence
Authors: Metrailer Georgette , Tavares Karina , Pault Mikayla Ver , Lopez Adamari , Denherder Shane , Hernandez Valencia Everlyn , DiMarzio Karissa , Highlander April , Merrill Sarah M. , Rojo-Wissar Darlynn M. , Parent Justin
Published: December 2024

Early Life Adversity (ELA) has been linked to accelerated epigenetic aging. While positive parenting is hypothesized to buffer the detrimental effects of ELA on child development, its role in mitigating epigenetic age acceleration remains unclear. Data from 2,039 children (49.7% female) in the Future of Families and Child Wellbeing Study (FFCWS) were included in the current study (46.7% Black, 26.5% Hispanic, 19% White non-Hispanic). Home and community threat and observed parenting were measured from ages 3 to 9. Salivary epigenetic age acceleration was measured at ages 9 and 15. Positive parenting reduces the pace of epigenetic aging in low, but not high, community-threat environments. Interventions across home and community environments may be necessary to prevent ELA’s biological embedding.
Bradykinin Measurement by LC-MS/MS in Hereditary Angioedema Subjects Enhanced by Cold Activation
Authors: Chen Jinguo , Wu Yunkou , Chiao Joseph , Yu J. Joanna , Yu Jing , Scarupa Mark D. , Wan Lili , Li H. Henry
Published: December 2024

Background

Bradykinin (BK) is a key mediator responsible for swelling episodes in hereditary angioedema due to C1INH deficiency/dysfunction (HAE-C1INH). Current BK measurement faces many challenges primarily related to very low levels and instability, and is not feasible for application in clinical settings.

Objective

This study aimed to develop a novel method to overcome the issues in current protease inhibitor-based methods for measuring endogenous BK and its metabolites.

Methods

The blood from HAE-C1INH and healthy volunteers were collected and subjected to cold activation for contact system. Cold-induced BK and its major metabolites were measured via Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). The protocol was established according to the US FDA bioanalytical validation guidelines as a CLIA laboratory-developed test. The BK measurement was optimized based on blood sample types, collection methods, time windows, and temperature/storage conditions.

Results

EDTA whole blood samples without protease inhibitors incubated at 4 degree for 1 to 3 days produced over 100-fold differences in total BK levels between HAE-C1INH subjects and healthy volunteers (324.3 +/- 54.7 ng/mL, n=33; vs 2.3 +/- 0.3 ng/mL, n = 43; mean +/- S.E.M., p < 0.001). The sensitivity and specificity were 90.9% and 97.1% respectively. BK levels highly correlated with the plasma kallikrein activity in the same samples.

Conclusions

Whole blood under cold activation demonstrated remarkable elevation of BK levels in HAE-C1INH subjects, while minimally affecting healthy individuals. The assay has validated accuracy, precision and stability. It may serve as a reliable and robust tool for HAE diagnosis and management.

Clinical Implication

Cold-induced Bradykinin measurement can be used as a new biomarker for diagnosis, disease monitoring and guiding therapeutic options for HAE-C1INH and other bradykinin-mediated angioedema (AE-BK), with or without identifiable genetic mutations.
Thoracic Aorta Measurement Extraction from Computed Tomography Radiology Reports Using Instruction Tuned Large Language Models
Authors: Erez Ely , Dankwa Sedem , Tuttle McKenzie , Nasir Afsheen , Vallabhajosyula Prashanth , Schneider Eric B. , Assi Roland , Ong Chin Siang
Published: December 2024

Chest computed tomography (CT) is essential for diagnosing and monitoring thoracic aortic dilations and aneurysms, conditions that place patients at risk of complications such as aortic dissection and rupture. However, aortic measurements in chest CT radiology reports are often embedded in free-text formats, limiting their accessibility for clinical care, quality improvement and research purposes. In this study, we developed a multi-method pipeline to extract structured aortic measurements from radiology reports, and compared the performance of fine-tuned BERT-based models with instruction-tuned Llama large language models (LLMs). Applying the best-performing method to a real-world large chest CT radiology report database, we generated a comprehensive aortic measurement dataset that facilitates big data aortic disease research.
Measuring arterial tortuosity in the cerebrovascular system using Time-of-Flight MRI
Authors: Pan Yiyan , Kahru Kevin , Barinas-Mitchell Emma , Ibrahim Tamer S. , Andreescu Carmen , Karim Helmet
Published: December 2024

The Circle of Willis (CW) is a critical cerebrovascular structure that supports collateral blood flow to maintain brain perfusion and compensate for eventual occlusions. Increased tortuosity of highrisk vessels within the CW has been implicated as a marker in the progression of cerebrovascular diseases especially in structures like the internal carotid artery (ICA). This is partly due to age-related plaque deposition or arterial stiffening. Producing reliable tortuosity measurements for vessels segmented from magnetic resonance (MR) time-of-flight (TOF) images requires precise curvature estimation, but existent methods struggle with noisy or sparse segmentation data. We introduce an open-source, end-to-end pipeline that uses unit-speed spline fitting for accurate curvature estimation, generating robust curvature-based tortuosity metrics for the ICA combined with an indicator of spline fit quality. We test this with theoretical data and apply this method to TOF data from 22 participants. We report that our metrics are able to capture tortuosity even under heightened noise constraints and discriminate different types of abnormal arterial coiling. We found that our ICA tortuosity measures correlate positively with age and ultrasound measured carotid artery intima media thickness. This ultimately has important translational implications for being able to reliably generate TOF tortuosity measures and estimate cerebrovascular disease burden. We provide open-source code in a GitHub repository.
A single cell and spatial genomics atlas of human skin fibroblasts in health and disease
Authors: Steele Lloyd , Admane Chloe , Chakala Keerthi Priya , Foster April , Gopee Nusayhah Hudaa , Koplev Simon , Mazin Pasha , Olabi Bayanne , Roberts Kenny , Tudor Catherine , Winheim Elena , Annusver Karl , Correa-Gallegos Donovan , Forsthuber Agnes , Francis Luc , Frech Sophie , Ganier Clarisse , Layton Thomas , Liu Yingzi , Yuan Hao , Gudjonsson Johann E. , Lichtenberger Beate M. , Mahil Satveer , Nanchahal Jagdeep , O’Toole Edel A , Plikus Maksim , Rinkevich Yuval , Rognoni Emanuel , Smith Catherine , Teichmann Sarah A , Kasper Maria , Lotfollahi Mohammad , Haniffa Muzlifah
Published: December 2024

Fibroblasts are critical cells that shape the architecture and cellular ecosystems in multiple tissues. Understanding fibroblast heterogeneity and their spatial context in health and disease has enormous clinical relevance. In this study, we constructed a spatially-resolved atlas of human skin fibroblasts from healthy skin and 23 skin disorders. We define 6 major skin fibroblast populations in health and a further three skin disease-specific fibroblast subtypes, and demonstrate the fibroblast composition in different types of skin disease. We characterise a human-specific fibroblastic reticular cell (FRC)-like subtype in the skin perivascular niche and postulate their origin from prenatal skin lymphoid tissue organiser (LTo)-like cells. We also show that inflammatory myofibroblasts (IL11+MMP1+CXCL5+IL7R+) are a conserved fibroblast subtype in inflammatory disorders and cancers across multiple human tissues. We provide a harmonised nomenclature for skin fibroblasts that integrates previous findings from human skin and other tissues.
FAIRSCAPE: An Evolving AI-readiness Framework for Biomedical Research
Authors: Al Manir Sadnan , Levinson Maxwell Adam , Niestroy Justin , Churas Christopher , Parker Jillian A. , Clark Timothy
Published: December 2024

Motivation

Artificial intelligence (AI) applications require explainability (XAI) for FAIR, ethical deployment, whether in the clinic or in the laboratory. Richly descriptive XAI metadata representing how pre-model data were obtained, characterized, transformed, and distributed, should be available along with the data prior to training and application of AI models.

Results

The FAIRSCAPE framework generates, packages, and integrates critical pre-model XAI descriptive metadata, including deep provenance graphs and data dictionaries with feature validation on uploaded data, software, and computations, with special reference to biomedical datasets. It provides ethical and semantic characterization of the dataset along with licensing and availability information, and integrates seamlessly with NIH-recommended generalist repositories. The server is cloud-compliant and implemented in Python3. Client software in Python3 is callable from the command line or directly as python functions. We provide a REST API, and a GUI-based client in javascript is also available.

Availability and implementation

The code is freely available under MIT license and is hosted athttps://fairscape.github.io/, along with comprehensive documentation and tutorials.
WASp activity in macrophages prevents mechano-induced inflammation by protecting the nuclear envelope
Authors: Amadio Roberto , Bracchetti Giulia , Alraies Zahraa , Piperno Giulia Maria , Rodriguez Lucia Lopez , Maurin Mathieu , Conti Martina , Andolfi Laura , Castiello Maria Carmina , Ferrua Francesca , Villa Anna , Aiuti Alessandro , Lennon-Dumenil Ana-Maria , Benvenuti Federica
Published: December 2024

Mutations in the immune-specific actin regulator WASp induce a proinflammatory state in myeloid cells, whose underlying causes remain poorly defined. Here, we applied microfabricated tools that mimic tissue mechanical forces to explore the role of WASp in connecting mechano-sensing to the activation of inflammatory responses in macrophages. We show that WASp-deficient macrophages carry alterations in nuclear structure and undergo increased blebbing and nuclear rupture when exposed to mechanical confinement. High-resolution imaging indicates that WASp drives the formation of protective perinuclear actin structures in response to confinement. Functionally, a proinflammatory gene signature linked to nuclear envelope rupture is preferentially active in confined WASp null macrophages, which partially depends on the cGAS-STING pathway of cytosolic DNA sensing. Analysis of transcriptional datasets of human and mouse tissue macrophages confirmed elevated inflammatory activation in WASp null cells. Together, these data uncover that WASp restricts pro-inflammatory activation of macrophages by preserving nuclear integrity in confined environments, providing novel clues to understand inflammatory activation in Wiskott-Aldrich Syndrome.
YDS-Ternoplex: Surpassing AlphaFold 3-Type Models for Molecular Glue-Mediated Ternary Complex Prediction
Authors:   The Statistical Mechanics Inference Team, Che Xing
Published: December 2024

Molecular glues represent an innovative class of drugs that enable previously impossible protein-protein interactions, but their rational design remains challenging, a problem that accurate ternary complex modeling can significantly address. Here we present YDS-Ternoplex, a novel computational approach that enhances AlphaFold 3-type models by incorporating enhanced sampling inductive bias during inference to accurately predict molecular glue-mediated ternary complex structures. We demonstrate YDS-Ternoplex’s capabilities across seven diverse test cases, including both E3 ligase-based systems (VHL:CDO1 and CRBN complexes with mTOR-FRB, NEK7, and VAV1-SH3c) and non-E3 ligase complexes (FKBP12 complexes with mTOR-FRB, BRD9 and QDPR). The model achieves remarkable accuracy with RMSD values as low as 1.303 Å compared to experimental structures and successfully predicts novel protein-protein interfaces not present in training data. Notably, in the FKBP12:mTOR-FRB case, YDS-Ternoplex correctly predicts a novel interface configuration instead of defaulting to known interactions present in training data, demonstrating strong generalization capabilities. Our results suggest that strategic enhancement of the inference process through inductive bias can significantly improve ternary complex prediction accuracy, potentially accelerating the development of molecular glue therapeutics for previously undruggable targets.
Biology exams rarely use visual models to engage higher-order cognitive skills
Authors: Uminski Crystal , Cammarota Christian , Couch Brian A. , Wright L. Kate , Newman Dina L.
Published: December 2024

Visual models are a necessary part of molecular biology education because submicroscopic compounds and processes cannot be directly observed. Accurately interpreting the biological information conveyed by the shapes and symbols in these visual models requires engaging visual literacy skills. For students to develop expertise in molecular biology visual literacy, they need to have structured experiences using and creating visual models, but there is little evidence to gauge how often undergraduate biology students are provided such opportunities. To investigate students’ visual literacy experiences, we surveyed 66 instructors who taught lower division undergraduate biology courses with a focus on molecular biology concepts. We collected self-reported data about the frequency with which the instructors teach with visual models and we analyzed course exams to determine how instructors incorporated visual models into their assessments. We found that most instructors reported teaching with models in their courses, yet only 16% of exam items in the sample contained a visual model. There was not a statistically significant relationship between instructors’ self-reported frequency of teaching with models and extent to which their exams contained models, signaling a potential mismatch between teaching and assessment practices. Although exam items containing models have the potential to elicit higher-order cognitive skills through model-based reasoning, we found that when instructors included visual models in their exams the majority of the items only targeted the lower-order cognitive skills of Bloom’s Taxonomy. Together, our findings highlight that despite the importance of visual models in molecular biology, students may not often have opportunities to demonstrate their understanding of these models on assessments.
Assessment of Contralateral Efferent Effects in HumanViaECochG
Authors: Verschooten Eric , Strickland Elizabeth A. , Verhaert Nicolas , Joris Philip X.
Published: December 2024

Efferent projections from the brainstem to the inner ear are well-described anatomically and physiologically but their precise function remains debated. The medial olivocochlear (MOC) system and its reflex, the MOCR, have been particularly well studied. In animals, anatomical and physiological data are fine-grained and extensive and suggest an important role for the MOCR in anti-masking e.g. to improve the detection of tones in background noise. Extensive behavioral studies in human support this role, but direct linking of behavioral paradigms to the MOCR is challenging because of the difficulty in obtaining appropriate human neural measures. We developed a new approach in which mass potentials were recorded near the cochlea of normal hearing and awake human volunteers to increase the signal-to-noise (SNR) ratio, and examined whether broadband noise to the contralateral ear elicited MOCR anti-masking effects as reported in animals. Probing the mass potential to the onset of brief tones at 4 and 6 kHz, convincing anti-masking or suppressive effects consistent with the MOCR were not detected. We then changed the recording technique to examine the neural phase-locked contribution to the mass potential in response to long, low-frequency tones, and found that contralateral sound suppressed neural responses in a systematic and progressive manner. We followed up with psychophysical experiments in which we found that contralateral noise elevated detection threshold for tones up to 4 kHz. Our study provides a new way to study efferent effects in the human peripheral auditory system and shows that contralateral efferent effects are biased towards low frequencies.
Inhibition of PDE5 induces rapid non-genomic increase in hippocampal dendritic spines via specific kinases
Authors: Soma Mika , Ogiue-Ikeda Mari , Horie Shigeo , Saito Minoru , Ishii Hirotaka , Kawato Suguru
Published: December 2024

Abstract

Cyclic guanosine monophosphate (cGMP) is a typical neuromodulator that is used in neuronal synapses. Inhibitor of phosphodiesterase 5 (PDE5) could regulates signaling pathways by elevating cGMP levels.

In the current study, we found that the treatments with tadalafil, a PDE5 inhibitor, for 2 h rapidly and non-genomically increased the total density of dendritic spines, using confocal imaging of Lucifer Yellow-injected hippocampal CA1 pyramidal neurons. Since inhibition of PDE5 elevates cGMP levels at synapses, we analyzed downstream nongenomic signaling. We analyzed the involvement of kinase signaling, because rapid postsynaptic modulation involves kinase networks observed from many investigations including our works.

Upon co-treatments of PKG inhibitor (KT5823) with tadalafil, the spine increase was considerably blocked. In addition, co-treatments of GSK-3 inhibitor (I8) also blocked the spine increase induced by tadalafil. However, inhibitors of other representative synaptic kinases, including LIMK, Erk/MAPK, PKA, PKC and PI3K, did not suppress the tadalafil-induced spine increases.

PDE5 inhibitors have attracted attention on their recovery effects from pathological damages, including memory improvement from cognitive impairment by Stroke, Amyloid β (Aβ) accumulation and tau phosphorylation. The current finding of tadalafil’s function about rapid modulation of neural plasticity may add new elemental steps of anti-aging capacity against cognitive decline.
DUAL SECRETORY VESICLES CLUSTERING AND DYNAMICS DURING POLAR CELL ELONGATION IN THE PHYTOPATHOGENIC FUNGUSBOTRYTIS CINEREA
Authors: Hamandjian Adrien , Calvar Glen , Blandenet Matthieu , Crumière Mélanie , Poussereau Nathalie , Choquer Mathias , Bruel Christophe
Published: December 2024

Filamentous fungi grow through a process of polar elongation that is supported by secretory vesicles. These vesicles provide lipids to extend the plasma membrane and, among others, enzymes to synthesize the cell wall. We used confocal microscopy to locate and analyze the dynamics of secretory vesicles transporting a fluorescent chitin synthase CHSIIIa in the plant pathogenBotrytis cinerea. Two populations of growing hyphae were identified, one exhibiting a typical spheroidal spitzenkörper at the apex, the other one with vesicles forming a crescent instead. Neither curvature of the apex nor hyphal width significantly differ between the two populations. Mean hyphal elongation was also no different between the two populations, with two co-existing patterns of pronounced and less pronounced stepwise extensions. In contrast the growing spitzenkörper-hyphae displayed repetitive fluctuations in fluorescence intensity at the apex that were not detected in the crescent-hyphae. Using Fast Fourier Transform, these fluctuations were found periodic, and a single oscillator was determined that could explain the experimental data.
Dissecting the evolving cellular landscape of a remyelinating microenvironment
Authors: Melchor George S. , Baydyuk Maryna , Manavi Zeeba , Hu Jingwen , Huang Jeffrey K.
Published: December 2024

Demyelination, or the loss of myelin in the central nervous system (CNS) is a hallmark of multiple sclerosis (MS) and occurs in various forms of CNS injury and neurodegenerative diseases. The regeneration of myelin, or remyelination, occurs spontaneously following demyelination. The lysophosphatidylcholine (LPC)-induced focal demyelination model enables investigations into the mechanisms of remyelination, providing insight into the molecular basis underlying an evolving remyelinating microenvironment over a tractable time course. Here, we present a detailed analysis using high-resolution single nucleus RNA sequencing to investigate gene expression dynamics across multiple cell populations involved in the remyelination process. We examine three specific time points following focal demyelinating injury in mice, and by delineating activation states within the heterogeneous cell populations of demyelinated lesions, we highlight changes in gene expression within subclusters of each cell population from the early stages of injury response to the initiation and maintenance of remyelination. Our findings reveal how shifts in microglial, astrocytic and fibroblast activities within lesions are associated with efficient oligodendrocyte differentiation during remyelination.