bluuebunny/crossref_metadata_2025 huggingface dataset:
Chronic Wound Caused by Lymphorrhea after Skin Abscess Drainage on Lower Extremity: A Case Report
Authors: Tian Jin-yi
Published: August 2024

Surgical operations such as lymph node dissection may inadvertently damage the lymphatic system and lead to lymphorrhea. Excessive lymphatic exudation can cause a chronic wound. However, for surgery that does not involve the lymphatic system, lymphorrhea is a rare postoperative complication. This case report describes a 38-year-old patient who presented with lymphatic cutaneous leakage after incision and drainage of a skin abscess on the lower extremity. Persistent lymphorrhea increased the amount of wound exudation, which affected wound healing. After treatment of the lymphorrhea, the lower extremity wound healed completely within 4 weeks and did not result in lymphedema. Ligation of lymphatic vessels is a simple and easily performed treatment method for lymphatic leakage.
Systemic inflammation and menopausal symptomatology: insights from postmenopausal women
Authors: Korpe Busra , Kose Caner , Keskin Huseyin Levent
Published: August 2024

Objective

This study aims to investigate the association between systemic inflammation, measured by the systemic immune-inflammatory index (SII), and menopausal symptoms in postmenopausal women.

Methods

A cross-sectional study was conducted with 702 postmenopausal women recruited from a tertiary hospital. Participants completed the Menopause Rating Scale (MRS) to assess somatic, psychological, and urogenital symptoms. Blood samples were collected to calculate SII. Statistical analyses included correlation, univariate regression, and multivariate regression to determine the association between SII and menopausal symptoms.

Results

The most commonly reported symptoms were muscle and joint problems (75.9%), hot flashes and sweating (72.5%), sleeping problems (71.2%), and depressive mood (69.9%). Women with higher total and somatic subscale scores had significantly elevated SII levels compared with those with lower scores. SII was the most associated variable for high total MRS (odds ratio, 4.77; 95% CI, 3.36-6.78; P < 0.001) and somatic subscale scores (odds ratio, 6.32; 95% CI, 4.45-8.99; P < 0.001). Exercise and gravidity were negatively associated with high total MRS and somatic subscale scores. Conversely, no significant associations were observed between SII and the urogenital or psychological subscale scores.

Conclusion

Elevated SII levels were found associated with higher somatic subscale and total MRS scores, suggesting that inflammation may contribute to worsened somatic menopausal symptoms in this group. These findings suggest that exploring inflammatory pathways could be beneficial in managing menopausal symptoms and enhancing quality of life for postmenopausal women.
Clinical Presentation of Enterovirus D68 in a Swiss Pediatric University Center
Authors: Ott Chantal , Dutilh Gilles , Reist Josiane , Bingisser Roland , Egli Adrian , Heininger Ulrich
Published: August 2024

Background:

Enterovirus D68 (EV-D68) is responsible for millions of infections. In the last decade, there has been an increase in the number of children requiring hospital or critical care admission due to severe respiratory illness. Nevertheless, the epidemiological and clinical importance of EV-D68 infections remains unclear.

Objective:

We aimed to determine the local prevalence of EV-D68 infection in pediatric patients and to characterize its clinical presentation and disease burden compared with non-EV-D68 enterovirus and human rhinovirus (RV) infections.

Study design:

We performed a retrospective single-center study of children presenting with respiratory symptoms and positive respiratory panel polymerase chain reaction for EV/RV from November 2018 to December 2019. We tested EV/RV positive specimens with an EV-D68-specific polymerase chain reaction to discriminate EV-D68, non-EV-D68 and RV and compared their respective clinical presentation, outcomes and treatment.

Results:

We identified 224 patients (median age 21 months), of which 16 (7%) were EV-D68 positive. They presented with cough (88%), wheezing (62%) and dyspnea (75%). EV-D68 infection had an odds ratio regarding pediatric respiratory severity-score of 11.6 relative to non-EV-D68 [confidence intervals (CI): 3.51–41.14], and of 9.9 (CI: 3.75–27.95) relative to RV. The fitted logistic regression showed that the odds of intensive care were 5 times more likely with EV-D68 than RV infection (CI: 1.32–19.28; P = 0.001). Patients with EV-D68 infections were more likely to receive medical support in the form of supplementary oxygen, antibiotics and steroids.

Conclusions:

EV-D68 infection is associated with higher morbidity and a higher likelihood of intensive care treatment than non-EV-D68 and RV infections.
Sulfamethoxazole-Trimethoprim Prophylaxis in Pediatric Oncology Patients With Glucose-6-Phosphate Dehydrogenase Deficiency
Authors: Stone Rachael M. , Haidar Cyrine E. , Kornegay Nancy M. , Barker Patricia J. , Karol Seth E. , Wolf Joshua , Hankins Jane S. , Relling Mary V. , Crews Kristine R.
Published: August 2024

We sought to determine whether Pneumocystis jirovecii pneumonia prophylaxis with sulfamethoxazole-trimethoprim (SMX-TMP) is associated with an increased frequency of acute hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency versus non-G6PD-deficient controls in a pediatric oncology population. There was no statistically significant difference in change in hemoglobin or transfusion requirements after starting SMX-TMP between groups. These findings suggest no increased risk of acute hemolytic anemia with SMX-TMP administered at prophylaxis doses in patients with G6PD deficiency.
Burnout Reduction Strategies Using Mobile-Based Applications: The Creation and Development of the SANE Well App
Authors: Williams Deborah , Bouchard Lindsay , Giraldo Isabel , Carstensen Gary , Kiser Lisa , Acosta Lauren , Buxbaum Susan , Wong Ava , Taren Douglas
Published: August 2024

Introduction

Sexual assault nurse examiners (SANEs) provide specialized medical forensic care to survivors of sexual assault, often working in stressful conditions, with routine exposure to the traumatic experiences of their patients. SANEs experience high levels of both vicarious trauma and burnout.

Purpose

The purpose of this article was to describe the development of a SANE support application, accessible to all SANEs, that utilizes self-care and positive coping strategies to enhance SANE resilience and thereby reduce burnout.

Methods

The conceptual framework for the SANE support application was psychological first aid, an evidence-informed, manualized intervention to assist individuals in the immediate aftermath of exposure to potentially traumatic events. Focus groups with SANEs informed the content of the application named “SANE Well.”

Result

SANE Well delivers these helpful coping elements within an easy-to-use, mobile platform, at no cost. User testing during two SANE clinical skills laboratory trainings revealed the app had smooth and efficient functionality and meets its intended goals without unnecessary complexities.

Conclusion

There is an urgent need for SANEs to protect their well-being while they care for individuals who have experienced sexual assault. The SANE Well application offers a novel way to provide and encourage positive coping strategies for nurses to reduce burnout.
Leapfrog Safety Grades in California Hospitals: A Data Analysis
Authors: Razick Daniel , Amani Noorhan , Ali Lara , Bachir Mark , Salem Ahmed , Khatri Vijay
Published: August 2024

Within the realm of health care quality assessment, quality assurance and safety grading systems play a vital role in gauging hospital performance and communicating results to the general public. The primary objective of this review is to analyze the hospitals in California through the lens of Leapfrog Safety Grades and discuss the complex interplay of geographical location, hospital size, and larger system affiliation status. Leapfrog Safety Grades, hospital characteristics, and geographic information were collected. Hospitals were categorized by geographic region, size, rural/urban classification, and larger system affiliation status. Of the 284 hospitals included in the study, 95 were given a grade of A, 68 given a grade of B, 93 given a grade of C, 23 given a grade of D, 2 given a grade of F, and 3 were not graded. The vast majority of hospitals in California were classified as urban, with 183 falling under this category. The average number of hospital beds and SD was 227 ± 47.57. On average, hospitals that received a grade of D were significantly smaller in size than those that received a grade of A, while hospitals that received a grade of B or C were similar in size. A total of 107 hospitals were affiliated with a larger health care system. About 70% of hospitals affiliated with a system received an A or B grade, while 50% of unaffiliated hospitals received an A or B grade. Results of this study demonstrate a need for improving health care access and quality in medically underserved urban and rural areas. Hospitals affiliated with a larger health care system received higher grades than unaffiliated hospitals, suggesting that affiliation may also play a role in the implementation and mitigation of factors that contribute to Leapfrog Safety Grades.
The Impact of Transitional Shock on Newer Nurses in a Contemporary Healthcare Environment
Authors: Holtz Heidi , McQueen Amy , Weissinger Guy , Alderfer Mary , Swavely Deborah , Sledge Jennifer A. , Yu Lihua , Pohlman Megan , Adil Thomas , Mugoya Rosemary , Minchhoff Robin , Rushton Cynda
Published: August 2024

OBJECTIVE

The aim of this study was to understand newer nurses' perception and expectations of their work environment, professional and institutional satisfaction, and motivating/decision-making factors around nursing and intent to leave their positions.

BACKGROUND

Studies have shown newly graduated nurses face many challenges transitioning from a student to an independently practicing nurse. The COVID pandemic complicated this transition and created new stressors resulting in discouragement and turnover for newer nurses.

METHODS

This study used a qualitative approach through purposive sampling, semistructured qualitative interviews, and content analytic techniques. Transitional Shock Theory was used as the theoretical framework.

RESULTS

Four themes emerged from the study: 1) confronting the reality; 2) betrayal/mistrust; 3) relational integrity; and 4) enablers of clinical competence.

CONCLUSIONS

The findings will help nurse leaders understand the importance of organizational-level supports to improve the transition of newer nurses in typical periods and in times of additional stress.
Content Validation for a Medical-Surgical Orientation Competency Assessment Instrument
Authors: Hopkins Pepe Loraine , Duddy Patricia , Golbitz Patricia , Kling Karyn , Pecoraro Nicole , Poindijour Myriam , Smith Jessica , Altmiller Gerry
Published: August 2024

Demonstration of competency is an essential component of nursing orientation in the practice environment. Standardization of the assessment with a validated instrument supports high-quality care and patient safety. This study engaged six nurse experts to establish content validation for a newly developed competency-based assessment framed by the domains of the national standard for nursing education. Two rounds of rigorous review resulted in a scale content validity index universal agreement calculation of .891, indicating that all items were evaluated as relevant for inclusion in this comprehensive measure of registered nurse clinical competency in the medical-surgical specialty.
Critical elements of international academic partnerships in orthopaedic surgery: a modified Delphi approach
Authors: Flores Michael J. , MacKechnie Madeline C. , Rodarte Patricia , O'Marr Jamieson M. , Brown Kelsey E. , Shearer David W. , Miclau Theodore ,   COACT Delphi Study Group
Published: August 2024

Background:

Despite the recent emphasis on promoting international collaborations within orthopaedic surgery, criteria for determining the strengths of such partnerships has not been established. The purpose of this study was to evaluate orthopaedic experts' perceptions of the most valuable characteristics of international academic partnerships.

Methods:

This study was conducted using a modified Delphi methodology. Experts were identified through the Consortium of Orthopaedic Academic Traumatologists (COACT). Responses were collected from February to September 2022. Three rounds of surveys listing possible topics on a 5-point Likert scale were used to develop consensus among a group of experts. Consensus criteria for topic inclusion in the final scale was determined as a rating of “strongly agree” or “agree” by ≥70% of the participants in the third survey.

Results:

The Round 1 survey was distributed to 96 invited participants within the COACT network, of which 50 experts (52.1%) completed the first survey. Consensus was reached on 54 topics organized into the following 5 categories: Research, Advocacy/Leadership, Training/Surgical Skills, Education/Knowledge Exchange, and Sustainability and Safety (RATES Criteria).

Conclusions:

Determining the most valuable characteristics of successful international academic partnerships can lead to more sustainable, mutually beneficial collaborations. The criteria identified in this study can provide the foundation for developing new partnerships and assessing existing ones.
Traumatic Injuries From Low Speed Vehicles and Golf Carts
Authors: Barber Kristina , Nikolis Andrea , Machek Megan , Akuthota Venu , Odom Nathan
Published: August 2024

With increasing use of golf carts and low speed vehicles for recreational, work-related, and commuting purposes, the number of related injuries is also on the rise. The body of literature describing these injuries is informative but limited. From this scoping review, we found that low speed vehicle–related injuries preferentially affect children, older adults, and males. Common mechanisms of injury include ejection and collision. Associated alcohol consumption is common and typically related to increasing severity of injury. Various injuries may result from low speed vehicles as described in the review, including soft tissue injuries, orthopedic injuries, and traumatic brain injury. Description of trends and classifications of injury will hopefully improve reporting and ability to make recommendations on safe use and regulation.
THE ROLE OF TRANEXAMIC ACID IN POSTPARTUM HEMORRHAGE: A NARRATIVE REVIEW
Authors: Larson Nicholas J. , Mergoum Anaas Moncef , Dries David J. , Cook Alan , Blondeau Benoit , Rogers Frederick B.
Published: August 2024

Postpartum hemorrhage is the leading cause of preventable maternal illness and death globally and carries a disproportionately high burden of mortality in low- to middle-income countries. Tranexamic acid, an antifibrinolytic drug, has been widely adopted to control bleeding in trauma and other surgical conditions. Within the last decade, the World Health Organization updated their guidelines for the treatment of postpartum hemorrhage to include the use of tranexamic acid in all cases of postpartum hemorrhage. However, despite these guidelines and the proven utility of tranexamic acid to treat postpartum hemorrhage, widespread adoption of tranexamic acid into global standards of care across professional organizations has not been achieved. It is important for healthcare providers to understand the etiologies of postpartum hemorrhage, the mechanism of action and adverse effect profile of tranexamic acid, and the available literature regarding the use of tranexamic acid to prevent and treat postpartum hemorrhage to provide the best care for the pregnant patient.
The Role of Coronavirus Spike Protein in Inducing Optic Neuritis in Mice: Parallels to the SARS-CoV-2 Virus
Authors: Kasle Grishma , Das Sarma Jayasri
Published: August 2024

Background:

Optic neuritis (ON), one of the clinical manifestations of the human neurological disease multiple sclerosis (MS), was also reported in patients with COVID-19 infection, highlighting one potential neurological manifestation of SARS-CoV-2. However, the mechanism of ON in these patients is poorly understood.

Evidence Acquisition:

Insight may be gained by studying the neurotropic mouse hepatitis virus (MHV-A59), a β-coronavirus that belongs to the same family as SARS-CoV-2.

Results:

Mouse hepatitis virus-A59, or its isogenic spike protein recombinant strains, inoculation in mice provides an important experimental model to understand underpinning mechanisms of neuroinflammatory demyelination in association with acute stage optic nerve inflammation and chronic stage optic nerve demyelination concurrent with axonal loss. Spike is a surface protein that mediates viral binding and entry into host cells, as well as cell–cell fusion and viral spread. Studies have implicated spike-mediated mechanisms of virus-induced neuroinflammatory demyelination by comparing naturally occurring demyelinating (DM) and nondemyelinating (NDM) MHV strains.

Conclusions:

Here, we summarize findings in MHV-induced experimental ON and myelitis, using natural DM and NDM strains as well as engineered recombinant strains of MHV to understand the role of spike protein in inducing ON and demyelinating disease pathology. Potential parallels in human coronavirus-mediated ON and demyelination, and insight into potential therapeutic strategies, are discussed.
Microbial infection among SARS-COV-2-infected patients in a COVID-19-dedicated tertiary care hospital of Bangladesh: a cross-sectional study
Authors: Islam A. N. M. Shamsul , Farhana Nasreen , Choudhury Rafaat , Jahan Naznin Akter , Uddin Mohammad Jamal , Refat Md. Nazmul Hassan , Nasreen Fatima , Khanam Fahmida
Published: August 2024

Objectives. This study aimed to determine patterns of respiratory, blood-borne and uropathogenic microbial pathogens among SARS-CoV-2-infected patients in a COVID-19-(coronavirus disease 2019) dedicated tertiary care hospital in Dhaka, Bangladesh.

Design.This was a cross-sectional study.

Setting. In a COVID-19-dedicated tertiary care hospital in Dhaka, Bangladesh, conducted from March to June 2021.

Participants. Hospitalized individuals with COVID-19 infection regardless of age or sex.

Primary and secondary outcome measures. The percentage of co-infected COVID-19 patients and the characterization of the micro-organisms responsible for co-infection served as the primary outcome measures. Finding any associations between co-infection and age, co-infection and sex and co-infection and comorbidity was the secondary outcome variable.

Interventions. Not applicable.

Results. Out of 79 patients, 61 % were male, and the mean age was 49.53 years. Co-infection was seen in 7.7 % of patients, out of which 5.1 % of isolates were from urine samples, followed by 2.6 % from blood. Bacteria isolated from urine were Enterococcus (2.6 %), coagulase-negative Staphylococcus (CONS) (1.3 %) and Enterobacter spp. (1.3 %). Pseudomonas spp. was the only organism isolated from blood sample. Mixed growth was found in nasopharyngeal and throat swabs, with the predominant species being Staphylococcus aureus and Streptococcus spp. At the time of data collection, 55.7 % of patients had been given antimicrobials, and 30.4 % of patients had been given a single antimicrobial. HBsAg was positive in 1.3 % of patients and none were anti-hepatitis C or dengue NS1Ag positive.

Conclusion. Microbial infection has been seen to be associated with SARS-CoV-2 infections and is of great value in prescribing antimicrobials and reducing fatal outcomes of hospitalized patients.
CH-related Mutant ASXL1 Promotes Atherosclerosis in Mice via Dysregulated Innate Immunity
Authors: Sato Naru , Goyama Susumu , Chang Yu-Hsuan , Fujino Takeshi , Denda Tamami , Asada Shuhei , Shikata Shiori , Liu Xiaoxiao , Yonezawa Taishi , Takeda Reina , Yamamoto Keita , Tanaka Yosuke , Honda Hiroaki , Ota Yasunori , Shibata Takuma , Sekiya Motohiro , Koide Shuhei , Lamagna Chrystelle , Masuda Esteban , Iwama Atsushi , Shimano Hitoshi , Inoue Jun-ichiro , Miyake Kensuke , Kitamura Toshio
Published: August 2024

Certain somatic mutations confer a fitness advantage in hematopoietic stem and progenitor cells (HSPCs) over normal HSPCs, resulting in the clonal expansion of mutant blood cells1, otherwise known as clonal haematopoiesis (CH). CH is frequently observed among healthy elderly people and is closely associated with the risk of cardiovascular diseases (CVDs). The most frequently mutated genes of CH includeDNMT3A, TET2, andASXL12. Among them, even thoughASXL1mutations are clinically associated with the highest risk for developing CVDs, little is known whether and how the mutations contribute to CVDs. Here we show accelerated development of atherosclerosis and increased inflammatory monocytes in mice transplanted with the bone marrow cells (BMCs) from the mice expressing mutant ASXL1 (ASXL1-MT) selectively in hematopoietic cells. RNA sequencing analysis of the plaque-macrophages derived from BMCs expressing ASXL1-MT showed more inflammatory signatures than those from control BMCs. Mechanistically, wild-type ASXL1 inhibited innate immune signalling through direct interactions with IRAK1/TRAF6/TAK1 in the cytoplasm, while ASXL1-MT, which only interacted with TAK1, lost this regulatory function, leading to NF-κB activation. This mechanism is unique and distinct from those of CH withTet2orDnmt3amutations, where overactivation of the IL-1β/NLRP3 inflammasome plays critical roles3–5. Intriguingly, IRAK1/4 inhibition decreased the number of inflammatory monocytes and attenuated the development of atherosclerosis driven by ASXL1-MT. The present work connects the mutations of an epigenetic factor, ASXL1, with inflammation and CVDs and gives an indication for the prevention of CVDs in CH.
Social and health conditions that drive the need, demand, utilisation and expenditure on social care in the United Kingdom: a protocol for a systematic review
Authors: Amies-Cull Ben , Shepperd Sasha , Roberts Nia , Mason Anne , Bojke Laura , Clarkson Paul , Scott Anna Mae
Published: August 2024

Background

Social care is the personal and practical assistance provided to individuals in their daily activities, personalised around their circumstances to promote wellbeing. It is provided by formal and informal carers, with formal care supported by considerable public resources through the Adult Social Care function of local authorities. While it is a matter of great public and policy concern that the system better meet people’s needs and that public finances are not unsustainably strained, some key drivers of adult social care need, such as the relationships between age, social determinants, environmental conditions, and health status are not well understood at the system level. This is a protocol for a systematic review of the evidence to determine the health and social drivers that contribute to adults’ need and demand for and utilisation of social care in the UK, and how these interact.

Methods

We will include quantitative studies of any experimental, observational or simulation/modelling design with average participant age ≥60, that examine the relationships between health status and/or social conditions, and their impact on adult social care need, demand, utilisation and expenditure. Informal and formal domiciliary, residential and nursing care, professional social work and occupational therapy will be included.

Medline, CINAHL, EconLit, ASSIA Campbell Collaboration and grey literature will be searched. A single reviewer will screen titles/abstracts for eligibility, and two reviewers will independently screen the full-text of studies initially considered eligible. 15% of the included studies will be double-extracted, and remainder single extracted with an accuracy check.

Risk of bias will be assessed using Cochrane Risk of Bias 2 and ROBINS-I.

The findings will be grouped by health condition(s), the type of determinant, outcome and will be presented in an evidence gap map. If three or more comparable studies are identified, we will consider calculating the effect size. We will use GRADE to assess the evidence certainty.

Discussion

We will detail the evidence on the relationships (to include an indication of their contribution) between health status and social conditions with the need, demand, utilisation and expenditure on adult social care in the UK, informing further analyses in key evidence gaps.
The potential clinical impact and cost-effectiveness of the updated COVID-19 mRNA Autumn 2024 vaccines in the United Kingdom
Authors: Kohli Michele A. , Maschio Michael , Lee Amy , Joshi Keya , Carroll Stuart , Balogh Orsolya , van de Velde Nicholas , Beck Ekkehard
Published: August 2024

Aims

To estimate the potential clinical impact and cost-effectiveness of a United Kingdom (UK) Autumn 2024 vaccination campaign with an updated Moderna COVID-19 vaccine in adults ≥65 years and eligible persons 6 months to 64 years of age over a 1-year time horizon (September 2024-August 2025).

Materials and methods

A compartmental Susceptible-Exposed-Infected-Recovered model was adapted to reflect COVID-19 cases in the UK. Numbers of symptomatic infections, COVID-19– related hospitalizations and deaths, costs, and quality-adjusted life-years (QALYs) were predicted using a decision tree. The incremental cost-effectiveness ratio (ICER) of an updated Moderna mRNA vaccine (Moderna Autumn 2024 Campaign) was compared to no Autumn 2024 vaccine and to an updated Pfizer-BioNTech mRNA Autumn 2024 vaccine, from a healthcare perspective.

Results

The Moderna Autumn 2024 Vaccination Campaign is predicted to decrease the expected 8.3 million symptomatic infections with no vaccination by 19% to 6.7 million. Hospitalizations, long COVID cases, and deaths are expected to decline by 27,000 (−38%), 59,000 (−19%), and 6000 (−43%), respectively. The Moderna Autumn 2024 Campaign will increase QALYs by 78,000 and costs by £665 million, yielding an ICER of £8500/QALY gained. Sensitivity analyses suggest that vaccine effectiveness (VE) and waning, symptomatic infection incidence, hospitalization rates, and mortality rates drive cost-effectiveness. Vaccination remains cost-effective when lowering the target population to ≥50 years. Use of the Moderna vaccine is expected to prevent 8000 more hospitalizations and 1700 more deaths than the updated Pfizer-BioNTech vaccine.

Conclusions

Vaccination of the eligible population would contribute to significant reductions in hospitalizations, deaths, and long COVID in the UK in the 2024-2025 season. Expanding the target population continues to be cost-effective. Use of the Moderna Autumn 2024 Campaign is predicted to reduce SARS-CoV-2 infections and associated outcomes in a cost-effective manner and will contribute to a more resilient healthcare system in the UK.
Predicting the impact of non-pharmaceutical interventions against COVID-19 onMycoplasma pneumoniaein the United States
Authors: Park Sang Woo , Noble Brooklyn , Howerton Emily , Nielsen Bjarke F , Jiudice Sarah S , Ambroggio Lilliam , Dominguez Samuel , Messacar Kevin , Grenfell Bryan T
Published: August 2024

The introduction of non-pharmaceutical interventions (NPIs) against COVID-19 disrupted circulation of many respiratory pathogens and eventually caused large, delayed outbreaks, owing to the build up of the susceptible pool during the intervention period. In contrast to other common respiratory pathogens that re-emerged soon after the NPIs were lifted, longer delays (>3 years) in the outbreaks ofMycoplasma pneumoniae(Mp), a bacterium commonly responsible for respiratory infections and pneumonia, have been reported in Europe and Asia. As Mp cases are continuing to increase in the US, predicting the size of an imminent outbreak is timely for public health agencies and decision makers. Here, we use simple mathematical models to provide robust predictions about a large upcoming Mp outbreak in the US. Our model further illustrates that NPIs and waning immunity are important factors in driving long delays in epidemic resurgence.
Rethinking large scale phylogenomics with EukPhylo v1.0, a flexible toolkit to enable phylogeny-informed data curation and analyses of diverse eukaryotic lineages
Authors: Katz Laura A , Cote-L'Heureux Auden E , Leleu Marie , Ani Godwin , Gawron Rebecca
Published: August 2024

Eukaryotic diversity is largely microbial, with macroscopic lineages (plant, animals and fungi) nesting among a plethora of diverse protists. Understanding the evolutionary relationships among eukaryotes is rapidly advancing through omics analyses, but phylogenomics are challenging for microeukaryotes, particularly uncultivable lineages, as single-cell sequencing approaches generate a mixture of sequences from hosts, associated microbiomes, and contaminants. Moreover, many analyses of eukaryotic gene families and phylogenies rely on boutique datasets and methods that are challenging for other research groups to replicate. To address these challenges, we present EukPhylo v1.0, a modular, user-friendly pipeline that enables effective data curation through phylogeny-informed contamination removal, estimation of homologous gene families (GFs), and generation of both multisequence alignments and gene trees. Analyses can use a hook database of ~15k ancient GFs or users can easily replace this hook with a set of gene families of interest. We demonstrate the power of EukPhylo, including a suite of stand-alone utilities, through analyses of 500 conserved GFs sampled from 1,000 diverse species of eukaryotes, bacteria and archaea. We show improvements in estimates of the eukaryotic tree of life, recovering clades that are well established in the literature, through successive rounds of curation using the EukPhylo contamination loop. The final trees corroborate numerous hypotheses in the literature (e.g. Opisthokonta, Rhizaria, Amoebozoa) while challenging others (e.g. CRuMs, Obazoa, Diaphoretickes). We believe that the flexibility and transparency of EukPhylo sets standards for curation of omics data for future studies.
Uncovering immune characteristics of neurons in the context of multiple sclerosis and experimental autoimmune encephalomyelitis
Authors: Mohammadnia Abdulshakour , Drake Sienna Sage , Zandee Stephanie E.J. , Gosselin David , Antel Jack P. , Prat Alexandre , Fournier Alyson
Published: August 2024

Multiple sclerosis (MS) is an immune-mediated disease characterized by chronic inflammation and damage to the central nervous system, and substantial characterization of molecular signatures of glial and immune cells in the disease has been conducted. However, comparatively less well characterized is the molecular signature of pathologically inflamed neurons. Here, we accessed multi-omic high-throughput transcriptomic and epigenomic data to investigate the molecular signature of neurons from progressive MS patients and from mice subjected to experimental autoimmune encephalomyelitis (EAE). Our results indicate a shared and consistent neuronal gene expression signature in MS and EAE samples including a notable upregulation of immune system related genes and processes. Analysis of immune-enriched pathways in retinal ganglion cells (RGCs) and motor neurons from mice subjected to EAE revealed enrichment for the major histocompatibility complex class I pathway and interferon response genes in both types of neurons, and ATAC-seq analysis confirmed the accessibility of these genes. Parallel analyses of neurons from MS patients identified a signature of 48 commonly upregulated immune genes in neurons. Prediction of transcriptional regulators of these genes identified key upstream regulators including signal transducer and activation of transcription 1 (STAT1) and interferon response factor 5 (IRF5), highly involved in immune-related processes, with significant gene expression changes in both RGCs and motor neurons. Protein-protein interaction analyses among the transcriptional regulators unveiled intricate interactions among transcription factors, especially from the IRF and STAT families, suggesting their importance in regulating immune gene expression in inflamed neurons. Small molecule inhibition of IRF5 in inflamed neuronsin vitropromoted cell survival and reduced the expression of the immune gene signature, supporting the biological relevance of IRF5 in mediating the neuronal inflammatory response. Together, this study identifies regulated immune processes in neurons from EAE mice and from MS patient samples suggesting potential roles for neuronal immune molecules in disease progression, as revealed by transcriptomic, epigenomic, and experimental approaches. Further, the results strongly implicate active interferon signaling in neurons driving immune related changes in gene expression through IRF5 and STAT1 transcription factor activity, potentially impacting downstream neuronal survival through IRF5 activity.
Hepatic iNKT cells facilitate colorectal cancer metastasis by inducing a fibrotic niche in the liver
Authors: Nater Marc , Brügger Michael , Cecconi Virginia , Pereira Paulo , Forni Geo , Köksal Hakan , Dimakou Despoina , Herbst Michael , Calvanese Anna Laura , Lucchiari Giulia , Schneider Christoph , Valenta Tomas , van den Broek Maries
Published: August 2024

The liver is an important metastatic organ that contains many innate immune cells, yet little is known about their role in anti-metastatic defense. We investigated how invariant natural killer T (iNKT) cells influence colorectal cancer-derived liver metastasis using different models in immunocompetent mice. We found that hepatic iNKT cells promote metastasis by creating a supportive niche for disseminated cancer cells. Mechanistically, iNKT cells respond to disseminating cancer cells by producing the fibrogenic cytokines IL-4 and IL-13 in a TCR-independent manner. Selective abrogation of IL-4 and IL-13 sensing in hepatic stellate cells prevented their transdifferentiation into extracellular matrix-producing myofibroblasts, which hindered metastatic outgrowth of disseminated cancer cells. This study highlights a novel tumor-promoting axis driven by iNKT cells in the initial stages of metastasis.
Acute inhibition of iron-sulfur cluster biosynthesis disrupts metabolic flexibility in mice
Authors: Molenaars Marte , Mir Hannan , Alvarez Samantha W. , Arivazhagan Lakshmi , Rosselot Carolina , Zhan Di , Park Christopher Y , Garcia-Ocana Adolfo , Schmidt Ann Marie , Possemato Richard
Published: August 2024

Iron-sulfur clusters (ISCs) are cell-essential cofactors present in ∼60 proteins including subunits of OXPHOS complexes I-III, DNA polymerases, and iron-sensing proteins. Dysfunctions in ISC biosynthesis are associated with anemias, neurodegenerative disorders, and metabolic diseases. To assess consequences of acute ISC inhibition in a whole body setting, we developed a mouse model in which key ISC biosynthetic enzyme NFS1 can be acutely and reversibly suppressed. Contrary to in vitro ISC inhibition and pharmacological OXPHOS suppression, global NFS1 inhibition rapidly enhances lipid utilization and decreases adiposity without affecting caloric intake and physical activity. ISC proteins decrease, including key proteins involved in OXPHOS (SDHB), lipoic acid synthesis (LIAS), and insulin mRNA processing (CDKAL1), causing acute metabolic inflexibility. Age-related metabolic changes decelerate loss of adiposity substantially prolonged survival of mice with NFS1 inhibition. Thus, the observation that ISC metabolism impacts organismal fuel choice will aid in understanding the mechanisms underlying ISC diseases with increased risk for diabetes.

Graphical abstract

Highlights

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Acute ISC inhibition leads to rapid loss of adiposity in mice

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Multi-metabolic pathway disruption upon ISC deficiency blocks energy storage

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Nfs1 inhibition induces glucose dyshomeostasis due to ISC deficiency in β-cells

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Energy distress caused by inhibition of ISC synthesis is attenuated in aged mice
Cerebellar encoding of prior knowledge of temporal statistics
Authors: Koppen Julius , Bayones Lucas , Runge Marit , Klinkhamer Ilse , Narain Devika
Published: August 2024

We possess the ability to anticipate and preempt occurrences under familiar circumstances, which suggests a reliance on prior experience with regularities in our environment, especially when observations become more uncertain. We know little about the neural mechanisms that can learn the probabilities of events in the environment and use this prior experience to guide actions. To examine this, we studied a rudimentary predictive behavior, eyeblink conditioning, and asked whether a simple effector like the eyelid could adapt its movements to varying probabilities of environmental events that reflect different degrees of uncertainty. We found that predictive eyeblink behavior systematically changed almost all its properties according to the temporal statistics of stimulus probability distributions. We also found that the activity of cerebellar Purkinje cells and putative molecular layer interneurons changed concomitantly with temporal statistics of the stimuli and with behavior. Targeted optogenetic perturbation of Purkinje cells during critical time windows severely attenuated the predictive behavior but left reflexive eyeblinks intact. Furthermore, we discovered a novel Purkinje cell complex spike signal coinciding with the onset of the earliest probable time interval in prior distributions with high uncertainty. This signal could not be explained as a motor or sensory correlate and appears to be anticipatory in nature. Theoretical modeling results pointed to a possible synaptic mechanism for how Purkinje cells could encode prior experience of environmental statistics in their activity through the juxtaposition of long-term depression and potentiation dynamics.
Multimodal imaging reveals multiscale mechanical interplay in vertebral endplate microarchitecture during intervertebral disc loading
Authors: Parmenter Alissa L. , Newham Elis , Sharma Aikta , Disney Catherine M. , Deyhle Hans , Bosi Federico , Terrill Nick J. , Bay Brian K. , Pitsillides Andrew A. , Gupta Himadri S. , Lee Peter D.
Published: August 2024

The optimal biomechanical function of the spine depends on hierarchical structures spanning the whole joint to molecular scales. The vertebral endplates experience complex, location specific loading from the intervertebral discs, and their biomechanical behaviour is governed by the microarchitecture, mineralisation, and prestrain of their constituent bone and cartilage. Here we use a combination of synchrotron X-ray tomography, digital volume correlation, and wide-angle X-ray diffraction to investigate relationships between microstructure and mechanics, nanoscale mineral structure, and molecular level prestrain in murine vertebral endplates. Our results show radial variation in endplate structure and local mechanical strain, revealing tensile and shear strains as potential drivers of the cartilage to bone transition. Bone contained narrower mineral crystallites under greater compressive prestrain when compared to calcified cartilage. This multiscale structural adaptation supports load resistance adjacent to the annulus fibrosus and elastic deformation below the nucleus pulposus. Our findings reveal the multiscale mechanics of these mineralised tissues, and the methods presented here have the potential to enhance our understanding of biomechanics in health, disease, and aging.
Fast implicit and slow explicit learning of temporal context in cortico-cerebellar loops
Authors: Mangili Luca , Wissing Charlotte , Narain Devika
Published: August 2024

One is seldom aware of the anticipatory and preemptive feats that the eyeblink systems achieves in daily life but it frequently protects the eye from projectiles gone awry and insects on apparent collision courses. This poor awareness is why predictive eyeblinks are considered a form of implicit learning. In motor neuroscience, implicit learning is considered to be slow and, eyeblink conditioning, in particular, is believed to be a rigid and inflexible cerebellar-dependent behavior. In cognitive neuroscience, however, implicit and automatic processes are thought to be rapidly acquired. Here we show that the eyeblink system is, in fact, capable of remarkable cognitive flexibility and can learn on more rapid timescales than previously expected. In a task where we yoked contextual learning of predictive eyeblinks and manual responses in humans, well-timed eyeblink responses flexibly adjusted to external context on each trial. The temporal precision of the predictive eyeblinks exceeded that of manual response times. Learning of the well-timed eyeblink responses was also more rapid than that for the manual response times. This pattern persevered with the use of a cognitive strategy, which seemed to accelerate both types of learning. These results suggest that behaviors associated with the cerebellar cortex that were previously believed to be inflexible and largely implicit, can demonstrate rapid and precise context-dependent temporal control.
Malnutrition drives infection susceptibility and dysregulated myelopoiesis that persists after refeeding intervention
Authors: Sukhina Alisa , Queriault Clemence , Hall Elise , Rome Kelly , Aggarwal Muskaan , Nunn Elizabeth , Weiss Ashley , Nguyen Janet , Bailis Will
Published: August 2024

Undernutrition is one of the largest persistent global health crises, with nearly 1 billion people facing severe food insecurity. Infectious disease represents the main underlying cause of morbidity and mortality for malnourished individuals, with infection during malnutrition representing the leading cause of childhood mortality worldwide. In the face of this complex challenge, simple refeeding protocols have remained the primary treatment strategy. Although an association between undernutrition and infection susceptibility has been appreciated for over a century, the underlying mechanisms remain poorly understood and the extent to which refeeding intervention is sufficient to reverse nutritionally acquired immunodeficiency is unclear. Here we investigate how malnutrition leads to immune dysfunction and the ability of refeeding to repair it. We find that chronic malnutrition severely impairs the ability of animals to control a sub-lethal bacterial infection. Malnourished animals exhibit blunted immune cell expansion, impaired immune function, and accelerated contraction prior to pathogen clearance. While this defect is global, we find that myelopoiesis is uniquely impacted, resulting in in reduced neutrophil and monocyte numbers prior to and post-infection. Upon refeeding, we observe that animals recover body mass, size, cellularity across all major immune organs, the capacity to undergo normal immune cell expansion in response to infection, and a restoration in T cell responses. Despite this broad improvement, refed animals remain susceptible to bacterial infection, uncoupling global lymphoid atrophy from immunodeficiency. Mechanistically, we find peripheral neutrophil and monocyte numbers fail to fully recover and refed animals are unable to undergo normal emergency myelopoiesis. Altogether, this work identifies a novel cellular link between prior nutritional state and immunocompetency, highlighting dysregulated myelopoiesis as a major driver. We believe these findings illustrate how exposure to food scarcity is an immunologic variable, even post-recovery, which should be accounted for in patient medical history and current global public health policy.
CCCTC-binding Factor (CTCF) N-terminal Domain Regulates Clustered Protocadherin Gene Expression by Enhancing Cohesin Processivity
Authors: Zhang Yijun , Wu Qiang
Published: August 2024

CTCF (CCCTC-binding factor) instructs three-dimensional (3D) genome folding by anchoring or forestalling cohesin loop extrusion, but the exact mechanism remains obscure. Here, using clustered protocadherins (cPcdh) as model genes, we report that CTCF assists or facilitates cohesin loop extrusion by enhancing its processivity. Specifically, we show that, compared with thePcdh αandγgene clusters, thePcdhβcluster is greatly affected upon CTCFY226A/F228Amutation in the N-terminal domain. Given the long-range distance of thePcdhβcluster from the distal enhancer, this finding has interesting implications in CTCF regulation of cohesin processivity along the linear chromatin during DNA loop extrusion. In particular, the effect on cohesin processivity upon CTCFY226A/F228Amutation is conspicuously similar to that of WAPL overexpression, suggesting that, in addition to the general view of blocking or forestalling cohesin, CTCF may actually enhance or facilitate cohesin loop extrusion during 3D genome folding. We conclude that CTCF enhances cohesin enrichments via the N-terminal YDF motif in clustered protocadherin genes in a genomic-distance biased manner.
Computational Simulations of Hyoid Bone Position and Tracheal Displacement: Effects on Upper Airway Patency and Tissue Mechanics
Authors: Bekdache Dana , Amatoury Jason
Published: August 2024

Surgical hyoid repositioning (HR) improves upper airway (UA) patency. Tracheal displacement (TD) is likely to impact HR outcomes, and vice versa, due to hyoid-trachea connections. This study used computational modeling to investigate the influence of TD and HR on UA outcomes and examine the impact of a more caudal baseline hyoid position (OSA phenotype).

Methods

A 2D finite element model of the rabbit UA was used to simulate TD and HR (in different directions), separately and combined. Model outcomes included UA closing pressure (Pclose), area, anteroposterior diameter (APD) and soft tissue mechanics (stress/strain). Simulations were repeated with a more caudal baseline hyoid position.

Results

Compared to baseline (TD=HR=0mm), TD alone reduced Pclose by −34%, increased area by 21% and APD by up to 18%. HR alone (except caudal) improved outcomes, particularly anterior-cranial HR which decreased Pclose by −106%, increased area by 32% and APD by up to 107%. TD+HR (except caudal) enhanced these outcomes, with TD+anterior-cranial HR further decreasing Pclose (−131%) and increasing area (55%) and APD (128%). A more caudal baseline hyoid position reduced the effect of TD+anterior-cranial HR on Pclose (−43%), area (49%) and APD (115%).

Conclusion

The combination of TD and HR (except caudal) improved UA outcomes even further than when either intervention was applied alone. A more caudal baseline hyoid position reduced the overall impact of each intervention. This study suggests that considering the baseline hyoid position, the degree of TD, and the extent/direction of surgical HR could be crucial in optimizing OSA treatment outcomes.

Key points summary

Surgical hyoid repositioning can improve upper airway patency and is a treatment for obstructive sleep apnea (OSA).

Tracheal displacement, also critical to upper airway function, likely influences hyoid repositioning outcomes due to hyoid-trachea connections.

This study used a computational model of the upper airway to simulate tracheal displacement and hyoid repositioning in various directions and magnitude, assessing their impact on upper airway collapsibility, size, and soft tissue mechanics. The influence of a more caudal baseline hyoid position, like in OSA, was also simulated.

Combining tracheal displacement with anterior-based hyoid repositioning, in particular, resulted in greater improvements in upper airway outcomes compared to tracheal displacement and hyoid repositioning alone.

A more caudal baseline hyoid position diminished the upper airway improvements with both interventions

Optimizing OSA treatment outcomes with hyoid surgeries may require considering the baseline hyoid position, the degree of tracheal displacement, and the direction/magnitude of surgical hyoid repositioning.