bluuebunny/crossref_metadata_2025 huggingface dataset:
Operationalization of Clinical Placements in Graduate Nursing
Authors: Gonzalez John D. , Eckhardt Ann L.
Published: July 2023

Background:

Nurse practitioner (NP) program accreditation standards require that programs secure clinical placements for all students. As NP programs increase enrollment to meet the demand for primary care providers, it is vital that they deploy a formalized clinical placement process that ensures all students have a clinical placement.

Problem:

Although NP programs have consistently increased enrollment, the shortage of clinical sites and preceptors continues to be a barrier to admission.

Approach:

Described in this article is the operationalization of graduate nursing clinical placement at one large university with 7 NP tracks.

Outcomes:

A formalized clinical placement process ensures that all students receive an appropriate placement and graduate on time. Having a dedicated team of NP faculty members to provide clinical placements services for NP students is highly effective.
Engagement Across Professions
Authors: Chipman Micheline L. , Schreiber Christine M. , Fey Jamie M. , Lane Susan J. , DiLisio Chris , Mallory Leah A.
Published: July 2023

Introduction

Simulation is an ideal tool for interprofessional (IP) team training. Debriefing after simulation is key to IP learning, although engagement and participation may be adversely influenced by cultural and hierarchical barriers. This mixed-methods study explored factors influencing learner engagement and participation in IP debriefing and the experience of “silent but apparently engaged” participants.

Methods

Semistructured profession-specific focus groups were conducted with participants from a weekly IP pediatric simulation program. Focus groups were recorded, transcribed, and thematically analyzed. Eligible participants were assigned to “silent” or “verbal” groups according to observed behavior and received a questionnaire. Participants' self-rated engagement scores were compared using a t test.

Results

Thirty-six of 81 eligible participants were included, 13 completed a questionnaire, and 23 (8 physicians, 10 nursing staff, 4 pharmacists, 1 respiratory therapist) participated in 13 focus groups. Twenty-two subthemes were grouped into 6 themes: psychological safety, realism, distractors, stress, group characteristics, and facilitator behavior, with differences in perspective according to profession. Of the 36 respondents, 18 were “silent” and 18 “verbal.” Self-rated engagement scores differed between groups (3.65 vs. 4.17, P = 0.06); however, “silent” participants described themselves as engaged.

Conclusions

Themes identified that influenced learner engagement in debriefing included aspects of prebriefing and the simulation. Some aligned with general simulation best practices, such as psychological safety, prebriefing, and facilitator behavior. Findings unique to IP simulation included importance of realism to nonphysician professions, protecting time for training, group composition, and direct probing by cofacilitators to decrease physician bias and emphasize IP contributions. Silent participants reported engagement.
Damage control surgery in emergency general surgery: What you need to know
Authors: Risinger William B. , Smith Jason W.
Published: July 2023

Damage-control surgery (DCS) is a strategy adopted to limit initial operative interventions in the unstable surgical patient, delaying definitive repairs and abdominal wall closure until physiologic parameters have improved. Although this concept of “physiology over anatomy” was initially described in the management of severely injured trauma patients, the approaches of DCS have become common in the management of nontraumatic intra-abdominal emergencies.

While the utilization of damage-control methods in emergency general surgery (EGS) is controversial, numerous studies have demonstrated improved outcomes, making DCS an essential technique for all acute care surgeons. Following a brief history of DCS and its indications in the EGS patient, the phases of DCS will be discussed including an in-depth review of preoperative resuscitation, techniques for intra-abdominal source control, temporary abdominal closure, intensive care unit (ICU) management of the open abdomen, and strategies to improve abdominal wall closure.
Curriculum in Neuro-Ophthalmic Principles for National Football League Game Officials: Comparison of Pretraining and Posttraining Ratings of Knowledge
Authors: Vogt Ashtyn Z. , Woodland Matthew Brent , Carter Michael J. , Lee Andrew G.
Published: July 2023

Background:

We hypothesize that creation of a structured curriculum in neuro-ophthalmology principles might improve self-rated learner satisfaction and knowledge base of National Football League (NFL) game officials. Our initial objective is to create the said curriculum in coordination with game official experts and staff at the NFL to increase levels of understanding of neuro-ophthalmology principles. We reviewed the prior published literature on applicable neuro-ophthalmic principles in professional sports. Major neuro-ophthalmic principles reviewed include both the efferent (e.g., saccadic and pursuit eye movements and vestibulo-ocular reflex) and afferent (visual field, dynamic visual acuity during body movement, and selective attention deficits).

Methods:

A 6-question survey pertaining to levels of understanding, future applicability, relevance, satisfaction, and interest in additional training was then given to 26 individuals before and after a lecture given by Dr. Andrew Lee in Plano, TX. The primary outcome measure was the creation of the curriculum followed by real-world testing for face and content validity and ending with a self-rated assessment.

Results:

Twenty-one individuals completed the prelecture and postlecture survey out of 26 individuals who attended. Prelecture means for the level of understanding of oculomotor terms and the likelihood of using said terms were 3.4 and 3.2, respectively. Postlecture means were 8.9 and 8.8, respectively. The lecture was rated 9.2 of 10 for relevance to coaching and teaching officials, and individuals rated their interest in further content as 9.4 of 10.

Conclusions:

This study found that NFL game officials are interested in learning more about the science behind play-calling in terms of neuro-ophthalmology principles and practices. In addition, from our pilot survey, it is evident that even one lecture can improve participants' level of understanding and likelihood of learning more about neuro-ophthalmic principles.
The Effect of Different Optic Nerve Sheath Diameter Measurements Using Ultrasound to Assess Intracranial Pressure in Patients With Acute Brain Injury
Authors: Tian Jun , Wu Guo-Biao , Liu Xiao-Bing , Wang Zhi-Yong , Guo Jian-Ying
Published: July 2023

Background:

Optic nerve sheath diameter (ONSD) is a promising, noninvasive invasive intracranial pressure (ICP) measurement method. This study aims to analyze the differences in ONSD between the left and right eyeballs and the differences in ultrasonic measurement between the transverse and sagittal planes.

Methods:

Data from a total of 50 eligible patients with various types of brain injury who were admitted to our hospital from May 2019 to June 2021 were analyzed. An ONSD assessment was then performed using Philips B-mode ultrasound, measuring ONSD 3 mm posterior to the eyeballs. The left and right ONSDs in the transverse and sagittal planes were measured. Intraparenchymal fiber optic sensors and catheters were inserted into the ventricles and connected to an external pressure transducer to measure ICP.

Results:

A total of 164 sonographic measurements of ONSD were performed in 50 patients with brain injury in a prospective observational study. Statistically significant differences were found in ONSD between the transverse and sagittal planes. The difference in the left ONSD between the transverse and sagittal planes was 0.007 ± 0.030 cm (P = 0.003). The Spearman rank correlation test showed that the correlation coefficient between ICP and left/right ONSD in the transverse/sagittal planes was 0.495 vs 0.546 and 0.559 vs 0.605, respectively. The results showed that the areas under the curve of ONSD in the transverse and sagittal planes were 0.843 and 0.805, respectively. Medcalc software was used to compare the areas under the receiver operator characteristic curve, and the results showed that ONSD in the sagittal plane is generally better than in the transverse plane (P = 0.0145).

Conclusions:

This study found that ONSD in the sagittal plane is superior to the transverse plane regarding the comprehensive efficacy of ICP, and unilateral measurement is sufficient.
Characteristics of Chryseobacterium bacteremia, associated risk factors and their antibiotic susceptibility pattern at a university hospital: a descriptive, retrospective study
Authors: Chaudhary Radhika , Kar Mitra , Jamwal Ashima , Dubey Akanksha , Singh Romya , Tejan Nidhi , Sahu Chinmoy , Patel Sangram Singh , Kumari Pooja , Ghar Malay
Published: July 2023

Abstract
Introduction: Chryseobacterium species are emerging bacteria capable of causing nosocomial infections in immunocompromised patients or patients with indwelling medical devices.
Hypothesis/ Gap statement: Information about the incidence of Chryseobacterium bacteremia from worldwide literature is limited.
Aim: We aimed to recognize the clinical characteristics, frequency of distribution of different Chryseobacterium species isolates, and their antimicrobial susceptibility profile from bloodstream infections. 
Methods: We performed a retrospective cohort study to identify all isolates of Chryseobacterium species from bloodstream infection from January 2018 to November 2022 at a university hospital in North India.
Results: We identified 42 non-duplicate isolates of Chryseobacterium species from bloodstream infection in the duration of our study. Mean age of the patients was 48.35 ± 16.63 years. Men (22/42, 52.2%) were more commonly affected in comparison to women (20/42, 47.6%) but the difference was not significant. The most common species identified was C.indologenes (40/42, 95.24%) followed by C. gleum (2/42, 4.76%). The co-morbidities commonly encountered in our study were chronic kidney disease (21/42, 50.0%) followed by diabetes mellitus (12/42, 28.6%) and chronic obstructive pulmonary disease (8/42, 19.05%). All patients had intravenous access to medications or fluid management via a central or peripheral line and mechanical ventilation was observed in 39 (39/42, 92.86%) patients. All the isolates were susceptible to minocycline (100%), followed by doxycycline (97.6%) and trimethoprim-sulfamethoxazole (95.2%).
Conclusion: Chryseobacterium species are capable of causing pneumonia, bacteremia and urinary tract infection in immunocompromised patients. Early diagnosis and prompt treatment with appropriate antibiotics can prevent progression to septicemia.
A knowledge, attitude and practices study on malaria in Kandhamal district, Odisha
Authors: Mohan Indumathi , Das Meenaketan , James Meenu Mariya , Dixit Rashi , Behera Sujit Kumar , Dhangadamajhi Gunanidhi , Kodali Prakash Babu , Balasubramani Karuppusamy , Nina Praveen Balabaskaran
Published: July 2023

Malaria is endemic in several tribal-dominated districts in India. Partnering and educating the tribal communities are key to malaria elimination efforts. A Knowledge, Attitude, and Practices (KAP) study was undertaken at Kandhamal, a tribal-dominated malaria endemic district in the state of Odisha, to assess the gaps in malaria awareness in this community for focused public health interventions. To assess the knowledge, attitudes, and practices on malaria in the tribal-dominated regions of Kandhamal district, Odisha. A descriptive KAP survey was carried out in the Kandhamal district at the household level. Three hundred households/respondents from 6 blocks distributed in 44 villages were selected through convenient sampling. Statistical analysis was carried out using SPSS (version 24), and ArcGIS software was used for GIS mapping. The respondents had good knowledge on the major malaria symptoms. Witchcraft, contaminated food/water, and contact with a malaria case were thought to transmit malaria by 5.3%, 14.3%, and 9.7% of respondents, respectively, and these clusters have been mapped by GIS. Logistic regression identified reduced level of education and open source of water supply to have a strong association with the misconceptions regarding malaria among the respondents. Knowledge and attitude regarding malaria were found to be associated with residence in a hilly area and an open source of water supply, respectively. Overall, the participants in Kandhamal had good KAP on malaria. The clusters with poor knowledge could be the target of focused public health interventions
Horizon, closing the gap between cinematic visualization and medical imaging
Authors: Guaje Javier , Koudoro Serge , Garyfallidis Eleftherios
Published: July 2023

Medical imaging has become a fascinating field with detailed visualizations of the body’s internal environments. Although the field has grown fast and is sensitive to new technologies, it does not use the latest rendering techniques available in other domains, such as day-to-day movie production or game development. In this work, we bring forward Horizon, a new engine that provides cinematic rendering capabilities in real-time for quality controlling medical data. In addition, Horizon is provided as free, open-source software to be used as a foundation stone for building the next generation of medical imaging applications. In this introductory paper, we focus on the extensive development of advanced shaders, which can be used to highlight untapped features of the data and allow fast interaction with machine learning algorithms. In addition, Horizon provides physically-based rendering capabilities, the epitome of advanced visualization, adapted for the needs of medical imaging analysis practices.
Meteorological Influence on Atrial Fibrillation and Flutter, A Nationwide Observational Study
Authors: Kim Andrew Geunwon , Park Chanjoo , Tokavanich Nithi , Sabanci Rand , Freel Rebeccah , Hayes Victoria , Thakur Ranjan
Published: July 2023

Background

The impact of meteorological factors, including atmospheric temperature, humidity, wind speed, and others, on the incidence of atrial fibrillation and flutter (AF) has been the subject of several studies, but the findings have been inconsistent. Given the complex and multifaceted nature of this relationship, a larger-scale study was necessary to provide sufficient statistical power and elucidate potential associations between them.

Methods

The South Korean government provides open access to national health insurance and weather data for its more than 50 million citizens from January 2010 to July 2022. The national health insurance data includes the monthly number of patients diagnosed with a specific condition, reflecting the incidence and prevalence of the condition. Pearson correlation analyses were performed using the statistical analysis software SAS for Academics to examine the association between each month’s national average climate data and the number of patients diagnosed with AF.

Results

The number of patients diagnosed with AF in the total population showed a statistically significant correlation only with average wind speed (r=-0.42, 95% CI -0.55 to -0.28, p<0.001) and sunshine duration (r=0.27, 95% CI 0.12 to 0.41, p<0.001). Among females aged 20 to 24 years, there was a statistically significant association with other variables, including average temperature, precipitation, humidity, and atmospheric pressure (p<0.05). Diurnal temperature variation showed inconsistent associations across different age and sex groups.

Conclusions

The number of patients diagnosed with AF is negatively correlated with average wind speed and positively correlated with sunshine duration in the general population, particularly among the elderly. There was no significant association between the number of patients diagnosed with AF and average temperature, precipitation, or humidity, except for females aged 20 to 24 years, who exhibited a significant association with these variables. However, it is important to note that these correlations do not establish causality.
Ten Years of Using Key Characteristics of Human Carcinogens to Organize and Evaluate Mechanistic Evidence in IARC Monographs on the Identification of Carcinogenic Hazards to Humans: Patterns and Associations
Authors: Rusyn Ivan , Wright Fred A.
Published: July 2023

Systematic review and evaluation of the mechanistic evidence only recently been instituted in cancer hazard identification step of decision-making. One example of organizing and evaluating mechanistic evidence is the Key Characteristics approach of the International Agency for Research on Cancer (IARC) Monographs on the Identification of Carcinogenic Hazards to Humans. The Key Characteristics of Human Carcinogens were proposed almost 10 years ago and have been used in every IARC Monograph since 2015. We investigated the patterns and associations in the use of Key Characteristics by the independent expert Working Groups. We examined 19 Monographs (2015-2022) that evaluated 73 agents. We extracted information on the conclusions by each Working Group on the strength of evidence for agent-Key Characteristic combinations, data types that were available for decisions, and the role mechanistic data played in the final cancer hazard classification. We conducted both descriptive and association analyses within and across data types. We found that IARC Working Groups were cautious when evaluating mechanistic evidence: for only ∼13% of the agents was strong evidence assigned for any Key Characteristic. Genotoxicity and cell proliferation were most data-rich, while little evidence was available for DNA repair and immortalization Key Characteristics. Analysis of the associations among Key Characteristics revealed that only chemical’s metabolic activation was significantly co-occurring with genotoxicity and cell proliferation/death. Evidence from exposed humans was limited, while mechanistic evidence from rodent studiesin vivowas often available. Only genotoxicity and cell proliferation/death were strongly associated with decisions on whether mechanistic data was impactful on the final cancer hazard classification. The practice of using the Key Characteristics approach is now well-established at IARC Monographs and other government agencies and the analyses presented herein will inform the future use of mechanistic evidence in regulatory decision-making.
Spectral phasor plot for hyperspectral imaging of acridine orange photophysics within the cell
Authors: Díaz Marcela , Zolessi Flavio R. , Malacrida Leonel
Published: July 2023

Acridine Orange (AO) has rich photophysics that has been exploited to study its interaction with RNA and DNA. Traditionally AO was used to stain cells differentiating nucleus and cytoplasm due to the differences in DNA and RNA differential composition. AO cell labeling shows complex behavior depending on several parameters, such as concentration, pH, etc. Such complex photophysics will benefit from a model-free analysis such as the spectral phasor (SP) for hyperspectral imaging. The SP linear combination and reciprocity principles allow us to understand better the AO spectral shift associated with its exploration of the different molecular environments in cells. Using this approach, we identified the SP fingerprints for RNA and DNA for in vitro experiments, which remain invariant for fixed and live cells. However, the SP analysis of the AO fluorescence from live cells shows the occurrence of a third spectral component at 640 nm. The linear properties of the SP analysis enable quantification of the AO bound to RNA, DNA, and a third component. By co-labeling with AO and LysoTracker, we associated part of these subcellular structures with acidic compartments. Nonetheless, we could differentiate AO self-interactions from its binding to RNA within cytoplasmic compartments by use of the SP analysis. This work establishes the use of SP for hyperspectral imaging of AO for the first time, expanding our knowledge of its complex photophysics and promoting further application for in vivo cell imaging.
Combination-Based Drug Screening for Induced Oligodendrocyte Differentiation Enables Mechanistic Insight and Identifies Optimal Drug Pairs for Remyelination
Authors: Beyer Brittney A. , Sul Amanda , Gillen Miller Jared T. , Neumann Björn , Plaisted Warren C. , Kondo Toru , Franklin Robin J.M. , Lairson Luke L.
Published: July 2023

Remyelination-promoting agents have significant potential utility as therapies for the treatment of demyelinating diseases, including multiple sclerosis. Clemastine and bexarotene have recently been evaluated in Phase II clinical trials to evaluate their potential in this context, with evidence for drug-induced remyelination being observed in both trials. Efficacy levels for both agents as monotherapies, as well as dose-limiting toxicities, highlight the need for more effective approaches. Additionally, questions about the relevance of M1R as the target of clemastine, and also around a mechanism involving accumulation of 8,9-unsaturated sterols, remain. Here, we have identified potent alternatives to clemastine (i.e., doxepin and orphenadrine), which are predicted to have superior tolerability and efficacy profiles and provide mechanistic insight related to M1R, and have completed pairwise drug combination screens using diverse classes of OPC differentiation-inducing agents. Vitamin D receptor agonists were found to enhance M1R antagonist-induced OL differentiation. Select compounds implicated in 8,9-unsaturated sterol accumulation synergistically enhanced the activity of bexarotene in OPCs, which resulted in insights that implicate a critical role for liver-X-receptor in the mechanisms of both sterol-dependent and bexarotene-induced remyelination.
Simulations of sequence evolution: how (un)realistic they are and why
Authors: Trost Johanna , Haag Julia , Höhler Dimitri , Jacob Laurent , Stamatakis Alexandros , Boussau Bastien
Published: July 2023

Motivation

Simulating Multiple Sequence Alignments (MSAs) using probabilistic models of sequence evolution plays an important role in the evaluation of phylogenetic inference tools, and is crucial to the development of novel learning-based approaches for phylogenetic reconstruction, for instance, neural networks. These models and the resulting simulated data need to be as realistic as possible to be indicative of the performance of the developed tools on empirical data and to ensure that neural networks trained on simulations perform well on empirical data. Over the years, numerous models of evolution have been published with the goal to represent as faithfully as possible the sequence evolution process and thus simulate empirical-like data. In this study, we simulated DNA and protein MSAs under increasingly complex models of evolution with and without insertion/deletion (indel) events using a state-of-the-art sequence simulator. We assessed their realism by quantifying how accurately supervised learning methods are able to predict whether a given MSA is simulated or empirical.

Results

Our results show that we can distinguish between empirical and simulated MSAs with high accuracy using two distinct and independently developed classification approaches across all tested models of sequence evolution. Our findings suggest that the current state-of-the-art models fail to accurately replicate several aspects of empirical MSAs, including site-wise rates as well as amino acid and nucleotide composition.

Data and Code Availability

All simulated and empirical MSAs, as well as all analysis results, are available athttps://cme.h-its.org/exelixis/material/simulation_study.tar.gz. All scripts required to reproduce our results are available athttps://github.com/tschuelia/SimulationStudyandhttps://github.com/JohannaTrost/seqsharp.

Contact

julia.haag@h-its.org
A framework for modelling desert locust population dynamics and large-scale dispersal
Authors: Retkute Renata , Thurston William , Cressman Keith , Gilligan Christopher A.
Published: July 2023

As climate change leads to new areas being under threat from emerg-ing pests, there is increasing demand for approaches combining mechanistic models and geospatial information. Forecasting based on modelling can in-form surveillance, early warning and management. This paper introduces a novel framework for modelling desert locust population dynamics and migra-tion using knowledge of pest biology, climate and remote sensing data, wind trajectories and desert locust survey data from Locust Hub (FAO). Fur-thermore, we propose an algorithm for forecasting short-term and long-term desert locust migration based on limited reporting data.
PlantConnectome: knowledge graph encompassing >70,000 plant articles
Authors: Lim Shan Chun , Fo Kevin , Sunil Rohan Shawn , Itharajula Manoj , Chuah Yu Song , Foo Herman , Davey Emilia Emmanuelle , Fullwood Melissa , Thibault Guillaume , Mutwil Marek
Published: July 2023

One of the main quests of plant biology is understanding how genes and metabolites work together to form complex networks that drive plant growth, development, and responses to environmental stimuli. However, the ever-growing volume and diversity of scientific literature make it increasingly challenging to stay current with the latest advances in gene function studies. Here, we tackle the challenge by deploying the text-mining capacities of large language models to process over 71,000 plant biology abstracts. Our approach unveiled nearly 5 million functional relationships between a wide array of biological entities—genes, metabolites, tissues, and others—with a high accuracy of over 85%. We encapsulated these findings in PlantConnectome, a user-friendly database, and demonstrated its diverse utility by providing insights into gene regulatory networks, protein-protein interactions, and stress responses. We believe this innovative use of AI in the life sciences will allow plant scientists to keep up to date with the rapidly growing corpus of scientific literature. PlantConnectome is available athttps://plant.connectome.tools/.
Clinical proteomics reveals vulnerabilities in non-invasive breast ductal carcinoma and drives personalized treatment strategies
Authors: Mitsa Georgia , Florianova Livia , Lafleur Josiane , Aguilar-Mahecha Adriana , Zahedi Rene P. , del Rincon Sonia V , Basik Mark , Borchers Christoph H , Batist Gerald
Published: July 2023

Ductal carcinoma in situ (DCIS) is the most common type (80%) of noninvasive breast lesions. The lack of validated prognostic markers, limited patient numbers and variable tissue quality significantly impact diagnosis, risk stratification, patient enrolment, and results of clinical studies. We performed label-free quantitative proteomics on 50 clinical formalin-fixed, paraffin embedded biopsies, validating 22 putative biomarkers from independent genetic studies. Our comprehensive proteomic phenotyping reveals more than 380 differentially expressed proteins and metabolic vulnerabilities, that can inform new therapeutic strategies for DCIS and IDC. Due to the readily druggable nature of proteins and metabolites, this study is of high interest for clinical research and pharmaceutical industry. To further evaluate our findings, and to promote the clinical translation of our study, we developed a highly multiplexed targeted proteomics assay for 90 proteins associated with cancer metabolism, RNA regulation and signature cancer pathways, such as Pi3K/AKT/mTOR and EGFR/RAS/RAF.
Quantification of glutathione with high throughput live-cell imaging
Authors: Qi Xiaoli , Chen Jianwei , Jiang Xiqian , Lu Dong , Yu Xin , Lin Hanfeng , Monroy Erika Y. , Wang Meng C. , Wang Jin
Published: July 2023

Reduction oxidation (redox) reactions are central in life and altered redox state is associated with a spectrum of human diseases. Glutathione (GSH) is the most abundant antioxidant in eukaryotic cells and plays critical roles in maintaining redox homeostasis. Thus, measuring intracellular GSH level is an important method to assess the redox state of organism. The currently available GSH probes are based on irreversible chemical reactions with glutathione and can’t monitor the real-time glutathione dynamics. Our group developed the first reversible reaction based fluorescent probe for glutathione, which can measure glutathione levels at high resolution using a confocal microscope and in the bulk scale with a flow cytometry. Most importantly it can quantitatively monitor the real-time GSH dynamics in living cells. Using the 2ndgeneration of GSH probe, RealThiol (RT), this study measured the GSH level in living Hela cells after treatment with varying concentrations of DL-Buthionine sulfoximine (BSO) which inhibits GSH synthesis, using a high throughput imaging system, Cytation™ 5 cell imaging reader. The results revealed that GSH probe RT at the concentration of 2.0 µM accurately monitored the BSO treatment effect on GSH level in the Hela cells. The present results demonstrated that the GSH probe RT is sensitive and precise in GSH measurement in living cells at a high throughput imaging platform and has the potential to be applied to any cell lines.
A prefrontal motor circuit initiates persistent movement
Authors: Wang Yihan , Sun Qian-Quan
Published: July 2023

Persistence reinforces continuous action, which benefits animals in many aspects. Diverse information may trigger animals to start a persistent movement. However, it is unclear how the brain decides to persist with current actions by selecting specific information. Using single-unit extracellular recordings and opto-tagging in awake mice, we demonstrated that a group of dorsal mPFC (dmPFC) motor cortex projecting (MP) neurons initiate a persistent movement selectively encoding contextual information rather than natural valence. Inactivation of dmPFC MP neurons impairs the initiation and reduces neuronal activity in the insular and motor cortex. Finally, a computational model suggests that a successive sensory stimulus acts as an input signal for the dmPFC MP neurons to initiate a persistent movement. These results reveal a neural initiation mechanism on the persistent movement.
Neutrophils culturedex vivofrom CD34+stem cells are immature and genetically tractable
Authors: Naveh Claire A. , Roberts Kiran , Rice Christopher M. , Fleming Kathryn , Thompson Megan , Panyapiean Nawamin , Diezmann Stephanie , Moura Pedro L. , Toye Ashley M. , Amulic Borko
Published: July 2023

Neutrophils are essential antimicrobial effector cells with short lifespans. During infection or sterile inflammation, accelerated production and release of immature neutrophils from the bone marrow serves to boost circulating neutrophil counts. To facilitate the study of neutrophil development and function, we optimised a method forex vivoproduction of human neutrophils from CD34+haematopoietic progenitors. We obtain high yields of neutrophils, which phenotypically resemble immature neutrophils released into the circulation upon administration of GCSF to healthy donors. We show thatex vivodifferentiated immature neutrophils have similar rates of ROS production but altered degranulation, cytokine release and antifungal activity compared to mature neutrophils isolated from peripheral blood. We demonstrate thatex vivocultured neutrophils are genetically tractable via genome editing of precursors and thus provide a powerful model system for investigating the properties and behaviour of immature neutrophils.
Quantifying the impact of hospital catchment area definitions on hospital admissions forecasts: COVID-19 in England, September 2020 - April 2021
Authors: Meakin Sophie , Funk Sebastian
Published: July 2023

Background

Defining healthcare facility catchment areas is a key step in predicting future healthcare demand in epidemic settings. Forecasts of hospitalisations can be informed by leading indicators measured at the community level. However, this relies on the definition of so-called catchment areas, or the geographies whose populations make up the patients admitted to a given hospital, and which are often not well-defined. Little work has been done to quantify the impact of hospital catchment area definitions on healthcare demand forecasting.

Methods

We made forecasts of Trust-level hospital admissions using a scaled convolution of local cases (as defined by the hospital catchment area) and a delay distribution. Hospital catchment area definitions were derived from either simple heuristics (in which people are admitted to their nearest hospital or any nearby hospital) or historical admissions data (all emergency or elective admissions in 2019, or COVID-19 admissions), plus a marginal baseline definition based on the distribution of all hospital admissions. We evaluated predictive performance using each hospital catchment area definition using the Weighted Interval Score (WIS) and considered how this changed by the length of the predictive horizon, the date on which the forecast was made, and by location. We also considered the change, if any, on the relative performance of each definition in retrospective vs. real-time settings, or at different spatial scales.

Results

The choice of hospital catchment area definition affected the accuracy of hospital admission forecasts. The definition based on COVID-19 admissions data resulted in the most accurate forecasts at both a 7- and 14-day horizon, and was one of the top two best-performing definitions across forecast dates and locations. The “nearby” heuristic also performed well, but less consistently than the COVID-19 data definition. The marginal distribution baseline, which did not include any spatial information, was the lowest-ranked definition. The relative performance of the definitions was larger when using case forecasts compared to future observed cases. All results were consistent across spatial scales of the catchment area definitions.

Conclusions

Using catchment area definitions derived from context-specific data can improve local-level hospital admissions forecasts. Where context-specific data is not available, using catchment areas defined by carefully-chosen heuristics are a sufficiently-good substitute. There is clear value in understanding what drives local admissions patterns, and further research is needed to understand the impact of different catchment area definitions on forecast performance where case trends are more heterogeneous.
Epidemiological and health economic implications of symptom propagation in respiratory pathogens: A mathematical modelling investigation
Authors: Asplin Phoebe , Keeling Matt J. , Mancy Rebecca , Hill Edward M.
Published: July 2023

Background

Respiratory pathogens inflict a substantial burden on public health and the economy. Although the severity of symptoms caused by these pathogens can vary from asymptomatic to fatal, the factors that determine symptom severity are not fully understood. Correlations in symptoms between infector-infectee pairs, for which evidence is accumulating, can generate large-scale clusters of severe infections that could be devastating to those most at risk, whilst also conceivably leading to chains of mild or asymptomatic infections that generate widespread immunity with minimal cost to public health. Although this effect could be harnessed to amplify the impact of interventions that reduce symptom severity, the mechanistic representation of symptom propagation within mathematical and health economic modelling of respiratory diseases is understudied.

Methods and Findings

We propose a novel framework for incorporating different levels of symptom propagation into models of infectious disease transmission via a single parameter,α. Varyingαtunes the model from having no symptom propagation (α= 0, as typically assumed) to one where symptoms always propagate (α= 1). For parameters corresponding to three respiratory pathogens — seasonal influenza, pandemic influenza and SARS-CoV-2 — we explored how symptom propagation impacted the relative epidemiological and health-economic performance of three interventions, conceptualised as vaccines with different actions: symptom-attenuating (labelled SA), infection-blocking (IB) and infection-blocking admitting only mild breakthrough infections (IB MB).

In the absence of interventions, with fixed underlying epidemiological parameters, stronger symptom propagation increased the proportion of cases that were severe. For SA and IB MB, interventions were more effective at reducing prevalence (all infections and severe cases) for higher strengths of symptom propagation. For IB, symptom propagation had no impact on effectiveness, and for seasonal influenza this intervention type was more effective than SA at reducing severe infections for all strengths of symptom propagation. For pandemic influenza and SARS-CoV-2, at low intervention uptake, SA was more effective than IB for all levels of symptom propagation; for high uptake, SA only became more effective under strong symptom propagation. Health economic assessments found that for SA-type interventions, the amount one could spend on control whilst maintaining a cost-effective intervention (termed threshold unit intervention cost) was very sensitive to the strength of symptom propagation.

Conclusions

Overall, the preferred intervention type depended on the combination of the strength of symptom propagation and uptake. Given the importance of determining robust public health responses, we highlight the need to gather further data on symptom propagation, with our modelling framework acting as a template for future analysis.
Comparative Effectiveness of the Bivalent (Original/Omicron BA.4/BA.5) mRNA COVID-19 Vaccines mRNA-1273.222 and BNT162b2 Bivalent in Adults in the United States
Authors: Kopel Hagit , Nguyen Van Hung , Boileau Catherine , Bogdanov Alina , Winer Isabelle , Ducruet Thierry , Zeng Ni , Bonafede Mac , Esposito Daina B. , Martin David , Rosen Andrew , Van de Velde Nicolas , Vermund Sten H , Gravenstein Stefan , Mansi James A.
Published: July 2023

Background

The emergence of Omicron variants coincided with declining vaccine-induced protection against SARS-CoV-2 infection and other COVID-19-related outcomes. Two bivalent mRNA vaccines, mRNA-1273.222 (Moderna) and BNT162b2 Bivalent (Pfizer-BioNTech) were developed to provide greater protection against the predominate circulating variants by including the mRNA that encodes both the ancestral (original) strain and BA.4/BA.5. We estimated their relative vaccine effectiveness (rVE) in preventing COVID-19-related outcomes in the US.

Methods

We conducted a retrospective cohort study using a US nationwide dataset linking primary care electronic health records (EHR) and pharmacy/medical claims data. The adult study population (aged ≥18 years) received either mRNA-1273.222 or BNT162b2 Bivalent vaccination between August 31, 2022, and February 28, 2023. We used a propensity score weighting based on the inverse probability of treatment to adjust for the baseline differences in age, sex, race, ethnicity, geographic region, vaccination week, and health status between groups. Outcomes evaluated were rVE of the two bivalent mRNA vaccines against COVID-19-related hospitalizations (primary outcome) and outpatient visits (secondary). We weighted the vaccine groups prior to analysis and estimated adjusted hazard ratios (HR) using multivariable Cox regression models. We calculated rVE as (1−HR) × 100.

Results

We evaluated outcomes for 1,034,538 mRNA-1273.222 and 1,670,666 BNT162b2 Bivalent vaccine recipients. The adjusted rVE of mRNA-1273.222 versus BNT162b2 Bivalent vaccines against COVID-19-related hospitalization was 9.8% (95% confidence interval: 2.6%–16.4%). The adjusted rVE against COVID-19-related outpatient visits was 5.1% (95% CI: 3.2%–6.9%). When evaluated by age group, the incremental relative effectiveness was greater. Among adults ≥ 65, rVE against COVID-19-related hospitalizations and outpatient visits was 13.5% (95% CI: 5.5%–20.8%) and 10.7% (8.2%–13.1%), respectively.

Conclusion

We found greater effectiveness of mRNA-1273.222 compared with the BNT162b2 Bivalent vaccine in preventing COVID-19-related hospitalizations and outpatient visits, with increased benefits in older adults.
Breeding of a near-isogenic wheat line resistant to wheat blast at both seedling and heading stages through incorporation ofRmg8
Authors: Yoshioka Motohiro , Shibata Mai , Morita Kohei , Fujita Masaya , Hatta Koichi , Tougou Makoto , Tosa Yukio , Asuke Soichiro
Published: July 2023

Wheat blast caused byPyricularia oryzae Triticumpathotype (MoT) has been transmitted from South America to Bangladesh and Zambia and is now spreading in these countries. To prepare against its further spread to Asian countries, we introducedRmg8, a gene for resistance to wheat blast, into a Japanese elite cultivar, Chikugoizumi (ChI), through recurrent backcrosses, and established ChI near-isogenic lines, #2-1-10 with theRmg8/Rmg8genotype and #4-2-10 with thermg8/rmg8genotype. A molecular analysis suggested that at least 96.6% of the #2-1-10 genome was derived from the recurrent parent ChI. The #2-1-10 line was resistant to MoT not only in primary leaves at the seedling stage but also in spikes and flag leaves at the heading stage. The strength of the resistance in spikes of thisRmg8carrier was comparable to that of a carrier of the 2NS segment which has been the only one genetic resource released to farmer’s field for wheat blast resistance. On the other hand, the 2NS resistance was not expressed on leaves at the seedling stage nor flag leaves at the heading stage. Considering that leaf blast has been increasingly reported and regarded as an important inoculum source for spike blast,Rmg8expressed at both the seedling and heading stages, or more strictly in both leaves and spikes, is suggested to be useful to prevent the spread of MoT in Asia and Africa.
Multidimensional super-resolution microscopy unveils nanoscale surface aggregates in the aging of FUS condensates
Authors: He Changdong , Wu Chun Ying , Li Wan , Xu Ke
Published: July 2023

The intracellular liquid-liquid phase separation (LLPS) of biomolecules gives rise to condensates that act as membrane-less organelles with vital functions. FUS, an RNA-binding protein, natively forms condensates through LLPS and further provides a model system for the often disease-linked liquid-to-solid transition of biomolecular condensates during aging. However, the mechanism of such maturation processes, as well as the structural and physical properties of the system, remain unclear, partly attributable to difficulties in resolving the internal structures of the micrometer-sized condensates with diffraction-limited optical microscopy. Harnessing a set of multidimensional super-resolution microscopy tools that uniquely map out local physicochemical parameters through single-molecule spectroscopy, here we uncover nanoscale heterogeneities in the aging process of FUS condensates. Through spectrally resolved single-molecule localization microscopy (SR-SMLM) with a solvatochromic dye, we unveil distinct hydrophobic nanodomains at the condensate surface. Through SMLM with a fluorogenic amyloid probe, we identify these nanodomains as amyloid aggregates. Through single-molecule displacement/diffusivity mapping (SMdM), we show that such nanoaggregates drastically impede local diffusion. Notably, upon aging or mechanical shears, these nanoaggregates progressively expand on the condensate surface, thus leading to a growing low-diffusivity shell while leaving the condensate interior diffusion-permitting. Together, beyond uncovering fascinating nanoscale structural arrangements and aging mechanisms in the single-component FUS condensates, the demonstrated synergy of multidimensional super-resolution approaches in this study opens new paths for understanding LLPS systems.
AI2BMD: efficient characterization of protein dynamics withab initioaccuracy
Authors: Wang Tong , He Xinheng , Li Mingyu , Wang Yusong , Wang Zun , Li Shaoning , Shao Bin , Liu Tie-Yan
Published: July 2023

Biomolecular dynamics simulation is a fundamental technology for life sciences research, and its usefulness depends on its accuracy and efficiency. Classical molecular dynamics simulation is fast but lacks chemical accuracy. Quantum chemistry methods like density functional theory (DFT) can reach chemical accuracy but cannot scale to support large biomolecules. We introduce anAI-basedab initiobiomoleculardynamics system (AI2BMD) that can efficiently simulate large biomolecules withab initioaccuracy. AI2BMD uses a protein fragmentation scheme and machine learning force field to achieve generalizableab initioaccuracy for energy and force calculations for various proteins comprising over 10,000 atoms. Compared to DFT, it reduces computational time by several orders of magnitude. With several hundred nanoseconds of dynamics simulations, AI2BMD demonstrated its capability of efficiently exploring the conformational space of peptides and proteins, deriving accurate3J-couplingsthat match NMR experiments, and showing protein folding and unfolding tendencies. Furthermore, AI2BMD enables precise free energy calculations for protein folding, and the estimated melting temperatures are well aligned with experiments. AI2BMD could potentially complement wet-lab experiments, detect the dynamic processes of bioactivities, and enable biomedical research that is currently impossible to conduct.
Stem-loop induced ribosome queuing in the uORF2/ATF4 overlap fine-tunes stress-induced human ATF4 translational control
Authors: Smirnova Anna M , Hronova Vladislava , Mohammad Mahabub Pasha , Herrmannova Anna , Gunisova Stanislava , Petrackova Denisa , Halada Petr , Coufal Stepan , Swirski Michal , Rendelman Justin , Jendruchova Kristina , Hatzoglou Maria , Beznoskova Petra , Vogel Christine , Valasek Leos Shivaya
Published: July 2023

ATF4 is a master transcriptional regulator of the integrated stress response leading cells towards adaptation or death. ATF4's induction under stress was thought to be mostly due to delayed translation reinitiation, where the reinitiation-permissive uORF1 plays a key role. Accumulating evidence challenging this mechanism as the sole source of ATF4 translation control prompted us to investigate additional regulatory routes. We identified a highly conserved stem-loop in the uORF2/ATF4 overlap, immediately preceded by a near-cognate CUG, which introduces another layer of regulation in the form of ribosome queuing. These elements explain how the inhibitory uORF2 can be translated under stress, confirming prior observations, but contradicting the original regulatory model. We also identified two highly conserved, potentially modified adenines performing antagonistic roles. Finally, we demonstrate that the canonical ATF4 translation start site is substantially leaky-scanned. Thus, ATF4's translational control is more complex than originally described underpinning its key role in diverse biological processes.