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The association of clinical, treatment, and demographic characteristics with rearrest in a national dataset

RESUSCITATION 2024年 196卷 110135-110135页

作者： Suchko, Sarah Smida, Tanner Crowe, Remle P. Menegazzi, James J. Scheidler, James F. Shukis, Michael Martin, P. S. Bardes, James M. Salcido, David D. Univ Pittsburgh Sch Med Dept Emergency Med Pittsburgh PA USA West Virginia Univ MD PhD Program Morgantown WV 26506 USA ESO Inc Austin TX USA West Virginia Univ Dept Emergency Med Div Prehosp Med Morgantown WV USA

Introduction: Following initial resuscitation from out-of-hospital cardiac arrest, rearrest frequently occurs and has been associated with adverse outcomes. We aimed to identify clinical, treatment, and demographic characteristics associated with prehospital rearrest at the encounter and agency levels. Methods: Adult non-traumatic cardiac arrest patients who achieved ROSC following EMS resuscitation in the 2018-2021 ESO annual datasets were included in this study. Patients were excluded if they had a documented DNR/POLST or achieved ROSC after bystander CPR only. Rearrest was defined as post-ROSC CPR initiation, administration of >= 1 milligram of adrenaline, defibrillation, or a documented non-perfusing rhythm on arrival at the receiving hospital. Multivariable logistic regression modeling was used to evaluate the association between rearrest and case characteristics. Linear regression modeling was used to evaluate the association between agency-level factors (ROSC rate, scene time, and scene termination rate), and rearrest rate. Results: Among the 53,027 cases included, 16,116 (30.4%) experienced rearrest. Factors including longer response intervals, longer 'low-flow' intervals, unwitnessed OHCA, and a lack of bystander CPR were associated with rearrest. Among agencies that treated >= 30 patients with outcome data, the agency-level rate of rearrest was inversely associated with agency-level rate of survival to discharge to home (R-2 = -0.393, p < 0.001). Conclusions: This multiagency retrospective study found that factors associated with increased ischaemic burden following OHCA were associated with rearrest. Agency-level rearrest frequency was inversely associated with agency-level survival to home. Interventions that decrease the burden of ischemia sustained by OHCA patients may decrease the rate of rearrest and increase survival.

关键词： Rearrest Post ROSC Post resuscitation Antiarrhythmic System factors Outcome

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Molecular targets and strategies in the development of nucleic acid cancer vaccines: from shared to personalized antigens

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JOURNAL OF BIOMEDICAL SCIENCE 2024年第1期31卷 1-26页

作者： Chi, Wei-Yu Hu, Yingying Huang, Hsin-Che Kuo, Hui-Hsuan Lin, Shu-Hong Kuo, Chun-Tien Jimmy Tao, Julia Fan, Darrell Huang, Yi-Min Wu, Annie A. Hung, Chien-Fu Wu, T. -C Weill Cornell Med Physiol Biophys & Syst Biol Grad Program New York NY USA Mem Sloan Kettering Canc Ctr Triinst PhD Program Chem Biol New York NY USA Weill Cornell Med Pharmacol PhD Program New York NY USA Univ Texas MD Anderson Canc Ctr Dept Epidemiol Houston TX USA Univ Texas Houston Grad Sch Biomed Sci Houston TX USA MD Anderson Canc Ctr Houston TX USA Ohio State Univ Coll Pharm Div Pharmaceut & Pharmacol Columbus OH USA Johns Hopkins Sch Med Dept Pathol 1550 Orleans StCRB 2Room 309 Baltimore MD 21287 USA Johns Hopkins Sch Med Dept Oncol Baltimore MD 21287 USA Johns Hopkins Sch Med Dept Obstet & Gynecol Baltimore MD 21287 USA Johns Hopkins Bloomberg Sch Publ Hlth Dept Mol Microbiol & Immunol Baltimore MD 21205 USA

Recent breakthroughs in cancer immunotherapies have emphasized the importance of harnessing the immune system for treating cancer. Vaccines, which have traditionally been used to promote protective immunity against pathogens, are now being explored as a method to target cancer neoantigens. Over the past few years, extensive preclinical research and more than a hundred clinical trials have been dedicated to investigating various approaches to neoantigen discovery and vaccine formulations, encouraging development of personalized medicine. Nucleic acids (DNA and mRNA) have become particularly promising platform for the development of these cancer immunotherapies. This shift towards nucleic acid-based personalized vaccines has been facilitated by advancements in molecular techniques for identifying neoantigens, antigen prediction methodologies, and the development of new vaccine platforms. Generating these personalized vaccines involves a comprehensive pipeline that includes sequencing of patient tumor samples, data analysis for antigen prediction, and tailored vaccine manufacturing. In this review, we will discuss the various shared and personalized antigens used for cancer vaccine development and introduce strategies for identifying neoantigens through the characterization of gene mutation, transcription, translation and post translational modifications associated with oncogenesis. In addition, we will focus on the most up-to-date nucleic acid vaccine platforms, discuss the limitations of cancer vaccines as well as provide potential solutions, and raise key clinical and technical considerations in vaccine development.

关键词： Cancer vaccine Tumor antigens Neoantigens DNA mRNA Clinical trial

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Mechanism for the initiation of spliceosome disassembly

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NATURE 2024年第8024期632卷 443页

作者： Vorlaender, Matthias K. Rothe, Patricia Kleifeld, Justus Cormack, Eric D. Veleti, Lalitha Riabov-Bassat, Daria Fin, Laura Phillips, Alex W. Cochella, Luisa Plaschka, Clemens Vienna BioCtr VBC Res Inst Mol Pathol IMP Vienna Austria Univ Vienna Doctoral Sch Vienna BioCtr PhD Program Vienna Austria Med Univ Vienna Vienna Austria Johns Hopkins Univ Dept Mol Biol & Genet Sch Med Baltimore MD 21218 USA

Precursor-mRNA (pre-mRNA) splicing requires the assembly, remodelling and disassembly of the multi-megadalton ribonucleoprotein complex called the spliceosome1. Recent studies have shed light on spliceosome assembly and remodelling for catalysis2-6, but the mechanism of disassembly remains unclear. Here we report cryo-electron microscopy structures of nematode and human terminal intron lariat spliceosomes along with biochemical and genetic data. Our results uncover how four disassembly factors and the conserved RNA helicase DHX15 initiate spliceosome disassembly. The disassembly factors probe large inner and outer spliceosome surfaces to detect the release of ligated mRNA. Two of these factors, TFIP11 and C19L1, and three general spliceosome subunits, SYF1, SYF2 and SDE2, then dock and activate DHX15 on the catalytic U6 snRNA to initiate disassembly. U6 therefore controls both the start5 and end of pre-mRNA splicing. Taken together, our results explain the molecular basis of the initiation of canonical spliceosome disassembly and provide a framework to understand general spliceosomal RNA helicase control and the discard of aberrant spliceosomes. Cryo-electron microscopy structures of human and nematode spliceosomes show that the disassembly of this complex is initiated by the licensing of the disassembly helicase to act on the catalytic U6 small nuclear RNA.

关键词： Cryoelectron microscopy RNA splicing

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Carcinogenetic mechanisms employed by the oral microbiome: A narrative review

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AMERICAN JOURNAL OF THE MEDICAL SCIENCES 2025年第5期369卷 556-561页

作者： Menghani, Sanjay, V Univ Arizona Coll Med Tucson Tucson AZ USA Univ Arizona Coll Med Tucson Med Scientist Training MD PhD Program Tucson AZ USA NYU Grossman Sch Med Internal Med New York NY USA

Cancers of the oral cavity, lip, salivary gland, and oropharynx cause substantial global disease burden. While tobacco-use and alcohol use are highly associated with oral cancers, the rising incidence of disease in patients who do not use tobacco or alcohol points to additional carcinogenic risk factors. Chronic inflammation, disruption of the oral microbiome, and dysbiosis are becoming more widely implicated in the pathogenesis of oral cancer. Several studies have identified specific bacterial species enriched in patients with oral cancer, including Porphyromonas gingivalis and Fusobacterium nucleatum. In this narrative review, we describe potential carcinogenic mechanisms exhibited by these species and other microbes in the development of oral cancer.

关键词： Oral microbiome Oral cancer Carcinogenesis Immunology Porphyromonas gingivalis Fusobacterium nucleatum

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Vessel Rupture Thresholds for Vessel-Bubble Interactions Using an Earthworm Vasculature Model

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ULTRASOUND IN MEDICINE AND BIOLOGY 2023年第5期49卷 1108-1117页

作者： Lopez, Asis Osborn, Jenna Irwin, Rachael Khismatullin, Damir B. Clement, Gregory T. Myers, Matthew R. Tulane Univ Biomed Engn Dept Bioinnovat PhD Program New Orleans LA USA US FDA Silver Spring MD 20993 USA George Washington Univ Biomed Engn Dept Washington DC USA Tulane Univ Biomed Engn Dept New Orleans LA USA

Objective: Intravenous microbubble oscillation in the presence of ultrasound has the potential to yield a wide range of therapeutic benefits. However, the likelihood of vessel damage caused by mechanical effects has not been quantified as a function of the numerous important parameters in therapeutic ultrasound procedures. In this study, we examined the effects of microbubbles injected into the vasculature of the earthworm. It was found that the elastic properties of earthworm blood vessels are similar to those of arteries in older humans, and that earth-worms are well suited to the large number of experiments necessary to investigate safety of procedures involving microbubble oscillation in sonicated vessels. Methods: Microbubbles were infused into earthworm vessels, and the rupture time during sonication was recorded as a function of ultrasound frequency, pulse repetition frequency and acoustic pressure. Discussion: A modified mechanical index (MMI) was defined that successfully captured the trends in rupture prob-ability and rupture time for the different parameter values, creating a database of vessel rupture thresholds. In the absence of bubbles, the product of MMI squared and rupture time was approximately constant, indicating a possi-ble radiation-force effect. Conclusion: The MMI was an effective correlating parameter in the presence of bubbles, though the mathematical dependence is not yet apparent. The results of the study are expected to be valuable in designing more refined studies in vertebrate models, as well as informing computational models.

关键词： Microbubbles Contrast agent Microvessels Blood vessel Vascular bio-effects Vessel rupture mechanism Blood -brain barrier Mechanical index Cavitation Therapeutic ultrasound Earthworm

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Protein-based nanoparticles for therapeutic nucleic acid delivery

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BIOMATERIALS 2024年 305卷 122464-122464页

作者： Eweje, Feyisayo Walsh, Michelle L. Ahmad, Kiran Ibrahim, Vanessa Alrefai, Assma Chen, Jiaxuan Chaikof, Elliot L. Harvard Med Sch Beth Israel Deaconess Med Ctr Dept Surg Boston MA 02215 USA MIT Harvard & MIT Div Hlth Sci & Technol Cambridge MA 02139 USA Harvard MIT MD PhD Program Boston MA 02115 USA Harvard Univ Wyss Inst Biol Inspired Engn Boston MA 02115 USA

To realize the full potential of emerging nucleic acid therapies, there is a need for effective delivery agents to transport cargo to cells of interest. Protein materials exhibit several unique properties, including biodegradability, biocompatibility, ease of functionalization via recombinant and chemical modifications, among other features, which establish a promising basis for therapeutic nucleic acid delivery systems. In this review, we highlight progress made in the use of non-viral protein-based nanoparticles for nucleic acid delivery in vitro and in vivo, while elaborating on key physicochemical properties that have enabled the use of these materials for nanoparticle formulation and drug delivery. To conclude, we comment on the prospects and unresolved challenges associated with the translation of protein-based nucleic acid delivery systems for therapeutic applications.

关键词： Drug delivery Gene therapy Recombinant proteins Nanoparticles Polypeptides

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Faster detection of somatic structural variants

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NATURE BIOMEDICAL ENGINEERING 2023年第7期7卷 847-848页

作者： Choo, Zi-Ning Imielinski, Marcin Weill Cornell Med Triinst MD PhD Program New York NY USA New York Genome Ctr New York NY 10013 USA NYU Grossman Sch Med Perlmutter Canc Ctr New York NY 10016 USA

The algorithmic detection of cancer-associated variants can be accelerated by leveraging machine-learning classifiers to filter out reads matched to pan-genome k-mer sets.

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Recycled Translation: Repurposing Drugs for Stroke

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TRANSLATIONAL STROKE RESEARCH 2022年第6期13卷 866-880页

作者： Spellicy, Samantha E. Hess, David C. Augusta Univ Med Coll Georgia Off Acad Affairs MD PhD Program Augusta GA 30912 USA Augusta Univ Med Coll Georgia Deans Off Augusta GA USA

Stroke, which continues to be a leading cause of death and long-term disability worldwide, has often been described as a clinical graveyard. While multiple small molecule therapeutics have undergone clinical trials in stroke, currently only one Food and Drug Administration (FDA)-approved medication exists for the treatment of stroke, the biological, recombinant tissue plasminogen activator (rt-PA). Repurposing of therapeutics which have previously gained FDA approval for alternative indications serves as a prospective option for stroke therapeutic translation. In contrast to de novo drug development, repurposing strategies have patient-centered and economic advantages. These include increased safety, increased chance of approval, decreased time to approval, and decreased capital investment. Presently, 37 active stroke clinical trials utilize repurposed therapeutics with various initial indications and dosing paradigms. The currently studied repurposed therapeutics fall into six mechanistic categories: (1) anticoagulation;(2) vasculature integrity, response, or red blood cell (RBC) alterations;(3) immune system regulation;(4) neurotransmission;and (5) neuroprotection. Directed hypothesis-driven computational investigation utilizing drug databases, in silico drug-protein interaction modeling, genomic data, and consensus methodology can determine if the current mechanistic repurposing categories have the highest chance of translational success or if other mechanistic avenues should be explored. With this increased focus on repurposed therapeutic strategies over de novo strategies, evolution and optimization of regulatory protections are needed to incentivize innovators and investigators.

关键词： Acute ischemic stroke Repurposed therapeutics Recycled therapeutics Clinical trials

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Arrest History and Health Among US Sexual and Gender Minority Youth, 2022

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AMERICAN JOURNAL OF PREVENTIVE MEDICINE 2024年第4期67卷 548-557页

作者： Harvey, Tyler D. Watson, Ryan J. Clark, Kirsty A. Yale Sch Med MD PhD Program 333 Cedar St New Haven CT 06511 USA Univ Connecticut Coll Liberal Arts & Sci Dept Human Dev & Family Sci Storrs CT USA Vanderbilt Univ Coll Arts & Sci Dept Med Hlth & Soc Program Publ Policy Studies Nashville TN USA Vanderbilt Univ Vanderbilt LGBTQ Policy Lab Nashville TN USA

Introduction: Sexual and gender minority youth, who experience high mental and behavioral health needs, are overrepresented in the criminal legal system, which may exacerbate these needs. This study examined the associations between arrest history and mental and behavioral health among sexual and gender minority youth. Methods: Using cross-sectional survey data from the 2022 LGBTQ+ National Teen Survey, this study created a case-control sample of 287 sexual and gender minority youth with an arrest history and 1,148 propensity-matched sexual and gender minority youth without an arrest history. Associations between arrest history and sexual and gender minority developmental milestones, minority stressors, and mental and behavioral health outcomes were examined. Statistical analyses were conducted between 2022 and 2024. Results: Arrest history was significantly associated with several sexual and gender minority developmental milestones (e.g., earlier age of identity realization and disclosure) and minority stressors (e.g., greater bullying and parental rejection). Sexual and gender minority youth with an arrest history had poorer mental and behavioral health, including greater sleep disturbance (AOR=1.46;95% CI=1.08, 2.00) and positive screenings for depression (AOR=1.60;95% CI=1.20, 2.14), anxiety (AOR=1.35;95% CI=1.01, 1.82), and risk for substance use disorder development (AOR=5.81;95% CI=4.26, 7.94). Conclusions: Arrest history is associated with the mental and behavioral health of sexual and gender minority youth, highlighting systemic inequities. Tailored public health interventions are needed to reduce criminal-legal contact in this population. (c) 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

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Exercise and Mortality in Heart Disease Cohorts Meta-Analysis to Augment Available Evidence

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 2022年第17期79卷 1701-1703页

作者： Ballantyne, Christie M. Davis, John W. Baylor Coll Med Dept Med Sect Cardiol Houston TX 77030 USA Univ Texas Med Branch MD PhD Combined Degree Program Galveston TX 77555 USA

Corresponding Author

关键词： coronary heart disease exercise lifestyle mortality physical activity survival trajectories

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