bluuebunny/crossref_metadata_2025 huggingface dataset:
A molecular epidemiological investigation of contagious caprine pleuropneumonia in goats and captive Arabian sand gazelle (Gazella marica) in Oman
Authors: Ali Haytham , El-Neweshy Mahmoud , Al Mawly Julanda , Heller Martin , Weber Michael , Schnee Christiane
Published: April 2024

Background

Contagious caprine pleuropneumonia (CCPP) is a fatal WOAH-listed, respiratory disease in small ruminants with goats as primary hosts that is caused by Mycoplasma capricolum subspecies capripneumoniae (Mccp). Twelve CCPP outbreaks were investigated in 11 goat herds and a herd of captive Arabian sand gazelle (Gazella marica) in four Omani governorates by clinical pathological and molecular analysis to compare disease manifestation and Mccp genetic profiles in goats and wild ungulates.

Results

The CCPP forms in diseased and necropsied goats varied from peracute (5.8%), acute (79.2%) and chronic (4.5%) while all of the five necropsied gazelles showed the acute form based on the clinical picture, gross and histopathological evaluation. Colonies of Mccp were recovered from cultured pleural fluid, but not from lung tissue samples of one gazelle and nine goats and all the isolates were confirmed by Mccp-specific real time PCR. Whole genome-single nucleotide polymorphism (SNP) analysis was performed on the ten isolates sequenced in this study and twenty sequences retrieved from the Genbank database. The Mccp strains from Oman clustered all in phylogroup A together with strains from East Africa and one strain from Qatar. A low variability of around 125 SNPs was seen in the investigated Omani isolates from both goats and gazelles indicating mutual transmission of the pathogen between wildlife and goats.

Conclusion

Recent outbreaks of CCPP in Northern Oman are caused by Mccp strains of the East African Phylogroup A which can infect goats and captive gazelles likewise. Therefore, wild and captive ungulates should be considered as reservoirs and included in CCPP surveillance measures.
BAG3 promotes proliferation and migration of arterial smooth muscle cells by regulating STAT3 phosphorylation in diabetic vascular remodeling
Authors: Huang Xinyue , Guo Jiayan , Ning Anqi , Zhang Naijin , Sun Yingxian
Published: April 2024

Background

Diabetic vascular remodeling is the most important pathological basis of diabetic cardiovascular complications. The accumulation of advanced glycation end products (AGEs) caused by elevated blood glucose promotes the proliferation and migration of vascular smooth muscle cells (VSMCs), leading to arterial wall thickening and ultimately vascular remodeling. Therefore, the excessive proliferation and migration of VSMCs is considered as an important therapeutic target for vascular remodeling in diabetes mellitus. However, due to the lack of breakthrough in experiments, there is currently no effective treatment for the excessive proliferation and migration of VSMCs in diabetic patients. Bcl-2-associated athanogene 3 (BAG3) protein is a multifunctional protein highly expressed in skeletal muscle and myocardium. Previous research has confirmed that BAG3 can not only regulate cell survival and apoptosis, but also affect cell proliferation and migration. Since the excessive proliferation and migration of VSMCs is an important pathogenesis of vascular remodeling in diabetes, the role of BAG3 in the excessive proliferation and migration of VSMCs and its molecular mechanism deserve further investigation.

Methods

In this study, BAG3 gene was manipulated in smooth muscle to acquire SM22αCre; BAG3FL/FL mice and streptozotocin (STZ) was used to simulate diabetes. Expression of proteins and aortic thickness of mice were detected by immunofluorescence, ultrasound and hematoxylin-eosin (HE) staining. Using human aorta smooth muscle cell line (HASMC), cell viability was measured by CCK-8 and proliferation was measured by colony formation experiment. Migration was detected by transwell, scratch experiments and Phalloidin staining. Western Blot was used to detect protein expression and Co-Immunoprecipitation (Co-IP) was used to detect protein interaction.

Results

In diabetic vascular remodeling, AGEs could promote the interaction between BAG3 and signal transducer and activator of transcription 3 (STAT3), leading to the enhanced interaction between STAT3 and Janus kinase 2 (JAK2) and reduced interaction between STAT3 and extracellular signal-regulated kinase 1/2 (ERK1/2), resulting in accumulated p-STAT3(705) and reduced p-STAT3(727). Subsequently, the expression of matrix metallopeptidase 2 (MMP2) is upregulated, thus promoting the migration of VSMCs.

Conclusions

BAG3 upregulates the expression of MMP2 by increasing p-STAT3(705) and decreasing p-STAT3(727) levels, thereby promoting vascular remodeling in diabetes. This provides a new orientation for the prevention and treatment of diabetic vascular remodeling.
Prediction of various insulin resistance indices for the risk of hypertension among military young adults: the CHIEF cohort study, 2014–2020
Authors: Tsai Kun-Zhe , Chu Chen-Chih , Huang Wei-Chun , Sui Xuemei , Lavie Carl J. , Lin Gen-Min
Published: April 2024

Background

Non-insulin-based insulin resistance (NI-IR) indices have been reported to have an association with prevalent hypertension, however, no cohort studies to date have compared their prediction of hypertension among young adults.

Methods

A total of 2,448 military men and women, aged 18–39 years, without baseline hypertension in Taiwan were followed for incident hypertension events from 2014 until the end of 2020. All subjects underwent annual health examinations including measurements of blood pressure (BP) in mmHg. Systolic BP (SBP) 130–139/diastolic BP (DBP) < 80, SBP < 130/DBP 80–89, and SBP 130–139/DBP 80–89 were respectively defined as stage I isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH) and combined hypertension (CH). The cut-off levels of stage II hypertension for SBP and DBP were 140–159 and 90–99, respectively. Four NI-IR indices included the ratio of serum triglycerides (TG) to high-density lipoprotein cholesterol (HDL-C), TyG index defined as ln[TG* fasting glucose (FG)/2], Metabolic Score for IR (METS-IR) defined as ln[(2* FG) + TG)* body mass index (BMI)/(ln(HDL-C))], and ZJU index defined as BMI + FG + TG + 3* alanine transaminase/aspartate transaminase (+ 2 if female). Multivariable Cox regression analysis was performed with adjustments for baseline age, sex, body mass index, BP, substance use, family history for early onset cardiovascular diseases or hypertension, low-density lipoprotein cholesterol, kidney function, serum uric acid and physical activity to determine the associations.

Results

During a median follow-up of 6.0 years, there were 920 hypertension events (37.6%). Greater TyG, TG/HDL-C and METS-IR indices were associated with a higher risk of stage I IDH (hazard ratios (HRs) and 95% confidence intervals: 1.376 (1.123–1.687), 1.082 (1.039–1.127) and 3.455 (1.921–6.214), respectively), whereas only greater ZJU index was associated with a higher risk of stage II IDH [HRs: 1.011 (1.001–1.021)]. In addition, greater ZJU index was associated with a higher risk of stage II ISH [HR: 1.013 (1.003–1.023)], and greater TyG index was associated with a higher risk of stage II CH [HR: 2.821 (1.244–6.395)].

Conclusion

Insulin resistance assessed by various NI-IR indices was associated with a higher risk of hypertension in young adults, while the assessment ability for specific hypertension category may differ by NI-IR indices.
Effects of whole grains on glycemic control: a systematic review and dose-response meta-analysis of prospective cohort studies and randomized controlled trials
Authors: Ying Tao , Zheng Jianheng , Kan Juntao , Li Wenyun , Xue Kun , Du Jun , Liu Yuwei , He Gengsheng
Published: April 2024

Purpose

Whole grains have recently been promoted as beneficial to diabetes prevention. However, the evidence for the glycemic benefits of whole grains seems to conflict between the cohort studies and randomized control trials (RCTs). To fill the research gap, we conducted a meta-analysis to determine the effects of whole grains on diabetes prevention and to inform recommendations.

Methods

We searched PubMed, Clarivate Web of Science, and Cochrane Library until March 2024. We used the risk ratio (RR) of type 2 diabetes to represent the clinical outcomes for cohort studies, while the biomarkers, including fasting blood glucose and insulin, HbA1C, and HOMA-IR, were utilized to show outcomes for RCTs. Dose-response relationships between whole grain intakes and outcomes were tested with random effects meta-regression models and restricted cubic splines models. This study is registered with PROSPERO, CRD42021281639.

Results

Ten prospective cohort studies and 37 RCTs were included. Cohort studies suggested a 50 g/day whole grain intake reduced the risk of type 2 diabetes (RR = 0.761, 95% CI: 0.700 to 0.828, I2 = 72.39%, P < 0.001) and indicated a monotonic inverse relationship between whole grains and type 2 diabetes rate. In RCTs, whole grains significantly reduced fasting blood glucose (Mean difference (MD) = -0.103 mmol/L, 95% CI: -0.178 to -0.028; I2 = 72.99%, P < 0.01) and had modest effects on HbA1C (MD = -0.662 mmol/mol (-0.06%), 95% CI: -1.335 to 0.010; I2 = 64.55%, P = 0.05) and HOMA-IR (MD = -0.164, 95% CI: -0.342 to 0.013; I2 = 33.38%, P = 0.07). The intake of whole grains and FBG, HbA1C, and HOMA-IR were significantly dose-dependent. The restricted spline curves remained flat up to 150 g/day and decreased afterward. Subgroup analysis showed that interventions with multiple whole-grain types were more effective than those with a single type.

Conclusion

Our study findings suggest that a daily intake of more than 150 g of whole grain ingredients is recommended as a population approach for diabetes prevention.
The potential use of nanozymes as an antibacterial agents in oral infection, periodontitis, and peri-implantitis
Authors: Hosseini Hooshiar Mohammad , Badkoobeh Ashkan , Kolahdouz Shirin , Tadayonfard Azadeh , Mozaffari Asieh , Nasiri Kamyar , Salari Sara , Safaralizadeh Reza , Yasamineh Saman
Published: April 2024

Several studies suggest that oral pathogenic biofilms cause persistent oral infections. Among these is periodontitis, a prevalent condition brought on by plaque biofilm. It can even result in tooth loss. Furthermore, the accumulation of germs around a dental implant may lead to peri-implantitis, which damages the surrounding bone and gum tissue. Furthermore, bacterial biofilm contamination on the implant causes soft tissue irritation and adjacent bone resorption, severely compromising dental health. On decontaminated implant surfaces, however, re-osseointegration cannot be induced by standard biofilm removal techniques such as mechanical cleaning and antiseptic treatment. A family of nanoparticles known as nanozymes (NZs) comprise highly catalytically active multivalent metal components. The most often employed NZs with antibacterial activity are those that have peroxidase (POD) activity, among other types of NZs. Since NZs are less expensive, more easily produced, and more stable than natural enzymes, they hold great promise for use in various applications, including treating microbial infections. NZs have significantly contributed to studying implant success rates and periodontal health maintenance in periodontics and implantology. An extensive analysis of the research on various NZs and their applications in managing oral health conditions, including dental caries, dental pulp disorders, oral ulcers, peri-implantitis, and bacterial infections of the mouth. To combat bacteria, this review concentrates on NZs that imitate the activity of enzymes in implantology and periodontology. With a view to the future, there are several ways that NZs might be used to treat dental disorders antibacterially.

Graphical Abstract
“It didn’t hurt me”: patients’ and providers’ perspectives on unsupervised take-home doses, drug diversion, and overdose risks in the provision of medication for opioid use disorder during COVID-19 in San Juan, Puerto Rico
Authors: Abadie Roberto , Fisher Celia B.
Published: April 2024

Background

During the COVID−19 pandemic, clinics offering medication for opioid use disorder (MOUD) needed to rapidly introduce unsupervised take−home dosing, while relapsing patients and patients unable to enter treatment faced increased risks of fentanyl−related overdose deaths and other drug−related harms. Based on a qualitative study of people who inject drugs (PWID) receiving MOUD treatment and MOUD staff in Puerto Rico, this paper documents the lived experiences of patients and providers during this period and the risk perceptions and management strategies to address substance misuse and drug diversion attributable to unsupervised take−home−dose delivery.

Methods

In−depth qualitative interviews were conducted with patients (N = 25) and staff (N = 25) in two clinics providing MOUD in San Juan, Puerto Rico, during 2022. Patients and staff were receiving or providing treatment during the pandemic, and patients reported injection drug use during the past thirty days.

Results

Patients were overwhelmingly male (84%), unmarried (72%), and unemployed (52%), with almost half (44%) injecting one to three times a day. Mean time in treatment was 7 years. Staff had a mean age of 46 years with more than half of the sample (63%) female. The majority of patients believed that unsupervised take−home dosing had no significant effect on their treatment adherence or engagement. In contrast, providers expressed concerns over the potential for drug diversion and possible increased risks of patient attrition, overdose episodes, and poor treatment outcomes.

Conclusion

This study underscores the importance of insider perspectives on harm−reduction changes in policy implemented during a health crisis. Of note is the finding that staff disagreed among themselves regarding the potential harms of diversion and changes in drug testing protocols. These different perspectives are important to address so that future pandemic policies are successfully designed and implemented. Our study also illuminates disagreement in risk assessments between patients and providers. This suggests that preparation for emergency treatment plans requires enhanced communication with patients to match treatments to the context of lived experience.
Endothelial cell dynamics in sepsis-induced acute lung injury and acute respiratory distress syndrome: pathogenesis and therapeutic implications
Authors: Qiao Xinyu , Yin Junhao , Zheng Zhihuan , Li Liangge , Feng Xiujing
Published: April 2024

Sepsis, a prevalent critical condition in clinics, continues to be the leading cause of death from infections and a global healthcare issue. Among the organs susceptible to the harmful effects of sepsis, the lungs are notably the most frequently affected. Consequently, patients with sepsis are predisposed to developing acute lung injury (ALI), and in severe cases, acute respiratory distress syndrome (ARDS). Nevertheless, the precise mechanisms associated with the onset of ALI/ARDS remain elusive. In recent years, there has been a growing emphasis on the role of endothelial cells (ECs), a cell type integral to lung barrier function, and their interactions with various stromal cells in sepsis-induced ALI/ARDS. In this comprehensive review, we summarize the involvement of endothelial cells and their intricate interplay with immune cells and stromal cells, including pulmonary epithelial cells and fibroblasts, in the pathogenesis of sepsis-induced ALI/ARDS, with particular emphasis placed on discussing the several pivotal pathways implicated in this process. Furthermore, we discuss the potential therapeutic interventions for modulating the functions of endothelial cells, their interactions with immune cells and stromal cells, and relevant pathways associated with ALI/ARDS to present a potential therapeutic strategy for managing sepsis and sepsis-induced ALI/ARDS.
Comparing outcomes in patients with exsanguinating injuries: an Eastern Association for the Surgery of Trauma (EAST), multicenter, international trial evaluating prioritization of circulation over intubation (CAB over ABC)
Authors: Ferrada Paula , García Alberto , Duchesne Juan , Brenner Megan , Liu Chang , Ordóñez Carlos , Menegozzo Carlos , Salamea Juan Carlos , Feliciano David
Published: April 2024

Introduction

Hemorrhage is a major cause of preventable trauma deaths, and the ABC approach is widely used during the primary survey. We hypothesize that prioritizing circulation over intubation (CAB) can improve outcomes in patients with exsanguinating injuries.

Methods

A prospective observational study involving international trauma centers was conducted. Patients with systolic blood pressure below 90 who were intubated within 30 min of arrival were included. Prioritizing circulation (CAB) was defined as delaying intubation until blood products were started, and/or bleeding control was performed before securing the airway. Demographics, clinical data, and outcomes were recorded.

Results

The study included 278 eligible patients, with 61.5% falling within the “CAB” cohort and 38.5% in the “ABC” cohort. Demographic and disease characteristics, including age, sex, ISS, use of blood products, and other relevant factors, exhibited comparable distributions between the two cohorts. The CAB group had a higher proportion of penetrating injuries and more patients receiving intubation in the operating room. Notably, patients in the CAB group demonstrated higher GCS scores, lower SBP values before intubation but higher after intubation, and a significantly lower incidence of cardiac arrest and post-intubation hypotension. Key outcomes revealed significantly lower 24-hour mortality in the CAB group (11.1% vs. 69.2%), a lower rate of renal failure, and a higher rate of ARDS. Multivariable logistic regression models showed a 91% reduction in the odds of mortality within 24 h and an 89% reduction at 30 days for the CAB cohort compared to the ABC cohort. These findings suggest that prioritizing circulation before intubation is associated with improved outcomes in patients with exsanguinating injuries.

Conclusion

Post-intubation hypotension is observed to be correlated with worse outcomes. The consideration of prioritizing circulation over intubation in patients with exsanguinating injuries, allowing for resuscitation, or bleeding control, appears to be associated with potential improvements in survival. Emphasizing the importance of circulation and resuscitation is crucial, and this approach might offer benefits for various bleeding-related conditions.
METTL14-mediated N6-methyladenosine modification induces the ferroptosis of hypoxia/reoxygenation-induced cardiomyocytes
Authors: Zhao Chunyu , Li Jianing
Published: April 2024

Background

Hypoxia/reoxygenation (H/R) induces cardiomyocyte ferroptosis, a core remodeling event in myocardial ischemia/reperfusion injury. Methyltransferase-like 14 (METTL14) emerges as a writer of N6-methyladenosine (m6A) modification. This study was conducted to decipher the role of METTL14 in H/R-induced cardiomyocyte ferroptosis.

Methods

Mouse cardiomyocytes HL-1 were cultured and underwent H/R treatment. The degree of ferroptosis after H/R treatment was appraised by the cell counting kit-8 assay, assay kits (ROS/GSH/Fe2+), and Western blotting (GPX4/ACSL4). The intracellular expressions of METTL14, pri-miR-146a-5p, miR-146a-5p, or adaptor protein phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1) were examined by real-time quantitative polymerase chain reaction or Western blotting, with m6A quantification analysis and RNA immunoprecipitation to determine the total m6A level and the expression of pri-miR-146a-5p bound to DiGeorge critical region 8 (DGCR8) and m6A-modified pri-miR-146a-5p. The binding of miR-146a-5p to APPL1 was testified by the dual-luciferase assay.

Results

H/R treatment induced cardiomyocyte ferroptosis (increased ROS, Fe2+, and ACSL4 and decreased GSH and GPX4) and upregulated METTL14 expression. METTL14 knockdown attenuated H/R-induced cardiomyocyte ferroptosis. METTL14 induced the recognition of pri-miR-146a-5p by DGCR8 by increasing m6A modification on pri-miR-146a-5p, which promoted the conversion of pri-miR-146a-5p into miR-146a-5p and further repressed APPL1 transcription. miR-146a-5p upregulation or APPL1 downregulation limited the inhibitory effect of METTL14 downregulation on H/R-induced cardiomyocyte ferroptosis.

Conclusion

METTL14 promoted miR-146a-5p expression through the recognition and processing of pri-miR-146a-5p by DGCR8, which repressed APPL1 transcription and triggered H/R-induced cardiomyocyte ferroptosis.
A retrospective analysis of mission reports in the national Swedish Police Registry on mountain rescue 2018–2022: here be snowmobiles
Authors: Westman Anton , Björnstig Johanna
Published: April 2024

Background

Increasing mountain activity and decreasing participant preparedness, as well as climate change, suggest needs to tailor mountain rescue. In Sweden, previous medical research of these services are lacking. The aim of the study is to describe Swedish mountain rescue missions as a basis for future studies, public education, resource allocation, and rescuer training.

Methods

Retrospective analysis of all mission reports in the national Swedish Police Registry on Mountain Rescue 2018–2022 (n = 1543). Outcome measures were frequencies and characteristics of missions, casualties, fatalities, traumatic injuries, medical conditions, and incident mechanisms.

Results

Jämtland county had the highest proportion of missions (38%), followed by Norrbotten county (36%). 2% of missions involved ≥ 4 casualties, and 44% involved ≥ 4 mountain rescuers. Helicopter use was recorded in 59% of missions. Non-Swedish citizens were rescued in 12% of missions. 37% of casualties were females. 14% of casualties were ≥ 66 or ≤ 12 years of age. Of a total 39 fatalities, cardiac event (n = 14) was the most frequent cause of death, followed by trauma (n = 10) and drowning (n = 8). There was one avalanche fatality. 8 fatalities were related to snowmobiling, and of the total 1543 missions, 309 (20%) were addressing snowmobiling incidents. Of non-fatal casualties, 431 involved a medical condition, of which 90 (21%) suffered hypothermia and 73 (17%) cardiovascular illness.

Conclusions

These baseline data suggest snowmobiling, cardiac events, drownings, multi-casualty incidents, and backcountry internal medicine merit future study and intervention.
Effects of risk factors on the development and mortality of early- and late-onset dementia: an 11-year longitudinal nationwide population-based cohort study in South Korea
Authors: Chun Min Young , Chae Wonjeong , Seo Sang Won , Jang Hyemin , Yun Jihwan , Na Duk L. , Kang Dongwoo , Lee Jungkuk , Hammers Dustin B. , Apostolova Liana G. , Jang Sung-In , Kim Hee Jin
Published: April 2024

Background

Early-onset dementia (EOD, onset age < 65) and late-onset dementia (LOD, onset age ≥ 65) exhibit distinct features. Understanding the risk factors for dementia development and mortality in EOD and LOD respectively is crucial for personalized care. While risk factors are known for LOD development and mortality, their impact on EOD remains unclear. We aimed to investigate how hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation, and osteoporosis influence the development and mortality of EOD and LOD, respectively.

Methods

Using the Korean National Health Insurance Service (NHIS) database, we collected 546,709 dementia-free individuals and followed up for 11 years. In the two study groups, the Younger group (< 65 years old) and the Older group (≥ 65 years old), we applied Cox proportional hazard models to assess risk factors for development of EOD and LOD, respectively. Then, we assessed risk factors for mortality among EOD and LOD.

Results

Diabetes mellitus and osteoporosis increased the risk of EOD and LOD development. Hypertension increased the risk of EOD, while atrial fibrillation increased the risk of LOD. Conversely, hyperlipidemia exhibited a protective effect against LOD development. Additionally, diabetes mellitus increased mortality in EOD and LOD. Hypertension and atrial fibrillation increased mortality in LOD, while hyperlipidemia decreased mortality in EOD and LOD.

Conclusions

Risk factors influencing dementia development and mortality differed in EOD and LOD. Targeted public health interventions addressing age-related risk factors may reduce dementia incidence and mortality.
Association of midlife body-weight variability and cycles with earlier dementia onset: a nationwide cohort study
Authors: Park Yujin , Kim Su Hwan , Ryu Jiwon , Yoon Hyung-Jin
Published: April 2024

Background

Given the rising awareness of health-related lifestyle modifications, the impact of changes in body weight (BW) on cognitive function and dementia generates significant concern. This study aimed to investigate the association between BW changes and dementia in a middle-aged Korean population.

Methods

A retrospective, population-based longitudinal study was conducted utilizing data from the National Health Insurance Service (NHIS) database. Participants aged 40 years or older in 2011 who underwent at least five health checkups between 2002 and 2011 were followed-up for dementia until 2020. A total of 3,635,988 dementia-free Korean aged < 65 at baseline were examined. We analyzed the association between BW variability independent of the mean (VIM) with BW cycle, defined as either an upward or a downward direction of BW, and the risk of incident dementia.

Results

The results showed an increased risk of dementia in the highest quartile of VIM quartile (hazard ratio [HR] 1.52, 95% confidence interval [CI] 1.47–1.58) compared to the lowest quartile of VIM. Additionally, the results showed an even higher increased risk of dementia in the highest BW cycle (≥ 2 cycles of 10% BW = HR 2.00, 95% CI 1.74–1.29). Notably, the combined concept of VIM with BW cycle showed an even higher dementia risk (highest quartile of VIM with ≥ 2 cycles of 10% BW = HR 2.37, 95% CI 2.05–2.74) compared to the baseline group (lowest quartile of VIM with < 3% BW cycle).

Conclusions

The present study highlights the importance of considering BW changes with BW variability along with the BW cycle to assess dementia risk in detail, providing valuable insights for preventive strategies.
Matrix-assisted laser desorption/ionization mass spectrometry imaging for quorum sensing
Authors: Kuik Christel , van Hoogstraten Sanne W.G. , Arts Jacobus J.C. , Honing Maarten , Cillero-Pastor Berta
Published: April 2024

Quorum sensing (QS) is a complex communication system in bacteria, directing their response to the environment. QS is also one of the main regulators of bacterial biofilms’ formation, maturation and dispersion. Matrix-assisted laser desorption ionization (MALDI) mass spectrometry imaging (MSI) is a molecular imaging technique that allows the mapping of QS molecules in bacterial biofilms. Here, we highlight the latest advances in MALDI-MSI in recent years and how this technology can improve QS understanding at the molecular level.
Structural properties of immune complexes formed by viral antigens and specific antibodies shape the inflammatory response of macrophages
Authors: Lučiūnaitė Asta , Mašalaitė Kristina , Plikusiene Ieva , Maciulis Vincentas , Juciute Silvija , Norkienė Milda , Žvirblienė Aurelija
Published: April 2024

Data on the course of viral infections revealed severe inflammation as a consequence of antiviral immune response. Despite extensive research, there are insufficient data on the role of innate immune cells in promoting inflammation mediated by immune complexes (IC) of viral antigens and their specific antibodies. Recently, we demonstrated that antigens of human polyomaviruses (PyVs) induce an inflammatory response in macrophages. Here, we investigated macrophage activation by IC. We used primary murine macrophages as a cell model, virus-like particles (VLPs) of PyV capsid protein as antigens, and a collection of murine monoclonal antibodies (mAbs) of IgG1, IgG2a, IgG2b subclasses. The inflammatory response was investigated by analysing inflammatory chemokines and activation of NLRP3 inflammasome. We observed a diverse pattern of chemokine secretion in macrophages treated with different IC compared to VLPs alone. To link IC properties with cell activation status, we characterised the IC by advanced optical and acoustic techniques. Ellipsometry provided precise real-time kinetics of mAb-antigen interactions, while quartz crystal microbalance measurements showed changes in conformation and viscoelastic properties during IC formation. These results revealed differences in mAb-antigen interaction and mAb binding parameters of the investigated IC. We found that IC-mediated cell activation depends more on IC characteristics, including mAb affinity, than on mAb affinity for the activating Fc receptor. IC formed by the highest affinity mAb showed a significant enhancement of inflammasome activation. This may explain the hyperinflammation related to viral infection and vaccination. Our findings demonstrate that IC promote the viral antigen-induced inflammatory response depending on antibody properties.
“We’re sinking”: a qualitative interview-based study on stakeholder perceptions of structural and process limitations to the Canadian healthcare system
Authors: Parsons Leigh Jeanna , Moss Stephana Julia , Mizen Sara J. , Sriskandarajah Cynthia , FitzGerald Emily A. , Quinn Amity E. , Clement Fiona , Farkas Brenlea , Dodds Alexandra , Columbus Melanie , Stelfox Henry T.
Published: April 2024

Background

Despite longstanding efforts and calls for reform, Canada’s incremental approach to healthcare changes has left the country lagging behind other OECD nations. Reform to the Canadian healthcare system is essential to develop a higher performing system. This study sought to gain a deeper understanding of the views of Canadian stakeholders on structural and process deficiencies and strategies to improve the Canadian healthcare system substantially and meaningfully.

Methods

We conducted individual, ~ 45-minute, semi-structured virtual interviews from May 2022 to August 2022. Using existing contacts and snowball sampling, we targeted one man and one woman from five regions in Canada across four stakeholder groups: (1) public citizens; (2) healthcare leaders; (3) academics; and (4) political decision makers. Interviews centered on participants’ perceptions of the state of the current healthcare system, including areas where major improvements are required, and strategies to achieve suggested enhancements; Donabedian’s Model (i.e., structure, process, outcomes) was the guiding conceptual framework. Interviews were audio-recorded, transcribed verbatim, and de-identified, and inductive thematic analysis was performed independently and in duplicate according to published methods.

Results

The data from 31 interviews with 13 (41.9%) public citizens, 10 (32.3%) healthcare leaders, 4 (12.9%) academics, and 4 (12.9%) political decision makers resulted in three themes related to the structure of the healthcare system (1. system reactivity; 2. linkage with the Canadian identity; and 3. political and funding structures), three themes related to healthcare processes (1. staffing shortages; 2. inefficient care; and 3. inconsistent care), and three strategies to improve short- and long-term population health outcomes (1. delineating roles and revising incentives; 2. enhanced health literacy; 3. interdisciplinary and patient-centred care).

Conclusion

Canadians in our sample identified important structural and process limitations to the Canadian healthcare system. Meaningful reforms are needed and will require addressing the link between the Canadian identity and our healthcare system to facilitate effective development and implementation of strategies to improve population health outcomes.
Balancing the books: unveiling the direct impact of an integrated energy system model on industries, households and government revenues
Authors: George Jan Frederick , Marx Alexander , Held Anne , Winkler Jenny , Bekk Anke , Ragwitz Mario
Published: April 2024

Background

The transition towards a sustainable energy system is reshaping the demand for final energy, driven by the diffusion of new end-use technologies. This shift not only impacts consumers’ energy expenses, but also holds implications for the public budget. Building on data from a German energy transition scenario, we analyse the direct impact of energy costs on industries, low-income households, and changes in government revenues from the taxes and levies on final energy carriers. Our analysis considers the impact of current policies and explores a scenario introducing additional excise tax rates to offset potential revenue losses.

Results

We found that substantial carbon price increases could generate revenues that offset the losses from excise taxes on fossil fuels while enabling the financing of renewable support from the public budget by the end of this decade. Nevertheless, a decline in government revenues from taxes and levies is anticipated after 2030 until the middle of the century due to the declining use of fossil fuels. Maintaining current excise tax revenues during the transition could be achieved by introducing additional excise taxes on fossil fuels and electricity. Lastly, our analysis indicated a continuous decline in household energy expenditures until 2050, whereas energy-intensive industries face adverse impacts due to decarbonisation.

Conclusions

This research provides valuable insights into the fiscal implications of the energy transition, shedding light on different industrial sectors and households while considering the evolving impact on the public budget. Policymakers may need to consider systemic reforms or alternative financing mechanisms outside the energy system to balance the books.
Assessment of the antibacterial efficacy of silver nanoparticles-based Artemisia annua against methicillin-resistant Staphylococcus aureus-infected lung tissues in albino rats
Authors: Shaaban Mohamed T. , Abdel-Hamid Marwa Salah , Orabi Sahar H. , Korany Reda M. S. , Elbawab Rania Hamed
Published: April 2024

The production of alternative and effective medicines is crucial given that antibiotic resistance is currently a global health concern. Several biochemical identification tests were used to screen for Staphylococcus aureus isolates. Analysis of Artemisia annua extract was performed using a trace GC‒mass spectrometer, which revealed that the A. annua extract contains numerous compounds, such as artemisinins, palmitic acid and other vital essential compounds that have antioxidant and anti-inflammatory properties. The isolate st.8 was resistant to cefoxitin, oxacillin, and cephalosporins; furthermore, MALDI-TOF/MS Biotyper® identified it as methicillin-resistant S. aureus with confidence value 99.9% of mass spectrum compared with reference spectra. The synthesis of green silver nanoparticles based on A. annua as a reducing agent was confirmed via partial characterizations: (HR-TEM), (XRD), (SEM), (EDX) and (FTIR) analysis. The significant of antibacterial activity of the new green material (AgNPs) was achieved by determining the agar well diffusion assay. Furthermore, compared with those in the Staphylococcus-infected group, a significant decrease in hematological parameters was observed, with an increase in antioxidant biomarkers, a decrease in interstitial tissue thickening by inflammatory cells, and a weak positive immune reaction in a few cells (TNF-α and iNOS) in rats. Overall, this study is a promising step toward the development of new and effective strategies for combating MRSA infections.
Predictors of contraceptive discontinuation in Rwanda: evidence from demographic and health survey 2019–2020
Authors: Jean de Dieu Harerimana , Lambert Mugabo
Published: April 2024

Background

Despite advancements, Rwanda continues to face challenges regarding contraceptive discontinuation. The 2019–2020 Rwanda Demographic and Health Survey (DHS) reported a 30% discontinuation rate among women within the first year of use. This study analyses predictors of discontinuation using this DHS data, with the goal of strengthening Rwanda’s family planning programs.

Methods

Data from the 2019-20 Rwanda DHS (14,634 women aged 15–49) was examined. A two-stage sampling design informed the survey. Life table methods and Cox proportional hazard models were used to analyze discontinuation rates, median usage duration across contraceptive methods, and the influence of demographic and other factors.

Results

Results indicated a progressive rise in contraceptive discontinuation over different period: 16.69% at 6 months, 29.29% at 12 months, and 47.21% at 24 months. Pills and male condoms showed higher discontinuation probabilities early on. While injectables and LAM initially showed lower discontinuation, rates rose significantly by the 24th month. Health concerns and side effects were the primary reasons cited for discontinuation. The Cox proportional hazards analysis revealed significant factors influencing discontinuation: contraceptive method, desire for pregnancy, husband’s disapproval, access/availability, and the desire for a more effective method.

Conclusion

This study highlights substantial contraceptive discontinuation rates in Rwanda, particularly for pills and injectables. Method type, health concerns, side effects, and method failure were associated with discontinuation. Interventions should focus on improving contraceptive continuation and investigating alternative methods with lower discontinuation tendencies.
Clinical value of semi-quantitative parameters in 68Ga-DOTANOC PET/CT in treatment and diagnostics of cranial meningioma in a single-center retrospective analysis
Authors: Weitzer Friedrich , Stanzel Susanne , Plhak Elisabeth , Aigner Reingard Maria
Published: April 2024

Background

The value of somatostatin-analogon PET tracers in theranostics in cranial meningioma has been demonstrated in several studies; however, the value of semi-quantitative parameters for therapy and patient outcome is still unclear.

Methods

A retrospective study was performed comparing measured semi-quantitative 68Ga-DOTANOC PET/CT parameters (maximum standardized uptake value = SUVmax, mean standardized uptake value = SUVmean, and metabolic tumor volume = MTV) and calculated ratios (SUVmax tumor to pituitary gland and SUVmax tumor to superior sinus sagittalis), versus the WHO grades and overall outcome. Patients with histological confirmed meningioma or high probability for meningioma in the previous cranial MRI were eligible.

Results

Thirty-two patients from January 2018 to February 2023 were retrospectively included. The WHO grade I meningioma was confirmed in 17 patients, the WHO grade II in five patients, and the WHO grade III in two patients, while in eight patients, diagnosis was solely based on MRI and 68Ga-DOTANOC PET/CT findings. In 12 cases, stable disease was present, in 15 cases, radiation therapy was chosen, in three cases, neurosurgery was preferred, while in two cases, palliative care was chosen. Median SUVmax values increased with the WHO grade (15.84, 17.22, and 28.4, p = 0.134, Kruskal–Wallis test), and no statistically significant difference was present for MTV, SUVmax, and calculated ratios.

Conclusion

Increased SUVmax values in the tumor in 68Ga-DOTANOC PET/CT are associated with higher WHO grade, although further studies including larger patient collectives are needed to solidify this hypothesis.
Climate limits vegetation green-up more than slope, soil erodibility, and immediate precipitation following high-severity wildfire
Authors: Crockett Joseph L. , Hurteau Matthew D.
Published: April 2024

Background

In the southwestern United States, post-fire vegetation recovery is increasingly variable in forest burned at high severity. Many factors, including temperature, drought, and erosion, can reduce post-fire vegetation recovery rates. Here, we examined how year-of-fire precipitation variability, topography, and soils influenced post-fire vegetation recovery in the southwestern United States as measured by greenness to determine whether erosion-related factors would have persistent effects in the longer post-fire period. We modeled relationships between post-fire vegetation and these predictors using random forest and examined changes in post-fire normalized burn ratio across fires in Arizona and New Mexico. We incorporated growing season climate to determine if year-of-fire effects were persistent during the subsequent 5 years or if temperature, water deficit, and precipitation in the years following fire were more influential for vegetation greenness. We expected that post-fire factors that drive erosion would reduce greenness; however, these effects would explain less variability in post-fire greenness than growing season climate.

Results

We found reductions in post-fire greenness in areas burned at high severity when heavy and intense precipitation fell on more erodible soils immediately post-fire. In highly erodible scenarios, when accounting for growing season climate, coefficient of variation for year-of-fire precipitation, total precipitation, and soil erodibility decreased greenness in the fifth year. However, more of the variation in greenness was explained by variability of growing season vapor pressure deficit and growing season precipitation.

Conclusions

Our results suggest that while the factors that contribute to post-fire erosion and its effects on vegetation recovery are important, at a regional scale, the majority of the variability in post-fire greenness in high-severity burned areas in southwestern forests is due to climatic drivers such as growing season precipitation and vapor pressure deficit. Given the increasing scale of area burned at high severity and the potential for more post-fire erosion, quantifying how these factors alter ecosystem development is central to understanding how different ecosystem types will be distributed across these landscapes with additional climate change.
Trastuzumab-Induced Cardiotoxicity: When and How Much Should We Worry?
Authors: Zheng Haoyi , Mahmood Syed S. , Khalique Omar K. , Zhan Huichun
Published: April 2024

This review critically analyzes the incidence of trastuzumab-induced left ventricular systolic dysfunction and congestive heart failure (CHF), distinguishing between cases with and without prior anthracycline exposure. It highlights the fact that the elevated risk of trastuzumab-induced cardiotoxicity is closely associated with prior anthracycline exposure. In the absence of prior anthracycline exposure, the incidence rates of trastuzumab-induced cardiotoxicity, particularly CHF (ranging from 0% to 0.5%), are largely comparable with those reported in the general population, especially when reversibility is taken into account. Current cardiac surveillance recommendations during trastuzumab treatment have not yet adapted to the increasing adoption of nonanthracycline treatment strategies and the associated low risk of cardiotoxicity. We propose a refined monitoring protocol to reduce the frequency of cardiac evaluations for low-risk to moderate-risk patients, especially those receiving nonanthracycline treatments. By focusing on patients at high risk or those with prior anthracycline exposure, this strategy seeks to optimize the cost-effectiveness of cardiac care in oncology.
Characterization of BRAFThr599dup Mutation as a Targetable Driver Mutation Identified in Lung Adenocarcinoma by Comprehensive Genomic Profiling
Authors: Watanabe Hirofumi , Inoue Yusuke , Karayama Masato , Yazawa Shusuke , Mochizuka Yasutaka , Yasui Hideki , Hozumi Hironao , Suzuki Yuzo , Furuhashi Kazuki , Enomoto Noriyuki , Fujisawa Tomoyuki , Shinmura Kazuya , Inui Naoki , Suda Takafumi
Published: April 2024

PURPOSE

Understanding the function of BRAF mutants is crucial for determining the best treatment strategy. This study aimed to characterize a rare BRAF variant, BRAFThr599dup, which was identified in a patient with lung adenocarcinoma (LUAD) by comprehensive genomic profiling.

MATERIALS AND METHODS

We report a case of LUAD with BRAFThr599dup treated with dabrafenib and trametinib. We conditionally expressed wild-type BRAF, BRAFV600E, or BRAFThr599dup in Ba/F3 cells and BEAS-2B cells. Ba/F3 cells carrying double-mutant BRAF (BRAFThr599dup/R509H, BRAFV600E/R509H, or BRAFK601E/R509H) that lacked the dimerizing ability were also established. Knockout of endogenous BRAF or CRAF in Ba/F3-BRAFThr599dup cells and Ba/F3-BRAFV600E cells was performed using the CRISPR/Cas9 system. Cell viability, mitogen-activated protein kinase (MAPK) signaling activity, and sensitivity to dabrafenib and trametinib were evaluated.

RESULTS

The patient was revealed to have BRAFThr599dup-positive tumor cells as a predominant clone, and dabrafenib and trametinib treatment showed modest efficacy. In Ba/F3 cells, both BRAFThr599dup and BRAFV600E similarly caused interleukin-3–independent proliferation and activated the MAPK pathway. Moreover, BRAFThr599dup and BRAFV600E similarly caused a significant increase in the anchorage-independent growth ability of BEAS-2B cells. Along with Ba/F3-BRAFV600E cells, Ba/F3-BRAFThr599dup cells were highly sensitive to a monomer-specific BRAF inhibitor, dabrafenib, with a half-maximal inhibitory concentration value of 29.7 nM. In the absence of wild-type BRAF, wild-type CRAF, or an intact dimer interface, the ability to induce oncogenic addiction and MAPK pathway activation in Ba/F3-BRAFThr599dup cells was not affected, which was in contrast to the findings in the BRAFK601E/R509H double-mutant model.

CONCLUSION

BRAFThr599dup is a potent driver oncogene that activates the MAPK pathway without the requirement for dimerization in vitro. Because BRAFThr599dup has been recurrently reported across various cancer types, our findings should be further investigated both mechanistically and clinically.
Long-term Cumulative Incidence of Clinically Diagnosed Retinopathy in the Finnish Diabetes Prevention Study
Authors: Kaarniranta Kai , Valtanen Mikko , Keinänen-Kiukaanniemi Sirkka , Tuomilehto Jaakko , Lindström Jaana , Uusitupa Matti
Published: April 2024

Context

Lifestyle intervention reduces the incidence of type 2 diabetes (T2D) in people with impaired glucose tolerance (IGT).

Objective

This work aimed to find out whether participation in an earlier lifestyle intervention had an effect on the occurrence of clinically diagnosed diabetic retinopathy (DR) during a median of 22 years of follow-up time.

Methods

The study included 505 individuals from the Finnish Diabetes Prevention Study (DPS) (mean age 55; range, 40-64 years at the onset of the study) with IGT who were originally randomly assigned to the intervention (weight loss, healthy diet, and physical activity) (N = 257) and usual care control groups (N = 248). The median follow-up was 22 years. Clinical retinopathy diagnoses were obtained from the Finnish national hospital Care Register for Health. Data on glycemic parameters, serum lipids, and blood pressure were available from both the intervention (median 4 years) and postintervention period (until year 7).

Results

No significant difference was found in the cumulative incidence of clinically diagnosed DR between the original intervention (N = 23, 8.9%) and control groups (N = 19, 7.7%) during the extended follow-up (odds ratio: 1.15; 95% CI, 0.61-2.21). A higher cumulative glycated hemoglobin A1c (HbA1c) was significantly associated with a higher risk of retinopathy (hazard ratio 1.4; 1.02-1.88, 95% posterior interval, adjusted for group, age, and sex). Furthermore, the incidence of retinopathy diagnosis was numerically more common among individuals who had developed diabetes during the follow-up (33/349) compared with those who had not (9/156); however, the comparison was not statistically significant (odds ratio: 1.86, 95% CI, 0.89-4.28, adjusted for group, age, and sex).

Conclusion

A higher cumulative HbA1c was significantly associated with a higher risk of retinopathy. No evidence was found for a beneficial effect of a 4-year lifestyle intervention on the long-term occurrence of clinical DR during a median of 22-year follow-up.