bluuebunny/crossref_metadata_2025 huggingface dataset:
A qualitative study of emergency nurses’ perspectives on intranasal ketamine for procedural sedation in children
Authors: Wonnacott David , Scott Shannon D. , Flynn Rachel , Ali Samina , Van Der Vaart Everly , Poonai Naveen
Published: May 2024

Purpose

There is mounting evidence supporting a role for intranasal (IN) ketamine for procedural sedation in children due to its less invasive delivery. Drug administration and monitoring is largely performed by nurses and clinical uptake requires understanding their perceptions. We explored nursing perspectives of IN ketamine for procedural sedation in children to understand facilitators and barriers and inform institutional guidelines.

Design and Methods

From January to February, 2018, we conducted 2 focus groups with 8 registered nurses in a Canadian tertiary care paediatric ED. Following professional transcription, data were analyzed using an inductive qualitative approach.

Results

Seven of 8 participants had experience administering IN ketamine to children for procedural sedation. Nurses perceived that IN ketamine had the potential to reduce children’s distress and improve nursing resource use. Perceived barriers included: 1) uncertainty regarding sedation effectiveness and incorporation into institutional sedation protocols, 2) perceptions that IN ketamine produced a relatively lighter, slower-onset, and less titratable sedation, and 3) healthcare providers’ lack of familiarity with IN ketamine and reluctance to change their current approach to sedation.

Conclusions

We identified barriers to adoption of IN ketamine such as uncertainty regarding its pharmacodynamic properties, safety, and impact on workflow, along with facilitators such as fewer adverse events and nursing resources, and less procedural distress for children.

Practice Implications

Provider education should focus on IN ketamine’s pharmacodynamic properties and development of institutional sedation guidelines that define indications for use, support engagement of child life specialists, and operationalize the type and duration of monitoring requirements.

CLINICIAN’S CAPSULE

What is known about the topic?

Intranasal ketamine is an emerging agent for procedural sedation and analgesia in the emergency department due to ease of administration.

What did this study ask?

What are paediatric nurses’ perspectives on intranasal ketamine for procedural sedation among children in the emergency department?

What did this study find?

Nurses identified advantages to intranasal ketamine but expressed considerable uncertainty regarding its pharmacodynamic properties and its incorporation into clinical practice.

Why does this study matter to clinicians?

Provider education may overcome some uncertainty and should focus on intranasal ketamine’s pharmacodynamic properties and incorporation into institutional sedation protocols.

Meetings

Pediatric Academic Societies (Baltimore, Maryland, April 30, 2019); Canadian Association of Emergency Physicians (Halifax, Nova Scotia, May 29, 2019); Canadian Paediatric Society (Toronto, Ontario, June 7, 2019)
Preliminary findings from the Dynamics of the Immune Responses to Repeat Influenza Vaccination Exposures (DRIVE I) Study: a Randomized Controlled Trial
Authors: Cowling Benjamin J. , Wong Sook-San , Santos Jefferson J. S. , Touyon Lisa , Ort Jordan , Ye Naiqing , Kwok Natalie K. M. , Ho Faith , Cheng Samuel M. S. , Ip Dennis K. M. , Peiris Malik , Webby Richard J. , Wilson Patrick C. , Valkenburg Sophie A. , Tsang John S. , Leung Nancy H. L. , Hensley Scott E. , Cobey Sarah
Published: May 2024

Background

Studies have reported that repeated annual vaccination may influence the effectiveness of the influenza vaccination in the current season. The mechanisms underlying these differences are unclear but might include “focusing” of the adaptive immune response to older strains.

Methods

We established a 5-year randomized placebo-controlled trial of repeated influenza vaccination (Flublok, Sanofi Pasteur) in adults 18-45 years of age. Participants were randomized equally between five groups, with planned annual receipt of vaccination (V) or saline placebo (P) as follows: P-P-P-P-V, P-P-P-V-V, P-P-V-V-V, P-V-V-V-V, or V-V-V-V-V. Serum samples were collected each year just before vaccination and after 30 and 182 days. A subset of sera were tested by hemagglutination inhibition assays, focus reduction neutralization tests and enzyme-linked immunosorbent assays against vaccine strains.

Results

From 23 October 2020 through 11 March 2021 we enrolled and randomized 447 adults. We selected sera from 95 participants at five timepoints from the first two study years for testing. Among vaccinated individuals, antibody titers increased between days 0 and 30 against each of the vaccine strains, with substantial increases for first-time vaccinees and smaller increases for repeat vaccinees, who had higher pre-vaccination titers in year 2. There were statistically significant reductions in the proportion of participants achieving a four-fold greater rise in antibody titer for the repeat vaccinees for A(H1N1), B/Victoria and B/Yamagata, but not for influenza A(H3N2). There were no statistically significant differences between groups in geometric mean titers at day 30 or the proportions of participants with antibody titers ≥40 at day 30 for any of the vaccine strains.

Conclusions

In the first two years, repeat vaccinees and first-time vaccinees had similar post-vaccination geometric mean titers to all four vaccine strains, indicative of similar levels of clinical protection. The vaccine strains of A(H1N1) and A(H3N2) were updated in year 2, providing an opportunity to explore antigenic distances between those strains in humans in subsequent years.
Mass drug administration coverage and determinants of drug uptake for elimination of Onchocerciasis in Ulanga District
Authors: Mhiche Ambakisye , Gasarasi Dinah , Kabona George , Hussein Ally , Abade Ahmed Mohamed
Published: May 2024

Background

Onchocerciasis remain to be an important public health problem targeted for elimination in Tanzania. Ulanga District was known for its high endemicity since 1960s and has been implementing MDA through Community Directed Treatment with Ivermectin (CDTI) strategy since 1998. However, current reports indicate high prevalence of Onchocerciasis in both human and vector species probably because of poor treatment coverage indicating limited evidence for transmission. This study was conducted to assess treatment coverage and explore determinants of drug uptake during MDA program.

Methods

A cross-sectional community-based study using multistage cluster sampling was carried out in Ulanga District, Morogoro Tanzania from April-June 2019. Study participants were randomly selected from households and interviewed using a structured questionnaire. Modified Poisson regression was performed to determine independent factors associated with MDA uptake.

Results

A total of 502 participants were recruited during the study period with a response rate of 96%. The majority (67%) were females, and the mean age of the study participants was 37.8 ±15 years with an age range of 25–34 (25.5 %). MDA coverage for the studied villages was as follows; Mawasiliano (68%) Uponera (83%), Isongo (84%) and Togo (79%). The drug uptake for all villages was below the optimal coverage recommended by WHO (85%) for successful transmission interruption. Having an age of ≤ 24 years [Adjusted Prevalence Ration (APR) = 3.9(95% CI:1.9-8.3), p < 0.05)], Living in the village for at least a year [APR = 3.4 (95% CI:2.4-4.8), p <0.05)] and believing IVM prevent Onchocerciasis [APR = 13.4(95% CI:2.9-60.9)], p<0.05) were associated with increased chances of Ivermectin uptake during MDA. In addition, decreased drug uptake [APR = 12(95% CI: 2.4-60.9), p<0.05)] was attributable to fear of restriction to drinking alcohol after taking drugs.

Conclusion

Low coverage below the WHO optimal recommended coverage has been demonstrated in the studied villages. This implies low drug uptake, delayed interruption of transmission and Onchocerciasis elimination. These findings, therefore, emphasize the need to intensify the MDA awareness campaigns targeting less compliant groups in the community to reinforce the benefits of ivermectin in Onchocerciasis control and address the community misconceptions about MDA.
Transcranial Focused Ultrasound Targeting the Default Mode Network for the Treatment of Depression
Authors: Schachtner Jessica N. , Dahill-Fuchel Jacob F. , Allen Katja E. , Bawiec Christopher R. , Hollender Peter J. , Ornellas Sarah B. , Konecky Soren D. , Achrol Achal S. , Allen John J.B.
Published: May 2024

Importance

Up to 50% of individuals fail to respond to current depression treatments. Repetitive negative thought and default mode network hyperconnectivity are central in depression and can be targeted using novel neuromodulation techniques.

Objective

This study assessed whether non-invasive transcranial focused ultrasound to the default mode network can decrease depression symptoms and repetitive negative thought, and improve quality of life.

Design

This open-label case series began in August 2023, with a six-month follow-up period (current).

Setting

A community-based study at the University of Arizona.

Participants

Twenty individuals aged 18 – 45 were enrolled from among 247 screened. Exclusion criteria included history of psychosis/mania, acute suicidality, MRI contraindications, pregnancy, and medical and neurological factors that may complicate diagnosis or brain function.

Intervention

Up to three weeks of transcranial ultrasound (11 sessions) targeting the anterior medial prefrontal cortex; ten minutes per session.

Main Outcomes and Measures

Depression severity (Beck Depression Inventory – II and the Hamilton Depression Rating Scale), repetitive negative thought (Perseverative Thinking Questionnaire), and quality of life (World Health Organization Quality of Life survey) were outcomes.

Results

This sample was young (mean 30.4 years ± 10.0), predominantly female (75%), with moderate to severe depression and high comorbidity. Fifty percent of participants endorsed current psychiatric medication use. Ten percent of subjects dropped out of the study. Significant decreases in depression occurred on self-report, 11.3 (p < 0.001, CI = −14.68, −8.15) and interview ratings, 4.3 (p < 0.001, CI = −6.21, −2.43). Repetitive negative thought decreased by 8.53 (p <0.001, CI = −11.01, −5.79). Physical and psychological well-being improved by 7.6 (p < 0.001, CI = 3.62, 11.63) and 11.9 points (p < 0.001, CI = 7.51, 16.21), respectively. Environment satisfaction increased by 5.0 (p = 0.001, CI = 2.24, 7.56).

Conclusions and Relevance

Transcranial ultrasound holds promise as a treatment for depression.

Trial Registration

Altering Default Mode Network Activity with Transcranial Focused Ultrasound to Reduce Depressive Symptoms (DMNtFUS). Registration number: 019782-00001 Clinical trials ID:NCT06320028URL:https://clinicaltrials.gov/study/NCT06320028?intr=Ultrasound&cond=depression&locStr=Arizona&country=United%20States&state=Arizona&rank=1
Estimates of Actual and Potential Lives Saved in the United States from the use of COVID-19 Convalescent Plasma
Authors: Dragotakes Quigly , Johnson Patrick W. , Buras Matthew R. , Carter Rickey E. , Joyner Michael J. , Bloch Evan , Gebo Kelly A. , Hanley Daniel F. , Henderson Jeffrey P. , Pirofski Liise-anne , Shoham Shmuel , Senefeld Jonathon W. , Tobian Aaron AR , Wiggins Chad C. , Wright R. Scott , Paneth Nigel S. , Sullivan David J. , Casadevall Arturo
Published: May 2024

In the Spring of 2020, the United States of America (USA) deployed COVID-19 convalescent plasma (CCP) to treat hospitalized patients. Over 500,000 patients were treated with CCP during the first year of the pandemic. In this study, estimated the number of actual inpatient lives saved by CCP treatment in the USA based upon CCP weekly use, weekly national mortality data, and CCP mortality reduction data from meta-analyses of randomized controlled trials and real-world data. We also estimate the potential number of lives saved if CCP had been deployed for 100% of hospitalized patients or used in 15% to 75% of outpatients. Depending on the assumptions modeled in stratified analyses, CCP was estimated to have saved between 16,476 and 66,296 lives. The CCP ideal use might have saved as many as 234.869 lives while preventing 1,136,133 hospitalizations. CCP deployment was a successful strategy for ameliorating the impact of the COVID-19 pandemic in the USA. This experience has important implications for convalescent plasma used in future infectious disease emergencies.

Significance statement

When the COVID-19 pandemic struck in 2020, the population lacked immunity, no validated therapies were available, and mortality was high. COVID-19 convalescent plasma (CCP) was authorized in the United States for treatment of hospitalized patients based on historical evidence of convalescent plasma (CP) efficacy and findings from a nationwide registry suggesting that it reduced mortality. However, this decision was controversial because it was not based on evidence from randomized controlled clinical trials. In this study, we leveraged CCP use and mortality data combined with CCP efficacy data to show that CCP reduced mortality and saved tens of thousands of lives the first year of the pandemic. This provides a powerful basis to consider CP deployment in future infectious disease emergencies.
Clinical Consequences of Occult Free Valproate Toxicity in Critically Ill Adult Patients: A Multicenter Retrospective Cohort Study
Authors: Webb Andrew J , Gagnon David J , Brown Caitlin S , Riker Richard R , Lopez Natasha D , Goodberlet Melanie Z , Schontz Michael J , Marino Kaylee K , Uljon Sacha N , Zafar Sahar F. , Rosenthal Eric S
Published: May 2024

Background and Objectives

Valproate has wide pharmacokinetic variability and a narrow therapeutic index. Its protein binding is unpredictable, particularly among critically ill patients who may experience unexpectedly elevated free concentrations. We sought to identify the clinical consequences and determinants of occult free valproate toxicity in critically ill adults.

Methods

We conducted a multicenter retrospective cohort study of adult patients admitted to an intensive care unit (ICU) who were receiving valproate and had concurrent total and free valproate concentrations measured. We examined whether valproate concentrations were independently associated with adverse drug effects (ADEs) including thrombocytopenia, hepatotoxicity, hyperammonemia, and pancreatic injury. Determinants of occult toxicity were also identified using logistic mixed-effects models, adjusting for age, weight, albumin, propofol and aspirin use, and blood urea nitrogen (BUN). Occult toxicity was defined as a free valproate concentration that was discordant with total concentration (e.g., supratherapeutic free concentration associated with therapeutic total concentration).

Results

311 unique patients (mean age 58 [±17] years, 36% female, 31% non-white, and 29% on valproate prior to admission) with 550 concurrent free and total valproate concentration pairs met inclusion criteria. The median (IQR) total valproate concentration was 46 mcg/mL (34-63) and the median free valproate concentration was 17 mcg/ml (11-23); median free fraction was 35% (25-63%). Eighty-four percent of total valproate concentrations represented occult free toxicity; a therapeutic total with a supratherapeutic free valproate concentration was the most common pattern (32% of concentration pairs). Each 2.5 mcg/mL increase in free valproate concentration was associated with thrombocytopenia (adjusted unit odds 1.15, 95% CI 1.05-1.26) and hepatotoxicity (adjusted unit odds 1.11, 95% CI 1.05-1.18). Albumin concentration (adjusted odds; aOR 0.17, 95% CI 0.08-0.36), BUN (aOR 1.36, 95% CI 1.09-1.70), and propofol exposure (aOR 3.06, 95% CI 1.38-6.79) were associated with occult toxicity.

Conclusion

Free valproate concentrations should be measured in critically ill patients because it is associated with ADEs and is often underrepresented by total concentrations. Most critically ill patients are at risk, especially those with hypoalbuminemia, uremia, and lipid exposure.
Exploring Multilevel Determinants of Stillbirth: A Comprehensive Analysis Across Sub-Saharan African Countries
Authors: Adeleye Khadijat , Ogungbe Oluwabunmi , Yeboah-Kordieh Yvette , Gresh Ashley , Iradukunda Favorite
Published: May 2024

Background

Stillbirths and associated outcomes remain a significant concern in Sub-Saharan Africa (SSA), with approximately 44% of global stillbirths.

Methods

Using Demographic and Health Surveys (DHS) data, this study examined determinants of stillbirth among women in 29 SSA countries. Our cross-sectional analysis included a weighted sample of women 15-49 years of age who had given birth or experienced stillbirth. We used bivariate analyses and multilevel logistic regression approaches.

Findings

Stillbirth prevalence was 319·06/1000 live births. Among individual-level factors, risk increased with age. Higher maternal education levels were significantly associated with decreased stillbirth risk. Single women had significantly lower odds of stillbirth compared to those who no longer lived together/separated from their partner. Contextually, women with a job had an increased risk compared to women without a job, and living in a rural residential area was a significant factor.

Interpretation

The complex interplay of individual-level factors and contextual factors influences stillbirth outcomes in SSA. Cross-sector holistic approaches to maternal and neonatal health are needed to address the multifaceted determinants of stillbirths.

Funding

There was no funding for the study.

Evidence before the study

The prevalence of stillbirth is higher in SSA compared to other regions. Factors influencing stillbirth are complex and include individual, household, and community-level factors. We searched PubMed and Medline with no language restrictions using the search terms (“stillbirth” AND “determinant” AND “Sub-Saharan Africa”). By 2023, no studies were published on the determinants of stillbirth in Sub-Saharan Africa. Earlier studies were conducted in the context of other countries without using the calendar method to calculate stillbirth or the national demographic dataset.

Added value of this study

The relative importance of risk factors for stillbirth in different SSA countries.

Protective effect of household leadership dynamics on reducing stillbirth odds in SSA.

Implications of all the available evidence

Focused interventions to reduce stillbirths, such as promoting female household leadership and equity.

Improving access to education and maternal health literacy.

Public health initiatives to prioritize social and familial support for pregnant women to create environments conducive to positive pregnancy outcomes.

Clinicians could promote pregnancy spacing and family planning to promote optimal maternal and child health, especially among women with higher parity.

Healthcare policies for more investment and strengthening of maternal and child care services.
The Congenital Heart Initiative: Results from a Patient-Centered Registry for Adults with Congenital Heart Disease
Authors: Leezer Scott , Messmer Mindi , Agarwal Anushree , Phillippi Ruth , Jackson Jamie L. , Roeder Mark , Marlin Aliza , Peyser Noah , Pletcher Mark J. , Krasuski Richard , Lewis Matthew , Reardon Leigh , Saidi Arwa , Kanter Ronald , Sandhu Satinder , Young Thomas , Jacobsen Roni , Ruckdeschel Emily , Lubert Adam , Singh Simran , Zaidi Ali , Halpern Dan H. , Mathews Anita , Mehta Rittal , Carton Thomas , John Anitha S.
Published: May 2024

Background

In the United States, there are over 1.5 million adults living with congenital heart disease (CHD). The Congenital Heart Initiative (CHI) is a digital, online patient empowered registry that was created to advance multicenter research and improve clinical care by gathering patient-reported outcomes (PROs) in adults with CHD.

Methods

After a two year design process, the CHI was created and launched nationally on December 7, 2020 using a human centered design approach. Demographics and validated survey tools on quality of life, mental health, physical activity and health care utilization were collected at baseline and every 4 months. Data were collected virtually and stored on Health Insurance Portability and Accountability Act (HIPAA)–compliant cloud-based servers with restricted access.

Results

By December 31, 2023, the CHI had enrolled 4558 participants (56% female) with an average age of 39 years ± 14, representing all 50 states. Approximately 88% of participants have completed at least one e-Visit as of December 31, 2023. The most prevalent CHD anatomy included tetralogy of Fallot (883, 22%), transposition of great arteries (452, 11%), and coarctation of the aorta (429, 11%). Approximately 88% of participants reported at least one co-morbidity, with arrhythmia (1310, 29%) and mood disorder (1339, 29%) as the most common cardiac and non-cardiac co-morbidity, respectively. Among female participants, 45% (n=1147) reported having had a pregnancy with 38% (n=967) resulting in biological children. Participants with complex CHD were less likely to meet recommended physical activity guidelines (X2(2, n = 917) = 15.9, p < 0.001), a factor that was more pronounced amongst female participants. Overall health-related quality of life was rated as good or better by 84% of participants with no difference by CHD complexity.

Conclusion

CHI is the largest ongoing registry of adults living with congenital heart disease in the US and includes patients with a wide variety of CHD subtypes. Many patients report mood disorders, but most report good or very good health-reported quality of life. The CHI is poised to facilitate multicenter research with the goal of improving clinical outcomes for all adults with CHD.
Comparative evaluation of machine learning models versus TIMI score in ST-segment-elevation myocardial infarction patients
Authors: Gupta Mohit D , Goyal Dixit , Kunal Shekhar , Shetty Manu Kumar , MP Girish , Batra Vishal , Bansal Ankit , Mishra Prashant , Shukla Mansavi , Gupta Aarti , Kohli Vanshika , Chadha Akul , Fatima Arisha , Muduli Subrat , Gupta Anubha , Yusuf Jamal
Published: May 2024

Background

Risk stratification is an integral component of ST-segment-elevation myocardial infarction (STEMI) management practices. This study aimed to derive a machine learning (ML) model for risk stratification and identification of factors associated with in-hospital and 30-day mortality in patients with STEMI and compare it with traditional TIMI score.

Methods

This was a single center prospective study wherein subjects >18 years with STEMI (n=1700) were enrolled. Patients were divided into two groups: training (n=1360) and validation dataset (n=340). Six ML algorithms (Extra Tree, Random Forest, Multiple Perceptron, CatBoost, Logistic Regression and XGBoost) were used to train and tune the ML model and to determine the predictors of worse outcomes using feature selection. Additionally, the performance of ML models both for in-hospital and 30-day outcomes was compared to that of TIMI score.

Results

Of the 1700 patients, 168 (9.88%) had in-hospital mortality while 30-day mortality was reported in 210 (12.35%) subjects. In terms of in-hospital mortality, Random Forest ML model (sensitivity: 80%; specificity: 74%; AUC: 80.83%) outperformed the TIMI score (sensitivity: 70%; specificity: 64%; AUC:70.7%). Similarly, Random Forest ML model (sensitivity: 81.63%; specificity: 78.35%; AUC: 78.29%) had better performance as compared to TIMI score (sensitivity: 63.26%; specificity: 63.91%; AUC: 63.59%) for 30-day mortality. Key predictors for worse outcomes at 30-days included mitral regurgitation on presentation, smoking, cardiogenic shock, diabetes, ventricular septal rupture, Killip class, age, female gender, low blood pressure and low ejection fraction.

Conclusions

ML model outperformed the traditional regression based TIMI score as a risk stratification tool in patients with STEMI.
Hydrocarbon-degrading microbial populations in permanently cold deep-sea sediments in the NW Atlantic
Authors: Adebayo Oyeboade , Bhatnagar Srijak , Webb Jamie , Campbell Calvin , Fowler Martin , MacAdam Natasha M. , Macdonald Adam , Li Carmen , Hubert Casey R.J.
Published: May 2024

Permanently cold deep-sea sediments (2500-3500 m water depth) with or without indications of thermogenic hydrocarbon seepage were exposed to naphtha to examine the presence and potential of aerobic hydrocarbon-degrading microbial populations. Monitoring these microcosms for volatile hydrocarbons by GC-MS revealed sediments withoutin situhydrocarbons responded more rapidly to naphtha amendment than hydrocarbon seep sediments overall, but seep sediments removed BTEX compounds more readily. Naphtha-driven aerobic respiration was more evident in surface sediment (0-20 cmbsf) than deeper anoxic layers (>130 cmbsf) that responded less rapidly. In all cases, enrichment of Gammaproteobacteria included lineages ofOleispira,Pseudomonas, andAlteromonasknown to be associated with marine oil spills. On the other hand, taxa known to be prevalentin situand diagnostic for thermogenic hydrocarbon seepage in deep sea sediment did not respond to naphtha amendment. This suggests a limited role for seep-associated populations in the context of oil spill biodegradation.
Large-scale estimation of bacterial and archaeal DNA prevalence in metagenomes reveals biome-specific patterns
Authors: Eisenhofer Raphael , Alberdi Antton , Woodcroft Ben J.
Published: May 2024

Metagenomes often contain many reads derived from eukaryotes. However, there is usually no reliable method for estimating the prevalence of non-microbial reads in a metagenome, forcing many analysis techniques to make the often-faulty assumption that all reads are microbial. For instance, the success of metagenome-assembled genome (MAG) recovery efforts is assessed by the number of reads mapped to recovered MAGs, a procedure which will underestimate the true fidelity if eukaryotic reads are present. Here we present “SingleM microbial_fraction” (SMF), a scalable algorithm that robustly estimates the number of bacterial and archaeal reads in a metagenome, and the average microbial genome size. SMF does not use eukaryotic reference genome data and can be applied to any Illumina metagenome. Based on SMF, we propose the “Domain-Adjusted Mapping Rate” (DAMR) as an improved metric to assess microbial genome recovery from metagenomes. We benchmark SMF on simulated and real data, and demonstrate how DAMRs can guide genome recovery. Applying SMF to 136,284 publicly available metagenomes, we report substantial variation in microbial fractions and biome-specific patterns of microbial abundance, providing insights into how microorganisms and eukaryotes are distributed across Earth. Finally, we show that substantial amounts of human host DNA sequence data have been deposited in public metagenome repositories, possibly counter to ethical directives that mandate screening of these reads prior to release. As the adoption of metagenomic sequencing continues to grow, we foresee SMF being a valuable tool for the appraisal of genome recovery efforts, and the recovery of global patterns of microorganism distribution.
Comprehensive Proteomic Analysis of HCoV-OC43 Virions and Virus-Modulated Extracellular Vesicles
Authors: Joharinia Negar , Bonneil Éric , Grandvaux Nathalie , Thibault Pierre , Lippé Roger
Published: May 2024

Viruses are obligate parasites that depend on the cellular machinery for their propagation. Several viruses also incorporate cellular proteins that facilitate viral spread. Defining these cellular proteins is critical to decipher viral life cycles and delineate novel therapeutic strategies. While numerous studies have explored the importance of host proteins in coronavirus spread, information about their presence in mature virions is limited. In this study, we developed a protocol to highly enrich mature HCoV-OC43 virions and characterize them by proteomics. Recognizing that cells release extracellular vesicles whose content is modulated by viruses, and given our ability to separate virions from these vesicles, we also analyzed their protein content in both uninfected and infected cells. We uncovered 69 unique cellular proteins associated with virions including 31 high confidence hits. These proteins primarily regulate RNA metabolism, enzymatic activities, vesicular transport, cell adhesion, metabolite interconversion and translation. We further discovered that the virus had a profound impact on exosome composition, incorporating 47 novel cellular proteins (11 high confidence) and excluding 92 others (61 high confidence) in virus-associated extracellular vesicles compared to uninfected cells. Moreover, a dsiRNA screen revealed that 11 of 18 select targets significantly impacted viral yields, including proteins found in virions or extracellular vesicles. Overall, this study provides new and important insights into the incorporation of numerous host proteins into HCoV-OC43 virions, their biological significance and the ability of the virus to modulate extracellular vesicles.

Importance

In recent years, coronaviruses have dominated global attention, making it crucial to develop methods to control them and prevent future pandemics. Besides viral proteins, host proteins play a significant role in viral propagation and offer potential therapeutic targets. Targeting host proteins is advantageous because they are less likely to mutate and develop resistance compared to viral proteins, a common issue with many antiviral treatments. In this study, we examined the protein content of the less virulent biosafety level 2 HCoV-OC43 virus as a stand-in for the more virulent SARS-CoV-2. Our findings reveal that several cellular proteins incorporated into the virion regulate viral spread. Additionally, we report that the virus extensively modulates the content of extracellular vesicles, enhancing viral dissemination. This underscores the critical interplay between the virus, host proteins, and extracellular vesicles.
Interleukin-1 prevents SARS-CoV-2-induced membrane fusion to restrict viral transmission via induction of actin bundles
Authors: Zheng Xu , Yu Shi , Zhou Yanqiu , Yu Kuai , Gao Yuhui , Chen Mengdan , Duan Dong , Li Yunyi , Cui Xiaoxian , Mou Jiabin , Yang Yuying , Wang Xun , Chen Min , Jiu Yaming , Zhao Jincun , Meng Guangxun
Published: May 2024

Innate immune responses triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection play pivotal roles in the pathogenesis of COVID-19, while host factors including pro-inflammatory cytokines are critical for viral containment. By utilizing quantitative and qualitative models, we discovered that soluble factors secreted by human monocytes potently inhibit SARS-CoV-2-induced cell-cell fusion in viral-infected cells. Through cytokine screening, we identified that interleukin-1β (IL-1β), a key mediator of inflammation, inhibits syncytia formation mediated by various SARS-CoV-2 strains. Mechanistically, IL-1β activates RhoA/ROCK signaling through a non-canonical IL-1 receptor-dependent pathway, which drives the enrichment of actin bundles at the cell-cell junctions, thus prevents syncytia formation. Notably,in vivoinfection experiments in mice confirms that IL-1β significantly restricted SARS-CoV-2 spreading in the lung epithelia. Together, by revealing the function and underlying mechanism of IL-1β on SARS-CoV-2-induced cell-cell fusion, our study highlights an unprecedented antiviral function for cytokines during viral infection.
Fungal pathogens exposed – genomic and phenotypic insights intoCandida aurisand its relatives of theCandida haemuloniispecies complex
Authors: de Jong Auke W. , Boden Sander , Zandijk Annemarie , Kortsinoglou Alexandra M. , Gerrits van den Ende Bert , Francisco Elaine C. , Nefeli Podimata Konstantina , Kouvelis Vassili N. , Zhou Miaomiao , Hagen Ferry
Published: May 2024

Candida aurisshowed the world the ability of fungi to rapidly emerge as an urgent threat to public health. Close relatives of theCandida haemuloniicomplex exhibit also a similar multi-drug resistant nature and are increasingly reported as nosocomial pathogens. Here, we analyze both complete genomes assemblies and extensive phenotypic data for the fiveC. aurisclades and pathogenic and non-pathogenic species related to theC. haemuloniispecies complex. First, we resolved the phylogeny of the species complex. Next, comparingC. auristo its pathogenic and non-pathogenic relatives we identified a pathogenic potential for the wholeC. haemuloniispecies complex by shared gene content and phenotypic traits linked to drug resistance and virulence.In vivovirulence assays using theGalleria mellonellafungal infection model show thatC. aurisstrains are significantly more virulent than any of the sibling species in theC. haemuloniicomplex. Phenotypic analysis links the increased virulence ofC. auristo a more stress resistant phenotype compared to its siblings.
Mass spectral feature analysis of ubiquitylated peptides provides insights into probing the dark ubiquitylome
Authors: Edgington Regina M , Wilburn Damien Beau
Published: May 2024

Ubiquitylation is a structurally and functionally diverse post translational modification that involves the covalent attachment of the small protein ubiquitin to other protein substrates. Trypsin-based proteomics is the most common approach for globally identifying ubiquitylation sites. However, we estimate that such methods are unable to detect ~40% of ubiquitylation sites in the human proteome - i.e., the dark ubiquitylome - including many important for human health and disease. In this meta-analysis of three large ubiquitylomic datasets, we performed a series of bioinformatic analyses to assess experimental features that could aid in uniquely identifying site-specific ubiquitylation events. Spectral predictions from Prosit were compared to experimental spectra of tryptic ubiquitylated peptides, revealing previously uncharacterized fragmentation of the diGly scar. Analysis of the LysC-derived ubiquitylated peptides reveal systematic, multidimensional peptide fragmentation, including diagnostic b-ions from fragmentation of the LysC ubiquitin scar. Comprehensively, these findings provide diagnostic spectral signatures of modification events that could applied to new analysis methods for non-tryptic ubiquitylomics.
A noncanonical GTPase signaling mechanism controls exit from mitosis in budding yeast
Authors: Zhou Xiaoxue , Weng Shannon Y. , Bell Stephen P. , Amon Angelika
Published: May 2024

In the budding yeastSaccharomyces cerevisiae, exit from mitosis is coupled to spindle position to ensure successful genome partitioning between mother and daughter cell. This coupling occurs through a GTPase signaling cascade known as the mitotic exit network (MEN). The MEN senses spindle position via a Ras-like GTPase Tem1 which localizes to the spindle pole bodies (SPBs, yeast equivalent of centrosomes) during anaphase and signals to its effector protein kinase Cdc15. How Tem1 couples the status of spindle position to MEN activation is not fully understood. Here, we show that Cdc15 has a relatively weak preference for Tem1GTPand Tem1’s nucleotide state does not change upon MEN activation. Instead, we find that Tem1’s nucleotide cycle establishes a localization-based concentration difference in the cell where only Tem1GTPis recruited to the SPB, and spindle position regulates the MEN by controlling Tem1 localization. SPB localization of Tem1 primarily functions to promote Tem1-Cdc15 interaction for MEN activation by increasing the effective concentration of Tem1. Consistent with this model, we demonstrate that artificially tethering Tem1 to the SPB or concentrating Tem1 in the cytoplasm with genetically encoded multimeric nanoparticles could bypass the requirement of Tem1GTPand correct spindle position for MEN activation. This localization/concentration-based GTPase signaling mechanism for Tem1 differs from the canonical Ras-like GTPase signaling paradigm and is likely relevant to other localization-based signaling scenarios.
Spike protein of the SARS-CoV-2 omicron variant interacts with actin
Authors: Fujimoto Ai , Kawai Haruki , Kawamura Rintaro , Kitamura Akira
Published: May 2024

The omicron variant of SARS-CoV-2 is responsible for the COVID-19 pandemic, serving as a significant origin for the variants still being detected today. It affects the spike protein that most vaccines used to target when the Omicron strain was discovered. Here, we demonstrate that the receptor binding domain (RBD) of the Omicron variant of SARS-CoV-2 exhibits an increased affinity for human angiotensin-converting enzyme type 2 (hACE2) as a viral cell receptor compared to the prototype RBD. We also identified that β- and γ-actin are Omicron-specific binding partners of RBD. Protein complex predictions suggested that many of the Omicron-specific amino acid substitutions might be involved in the affinity of RBD and actin. Accordingly, we highlight the intriguing observation that proteins expected to localize to different cellular compartments exhibit strong binding.
Changes in pain, mood, and functional connectivity following cryo-auriculotherapy in adults with chronic refractory low back pain: An open-label preliminary study
Authors: Vogt Keith M. , Khan Abdurrehman , Alter Benedict J , Emerick Trent D. , Ibinson James W. , Wasan Ajay D. , Sadhasivam Senthilkumar , Chelly Jacques E.
Published: May 2024

Introduction

This report describes the effects of auriculotherapy (AT) using cryogenic needles in a small cohort of chronic low back pain patients.

Methods

The effects of AT on pain, mood, and functioning were recorded in 10 patients with chronic back pain before and after cryogenic AT using patient-reported outcome instruments: Brief Pain Inventory (BPI), Patient Health Questionnaire (PHQ-9), General Anxiety Disorder (GAD-7), and Patient-Reported Outcomes Measurement Information System (PROMIS-29). In addition, resting-state MRI data collected before and 5-7 days after AT treatment were analyzed for changes in functional connectivity in 4 patients.

Results

GAD-7 scores decreased from 10.0 to 7.7 (95% confidence interval of difference= 0.2 – 4.4, p=0.036). Other patient-reported outcomes showed non-significant differences in this pilot cohort. Significant functional MRI connectivity changes were observed in 4 patients, suggesting that AT affected areas of the brain involved in pain processing.

Conclusion

Cryogenic AT is a technique that may reduce the psychological burden of low back pain, but further study is needed. Preliminary functional connectivity changes support the concept that the effect of AT is centrally mediated.
Lifespan analysis of repeat expression reveals age-dependent upregulation of HERV-K in the neurotypical human brain
Authors: Evans Taylor A. , Feltrin Arthur S. , Benjamin Kynon J. , Katipalli Tarun , Hyde Thomas , Kleinman Joel E. , Weinberger Daniel R. , Paquola Apua C. , Erwin Jennifer A.
Published: May 2024

DNA repetitive sequences (or repeats) comprise over 50% of the human genome and have a crucial regulatory role, specifically regulating transcription machinery. The human brain is the tissue with the highest detectable repeat expression and dysregulations on the repeat activity are related to several neurological and neurodegenerative disorders, as repeat-derived products can stimulate a pro-inflammatory response. Even so, it is unclear how repeat expression acts on the aging neurotypical brain. Here, we leverage a large postmortem transcriptome cohort spanning the human lifespan to assess global repeat expression in the neurotypical brain. We identified 21,696 differentially expressed repeats (DERs) that varied across seven age bins (Prenatal; 0-15; 16-29; 30-39; 40-49; 50-59; 60+) across the caudate nucleus (n=271), dorsolateral prefrontal cortex (n=304), and hippocampus (n=310). Interestingly, we found that long interspersed nuclear elements and long terminal repeats (LTRs) DERs were the most abundant repeat families when comparing infants to early adolescence (0-15) with older adults (60+). Of these differentially regulated LTRs, we identified 17 shared across all brain regions, including increased expression of HERV-K-int in older adult brains (60+). Co-expression analysis from each of the three brain regions also showed repeats from the HERV subfamily were intramodular hubs in its subnetworks. While we do not observe a strong global relationship between repeat expression and age, we identified HERV-K as a repeat signature associated with the aging neurotypical brain. Our study is the first global assessment of repeat expression in the neurotypical brain.
Untargeted Metabolome Atlas for Sleep Phenotypes in the Hispanic Community Health Study/Study of Latinos
Authors: Zhang Ying , Spitzer Brian W , Zhang Yu , Wallace Danielle A , Yu Bing , Qi Qibin , Argos Maria , Avilés-Santa M Larissa , Boerwinkle Eric , Daviglus Martha L , Kaplan Robert , Cai Jianwen , Redline Susan , Sofer Tamar
Published: May 2024

Sleep is essential to maintaining health and wellbeing of individuals, influencing a variety of outcomes from mental health to cardiometabolic disease. This study aims to assess the relationships between various sleep phenotypes and blood metabolites. Utilizing data from the Hispanic Community Health Study/Study of Latinos, we performed association analyses between 40 sleep phenotypes, grouped in several domains (i.e., sleep disordered breathing (SDB), sleep duration, timing, insomnia symptoms, and heart rate during sleep), and 768 metabolites measured via untargeted metabolomics profiling. Network analysis was employed to visualize and interpret the associations between sleep phenotypes and metabolites. The patterns of statistically significant associations between sleep phenotypes and metabolites differed by superpathways, and highlighted subpathways of interest for future studies. For example, some xenobiotic metabolites were associated with sleep duration and heart rate phenotypes (e.g. 1H-indole-7-acetic acid, 4-allylphenol sulfate), while ketone bodies and fatty acid metabolism metabolites were associated with sleep timing measures (e.g. 3-hydroxybutyrate (BHBA), 3-hydroxyhexanoylcarnitine (1)). Heart rate phenotypes had the overall largest number of detected metabolite associations. Many of these associations were shared with both SDB and with sleep timing phenotypes, while SDB phenotypes shared relatively few metabolite associations with sleep duration measures. A number of metabolites were associated with multiple sleep phenotypes, from a few domains. The amino acids vanillylmandelate (VMA) and 1-carboxyethylisoleucine were associated with the greatest number of sleep phenotypes, from all domains other than insomnia. This atlas of sleep-metabolite associations will facilitate hypothesis generation and further study of the metabolic underpinnings of sleep health.
Shared genetic features between lymphoma pathogenesis and oestrogen levels
Authors: Hill Claire , Muckian Marisa , Garre Marisa Cañadas , Greenfield Graeme , Maxwell Alexander P. , McShane Charlene M. , Anderson Lesley Ann , McKnight Amy Jayne
Published: May 2024

In the last decade, genetic analysis has aided lymphoma classification, alongside traditional phenotypic subdivision. Lymphomas exhibit sex differences in disease incidence and prevalence; therefore, scope existed to explore sex-specific genetic variation.

Harnessing UK Biobank genetic data (185,000 females, 176,000 males), sex-specific genome-wide genetic variation significantly associated with lymphoma subtypes was determined in both autosomal and sex chromosome genes. Sex-specific genetic variation significantly associated with sex-related characteristics was also identified. Functional predictions for those genes containing significant (p<5×10-5) genetic variation was carried out via ViSEAGO. For each lymphoma subtype, approximately 10-12% of the genes containing significantly associated genetic variants were shared between the sexes, highlighting largely sex-specific profiles for lymphoma subtypes.

Significantly associated X chromosome genetic variants were identified for Non-Hodgkin’s lymphoma (NHL) and Diffuse large B-cell lymphoma (DLBCL), such as variants withinSYTL5(in males) andPPP2R3B(in females); genes previously implicated in haematological malignancy biological processes. Additionally, in female NHL patients, a genetic variant mapped toESR1, the gene coding for oestrogen receptor-α was identified, adding to the body of evidence highlighting the relevance of oestrogen regulation for haematological malignancy subtypes.

Indeed, up to 9.1% of overlap was observed between those genes containing significant genetic variation associated with specific lymphoma subtypes, and those significantly associated with oestrogen level determination. Gene ontology analysis further emphasised functional overlaps between lymphoma and oestrogen level determination in females, highlighting predicted involvement in epigenetic modification, gene expression, and signalling.

This study revealed sex-specific genetic variation significantly associated with lymphoma, as well as hormone level determination, and revealed biological pathways potentially disrupted during lymphoma pathogenesis which are influenced by oestrogen. Exploring these pathways may advance our understanding of the sex-specificities of lymphoma, and may reveal therapeutic targets to advance patient care.
Predictors of Postviral Symptoms Following Epstein-Barr Virus-Associated Infectious Mononucleosis in Young People – Data from the IMMUC Study
Authors: Bodenhausen Maren , Geisperger Jonas , Lange de Luna Julia , Wendl Johannes , Hapfelmeier Alexander , Schulte-Hillen Lina , Pricoco Rafael , Körber Nina , Bauer Tanja , Mautner Josef , Hoffmann Dieter , Luppa Peter , Egert-Schwender Silvia , Nößner Elfriede , Delecluse Henri-Jacques , Delecluse Susanne , Hauck Fabian , Falk Christine , Schulz Thomas , Steinborn Marc-Matthias , Bietenbeck Andreas , Nieters Alexandra , Mihatsch Lorenz , Gerrer Katrin , Behrends Uta ,   the IMMUC Study Group
Published: May 2024

Background

Epstein-Barr virus-associated Infectious Mononucleosis (EBV-IM) is a common disease following primary EBV infection in children and adolescents. While EBV-IM is mostly self-limiting, symptoms like fatigue may persist over several months or even result in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This large clinical observational study aimed at identifying risk factors for protracted courses of EBV-IM in young people.

Methods

A cohort of N=200 children, adolescents, and young adults with acute primary EBV infection was recruited from hospitals and private practices. Data on the patients’ medical history as well as clinical and laboratory parameters were collected at a baseline visit (V1) within four weeks after symptom onset (Tonset) and at two follow-up visits (V2 and V3) one and six months after Tonset. Risk factors for protracted symptoms at V3 were modeled using multivariable logistic regressions.

Results

Protracted symptoms were observed in 55/183 (30.1%) and protracted fatigue in 34/181 (18.8%) patients at V3. A medical history indicating an increased susceptibility to infectious diseases as well as distinct severe IM symptoms, e.g. severe gastrointestinal symptoms, were significantly associated with protracted disease [OR: 2.31; P=0.011 and OR: 3.42; P=0.027] and with chronic fatigue [OR: 2.98; P=0.006 and OR: 3.54; P=0.034], respectively. Occurrence of twelve or more clinical and laboratory parameters until and including V1 discriminated between fatigue and no fatigue at V3 [OR 2.43, P=0.033].

Conclusion

A clinical history of immune dysregulation as well as distinct severe IM symptoms might predict protracted post-viral disease and thus help in the identification of young patients at risk.

Highlights

Severe gastrointestinal symptoms are associated with protracted course of Epstein-Barr virus-associated Infectious Mononucleosis (EBV-IM).

Signs of immune dysregulation prior to EBV-IM can indicate an increased risk of protracted symptoms.

Greater number of initial symptoms helps to identify patients developing postviral fatigue.