bluuebunny/crossref_metadata_2025 huggingface dataset:
The relationship between neighbourhood income and youth mental health service use differs by immigration experience: analysis of population-based data in British Columbia, Canada
Authors: Kaoser Ridhwana , Thakore Padmini , Peterson Sandra , Wiedmeyer Mei-ling , Sierra-Heredia Cecilia , Goldenberg Shira , Machado Stefanie , Hagos Selamawit , Tayyar Elmira , Bozorgi Yasmin , Lavergne M. Ruth
Published: December 2024

Background

We investigated the relationship between neighbourhood income quintile and mental health service use by immigration experience among youth and explored changes during the COVID-19 pandemic.

Method

We used administrative data to examine mental health service use among youth aged 10 to 24 in British Columbia, Canada, between April 1, 2019, and March 31, 2022. We compared rates of community-based mental health service use, emergency department visits, and hospitalizations and the proportion of involuntary admissions by neighbourhood income quintile and immigration. We used models stratified by immigration to estimate the relationship with income.

Results

Non-immigrant youth used substantially more services than immigrant youth. Service use increased following the pandemic’s start and peaked between January and March 2021. We observed a clear income gradient for community-based service use among both immigrant and non-immigrant youth, but the direction of the gradient was reversed. Service use was highest among non-immigrant youth in lower-income neighbourhoods and lowest for immigrant youth in lower-income neighbourhoods. We observed similar patterns of income gradient for non-immigrant youth for emergency department visits and hospitalization. The proportion of involuntary admissions was higher for immigrant youth.

Conclusions

Mental health service use was substantially lower among immigrant youth than non-immigrant youth, but higher proportions of immigrant youth were hospitalized involuntarily. The reverse income gradient patterns observed for community-mental health service use are noteworthy and suggest significant barriers to accessing preventable care among immigrant youth, particularly those living in lower-income neighbourhoods.
Predictors of quality of life among caregivers of patients with moderate to severe kidney disease: an Australian cross-sectional study
Authors: Zimbudzi Edward , Blessan Asha , Fraginal Denise , Gute Lelise , Wang Qiumian , Ziganay Shari
Published: December 2024

Background

Little is known about the quality of life (QoL) of caregivers of patients with chronic kidney disease (CKD) along the disease continuum. We investigated factors associated with low QoL among caregivers of patients with CKD including those on dialysis. We also examined the relationship between kidney disease severity and the QoL of caregivers.

Methods

We recruited caregivers of patients with CKD (stage 3 to 5) attending renal outpatient clinics as well as dialysis units of a tertiary hospital and patients from January 2018 to November 2023. Quality of life was assessed using a valid and reliable tool, the Adult Carer Quality of Life Questionnaire. Logistic regression analyses were performed to determine factors associated with low QoL among caregivers.

Results

A total of 278 dyads of caregivers and patients were studied with a mean age of 56.6 ± 15.2 and 63.7 ± 15.3 years respectively. The proportion of caregivers reporting low to mid-range QoL scores ranged from 37 to 73.3% across the eight domains, with 48% having low to mid-range overall QoL scores. The severity of CKD had no impact on overall QoL of caregivers in the personal growth and carer satisfaction domains where caregivers of patients on dialysis reported worse scores compared to caregivers of predialysis patients. Female gender of caregivers and patients, longer caregiving time, diagnosis of diabetes and lower socioeconomic status of patients were all associated with lower scores in one or more domains.

Conclusion

This study identified several factors associated with low QoL among caregivers of patients with CKD. An understanding of these factors provides insight into the development of targeted interventions to improve the QoL of caregivers.
Platelet-derived extracellular vesicles induced through different activation pathways drive melanoma progression by functional and transcriptional changes
Authors: Tavukcuoglu Zeynep , Butt Umar , Faria Alessandra V. S. , Oesterreicher Johannes , Holnthoner Wolfgang , Laitinen Saara , Palviainen Mari , Siljander Pia R-M
Published: December 2024

Background

Beyond their conventional roles in hemostasis and wound healing, platelets have been shown to facilitate hematogenous metastasis by interacting with cancer cells. Depending on the activation route, platelets also generate different platelet-derived extracellular vesicles (PEVs) that may educate cancer cells in the circulation or within the tumor microenvironment. We engaged different platelet-activating receptors, including glycoprotein VI and C-type lectin-like receptor 2, to generate a spectrum of PEV types. This allowed us to investigate the differential capacity of PEVs to alter cancer hallmark functions such as proliferation, invasion, and pro-angiogenic potential using melanoma as a model. Additionally, we analyzed changes in the cell transcriptomes and cancer EV profiles.

Methods

Two human melanoma cell lines (MV3 and A2058) with differential metastatic potential were studied in the 3D spheroid cultures. Human platelets were activated with collagen related peptide (CRP), fucoidan from Fucus vesiculosus (FFV), thrombin & collagen co-stimulus and Ca2+ ionophore, and PEVs were isolated by size-exclusion chromatography followed by ultrafiltration. Spheroids or cells were treated with PEVs and used in functional assays of proliferation, invasion, and endothelial tube formation as well as for the analysis of cancer EV production and their tetraspanin profiles. Differentially expressed genes and enriched signaling pathways in the PEV-treated spheroids were analyzed at 6 h and 24 h by RNA sequencing.

Results

Among the studied PEVs, those generated by CRP and FFV exhibited the most pronounced effects on altering cancer hallmark functions. Specifically, CRP and FFV PEVs increased proliferation in both MV3 and A2058 spheroids. Distinct tetraspanin signatures of melanoma EVs were induced by all PEV types. While the PI3K-Akt and MAPK signaling pathways were activated by both CRP and FFV PEVs, they differently upregulated the immunomodulatory TGF-β and type-I interferon signaling pathways, respectively.

Conclusions

Our study revealed both shared and distinct, cancer-promoting functions of PEVs, which contributed to the transcriptome and metastatic capabilities of the melanoma spheroids. Inhibiting the platelet receptors that modulate the PEVs’ cancer-promoting properties may open up new strategies for identifying promising treatment targets for cancer therapy.
The effectiveness of digital physical activity interventions in older adults: a systematic umbrella review and meta-meta-analysis
Authors: Alley Stephanie J. , Waters Kim M. , Parker Felix , Peiris D. L. I. H. K. , Fien Samantha , Rebar Amanda L. , Vandelanotte Corneel
Published: December 2024

Background

Physical activity is important for healthy ageing, however most older adults are inactive. Numerous reviews with a range of inclusion criteria have been conducted on digital interventions to promote physical activity in older adults, and a synthesis of these is needed. Therefore, the objective of this study is to conduct an umbrella review and meta-meta-analysis on the effectiveness of digital interventions to promote physical activity in older adults.

Methods

Nine databases were searched from January 2010 to December 2023. Systematic reviews and meta-analyses of primary studies using digital physical activity interventions to target healthy older adults or clinical populations of older adults with a self-reported or device measured physical activity outcome were eligible for inclusion.

Results

In total, 22 systematic reviews and meta-analyses covering 185 primary research papers were eligible for inclusion. The total number of participants across all primary studies was 28,198. Most (21, 95%) reviews and meta-analyses were rated as having a low or critically low AMSTAR-2 confidence rating. Of the 22 included systematic reviews, 13 (59%) conducted a meta-analysis and 10 (45%) conducted a narrative synthesis. Most systematic reviews with a narrative synthesis found strong evidence for a positive effect or moderate evidence for a positive effect for physical activity outcomes (7/9, 78%) and steps (3/3, 100%). The meta-meta-analysis of primary papers included in meta-analyses demonstrated a significant moderate effect for steps and a significant small effect for total PA and MVPA. The strength of effect did not vary by intervention components (activity tracker, app-based, SMS/phone, web-based, and face-to-face), population (primary or secondary prevention), control group (none, other digital intervention, or non-digital intervention), or outcome measurement (self-reported or device measured). Only 3 (14%) reviews included longer term follow up outcomes after the end of the intervention, with mixed results.

Conclusions

Evidence from 22 reviews and meta-analyses suggests that digital physical activity interventions are effective at increasing physical activity in older adults. Further primary research is needed in adults 65 years and over exclusively, and with longer-term follow up of physical activity outcomes. Future reviews should include a published protocol and interpret results according to risk-of-bias.
Systems analysis and improvement to optimize opioid use disorder care quality and continuity for patients exiting jail (SAIA-MOUD)
Authors: Gimbel Sarah , Basu Anirban , Callen Emily , Flaxman Abraham D. , Heidari Omeid , Hood Julia E. , Kellogg Anna , Kern Eli , Tsui Judith I. , Turley Ericka , Sherr Kenneth
Published: December 2024

Background

Between 2012–2022 opioid-related overdose deaths in the United States, including Washington State, have risen dramatically. Opioid use disorder (OUD) is a complex, chronic, and criminalized illness with biological, environmental, and social causes. One-fifth of people with OUD have recent criminal-legal system involvement; > 50% pass through WA jails annually.

Medications for Opioid Use Disorder (MOUD) can effectively treat OUD. WA has prioritized improving access to MOUD, including for those in jails. As patients in jail settings are systematically marginalized due to incarceration, it is critical to foster connections to MOUD services upon release, an acknowledged period of high overdose risk. Currently, there is insufficient focus on developing strategies to foster linkages between jail-based MOUD and referral services.

The Systems Analysis and Improvement Approach (SAIA), an evidence-based implementation strategy, may optimize complex care cascades like MOUD provision and improve linkages between jail- and community-based providers. SAIA bundles systems engineering tools into an iterative process to guide care teams to visualize cascade drop-offs and prioritize steps for improvement; identify modifiable organization-level bottlenecks; and propose, implement, and evaluate modifications to overall cascade performance. The SAIA-MOUD study aims to strengthen the quality and continuity of MOUD care across jail and referral clinics in King County, WA, and ultimately reduce recidivism and mortality.

Methods

We will conduct a quasi-experimental evaluation of SAIA effectiveness on improving MOUD care cascade quality and continuity for patients receiving care in jail and exiting to referral clinics; examine determinants of SAIA-MOUD adoption, implementation, and sustainment; and determine SAIA-MOUD’s cost and cost-effectiveness. Clinic teams with study team support will deliver the SAIA-MOUD intervention at the jail-based MOUD program and three referral clinics over a two-year intensive phase, followed by a one-year sustainment phase where SAIA implementation will be led by King County Jail MOUD staff without study support to enable pragmatic evaluation of sustained implementation.

Discussion

SAIA packages user-friendly systems engineering tools to guide decision-making by front-line care providers to identify low-cost, contextually appropriate health care improvement strategies. By integrating SAIA into MOUD care provision in jail and linked services, this pragmatic trial is designed to test a model for national scale-up.

Trial registration

ClinicalTrials.gov NCT06593353 (registered 09/06/2024; https://register.clinicaltrials.gov/prs/beta/studies/S000EVJR00000029/recordSummary).
Microglial CD2AP deficiency exerts protection in an Alzheimer’s disease model of amyloidosis
Authors: Zhang Lingliang , Huang Lingling , Zhou Yuhang , Meng Jian , Zhang Liang , Zhou Yunqiang , Zheng Naizhen , Guo Tiantian , Zhao Shanshan , Wang Zijie , Huo Yuanhui , Zhao Yingjun , Chen Xiao-fen , Zheng Honghua , Holtzman David M. , Zhang Yun-wu
Published: December 2024

Background

The CD2-associated protein (CD2AP) was initially identified in peripheral immune cells and regulates cytoskeleton and protein trafficking. Single nucleotide polymorphisms (SNPs) in the CD2AP gene have been associated with Alzheimer’s disease (AD). However, the functional role of CD2AP, especially its role in microglia during AD onset, remains elusive.

Methods

CD2AP protein levels in cultured primary cells and in 5xFAD mice was studied. Microglial CD2AP-deficient mice were crossed with 5xFAD mice and the offspring were subjected to neuropathological assessment, behavioral tests, electrophysiology, RNA-seq, Golgi staining, and biochemistry analysis. Primary microglia were also isolated for assessing their uptake and morphology changes.

Results

We find that CD2AP is abundantly expressed in microglia and its levels are elevated in the brain of AD patients and the 5xFAD model mice at pathological stages. We demonstrate that CD2AP haploinsufficiency in microglia significantly attenuates cognitive and synaptic deficits, weakens the response of microglia to Aβ and the formation of disease-associated microglia (DAM), and alleviates synapse loss in 5xFAD mice. We show that CD2AP-deficient microglia exhibit compromised uptake ability. In addition, we find that CD2AP expression is positively correlated with the expression of the complement C1q that is important for synapse phagocytosis and the formation of DAM in response to Aβ deposition. Moreover, we reveal that CD2AP interacts with colony stimulating factor 1 receptor (CSF1R) and regulates CSF1R cell surface levels, which may further affect C1q expression.

Conclusions

Our results demonstrate that CD2AP regulates microgliosis and identify a protective function of microglial CD2AP deficiency against Aβ deposition, suggesting the importance of detailed investigation of AD-associated genes in different brain cells for thoroughly understanding their exact contribution to AD.
Detection and classification of long terminal repeat sequences in plant LTR-retrotransposons and their analysis using explainable machine learning
Authors: Horvath Jakub , Jedlicka Pavel , Kratka Marie , Kubat Zdenek , Kejnovsky Eduard , Lexa Matej
Published: December 2024

Background

Long terminal repeats (LTRs) represent important parts of LTR retrotransposons and retroviruses found in high copy numbers in a majority of eukaryotic genomes. LTRs contain regulatory sequences essential for the life cycle of the retrotransposon. Previous experimental and sequence studies have provided only limited information about LTR structure and composition, mostly from model systems. To enhance our understanding of these key sequence modules, we focused on the contrasts between LTRs of various retrotransposon families and other genomic regions. Furthermore, this approach can be utilized for the classification and prediction of LTRs.

Results

We used machine learning methods suitable for DNA sequence classification and applied them to a large dataset of plant LTR retrotransposon sequences. We trained three machine learning models using (i) traditional model ensembles (Gradient Boosting), (ii) hybrid convolutional/long and short memory network models, and (iii) a DNA pre-trained transformer-based model using k-mer sequence representation. All three approaches were successful in classifying and isolating LTRs in this data, as well as providing valuable insights into LTR sequence composition. The best classification (expressed as F1 score) achieved for LTR detection was 0.85 using the hybrid network model. The most accurate classification task was superfamily classification (F1=0.89) while the least accurate was family classification (F1=0.74). The trained models were subjected to explainability analysis. Positional analysis identified a mixture of interesting features, many of which had a preferred absolute position within the LTR and/or were biologically relevant, such as a centrally positioned TATA-box regulatory sequence, and TG..CA nucleotide patterns around both LTR edges.

Conclusions

Our results show that the models used here recognized biologically relevant motifs, such as core promoter elements in the LTR detection task, and a development and stress-related subclass of transcription factor binding sites in the family classification task. Explainability analysis also highlighted the importance of 5’- and 3’- edges in LTR identity and revealed need to analyze more than just dinucleotides at these ends. Our work shows the applicability of machine learning models to regulatory sequence analysis and classification, and demonstrates the important role of the identified motifs in LTR detection.
Emergency call utilization over a 10-years period: an observational study in Region Zealand, Denmark, 2013–2022
Authors: Møller Thea Palsgaard , Jensen Josefine Tangen , Ersbøll Annette Kjær , Blomberg Stig Nikolaj Fasmer , Christensen Helle Collatz
Published: December 2024

Background

Improving prehospital emergency care requires a comprehensive understanding of the efficiency of emergency medical services and demand fluctuations. The medical emergency call is the primary contact between citizens and the emergency medical dispatch center, serving as the gateway to accessing emergency assistance. This study aimed to characterize the emergency call population and analyze the development of emergency call utilization in Region Zealand in Denmark during a 10-years period.

Methods

This was an observational register-based study of administrative data from the emergency medical dispatch center in Region Zealand. Data was collected from 1 January 2013 to 31 December 2022. All unique emergency calls from residents to the emergency number “1-1-2” were included. Descriptive analyses were used to characterize the study population. Poisson regression models were used to calculate ratio estimates for the association between years and hospital catchment areas, using the incidence rate of emergency calls as outcome measure.

Results

A total of 641,457 emergency calls were included. A significant increase in the total number of emergency calls was found, with an increase from 58,454 annual calls to 80,819 calls over the study period. The incidence rate per 1000 residents per year increased from 71.1 to 95.2, a 35% increase. The southern part of the region had significantly more emergency calls per 1000 residents per year during the study period compared to the eastern part of the region (IRR 1.70). Demographically, males comprised 52.3% of cases, and patients aged 65 and older represented 48.2% of calls. Emergency calls were “Emergency level A” in 45.5% and “Emergency level B” in 39.1%. In 22.3% of cases, the emergency call was categorized as “Unclear problem.” The most frequent categories were “chest pain” (12.7%), “impaired consciousness” (9.6%), “breathing difficulties” (8.8%), “accidents” (7.9%), and “minor injuries” (7.6%).

Conclusions

The study revealed a significant increase in emergency calls, both in absolute numbers and per 1000 residents per year, indicating growing demand for emergency care, along with a surge in activity at the region's dispatch center. Regional disparities underscores the potential necessity for tailored developmental approaches over time.
Methoxyflurane in early analgesic therapy by ski patrol members on Swiss ski slopes – an observational cohort study
Authors: Benz Lena , Knapp Jürgen , Roten Fredy-Michel , Huber Markus , Steffen Richard
Published: December 2024

Background

Pain therapy is an important first-response measure in the pre-clinical care of trauma patients. Injured individuals on ski slopes are usually given first aid by members of the ski patrol. The early implementation of adequate pain therapy by these paramedical rescuers can increase patient satisfaction and have a positive effect on the entire treatment process. In this context, we analysed the administration of methoxyflurane by ski patrol members on Swiss ski slopes.

Methods

In this retrospective observational study, we evaluated 172 datasets, of which 149 concerned patients who were administered methoxyflurane. These datasets were taken from a quality-control survey related to the administration of methoxyflurane by members of the ski patrol in seven ski resorts in the Swiss Alps. The data was collected in the winter months of 2022/23. The ski patrol members had been previously trained by medical professionals and employed methoxyflurane following a defined algorithm, according to which patients with an initial numeric pain score of ≥ 4 qualified for the use of methoxyflurane. After each treatment, data on effectiveness and feasibility were collected by means of a standardised questionnaire. The primary outcome was defined as achieving effective pain therapy, which was designated as a reduction on the numerical rating scale of two or more points and a pain score of seven or less after administration. We then performed a linear regression analysis with the relative pain reduction as the outcome and sex, age, ski resort and injury class as covariates.

Results

Methoxyflurane led to effective pain reduction in around two-thirds of patients on the ski slopes and was easy to use for trained ski patrol members. Median pain reduction was 2 points (interquartile range: 1 to 3) on the NRS scale. The regression model showed lower reduction in pain in lower extremity injuries. Sex, age and initial pain score were not associated with the extent of pain reduction. No serious side effects were observed.

Conclusion

The administration of methoxyflurane by trained ski patrol members is a safe and effective option for early pain management in ski slope injuries. Methoxyflurane could thus represent a useful bridging measure, enabling the ski patrol to relieve moderate to severe pain until professional rescue services arrive. However, it does not seem ideal for lower leg injuries.
Induction treatments with and without addition of one dose anthracycline to all-trans retinoid acid and arsenic in pediatric non-high-risk acute promyelocytic leukemia: study protocol for a randomized controlled trial
Authors: Fan Zhong , Huang Xiu-Ya , Huang Dan-Ping , Luo Jie-Si , Su Jia-Yin , Zhang Xiao-Li , Li Yu , Wang Li-Na , Liang Cong , Luo Xue-Qun , Huang Li-Bin , Tang Yan-Lai
Published: December 2024

Background

The treatment of all-trans retinoic acid (ATRA) and arsenical agent has revolutionarily improved the prognosis of acute promyelocytic leukemia (APL) both in adults and children. Nevertheless, coagulation disorder and differentiation syndrome (DS) are the main causes of early death in APL patients. Early chemotherapy to reduce leukocytes during induction is an important measure to reduce complications and mortality. However, the incidence of hyperleukocytosis (WBC > 10 × 109/L) was significantly higher in pediatric patients without chemotherapy than in adults. Although ATRA plus arsenic is the standard therapy for non-high-risk adult patients, it remains controversial whether chemotherapy is necessary for induction therapy in pediatric APL.

Methods

This study was designed as a multicenter randomized controlled trial. Children with APL were randomly assigned into experimental group (ATRA-RIF plus chemotherapy) and control group (ATRA-RIF). The experimental group was treated with ATRA-RIF plus chemotherapy for induction, while the control group was treated with ATRA-RIF alone. In addition, both groups received the same regimen of ATRA-RIF plus chemotherapy for consolidation and maintenance.

Discussion

This trial aims to compare the efficacy of ATRA-RIF plus chemotherapy versus ATRA-RIF in pediatric non-high-risk patients with APL to demonstrate that chemotherapy during induction therapy can reduce the incidence of complications such as hyperleukocytosis and DS, thereby reducing mortality.

Trial registration

Chinese Clinical Trials Registry, ID: ChiCTR2000038877. Registered on October 8, 2020, https://www.chictr.org.cn/showproj.html?proj=60733. V1.0 date 08/01/2020.
Immune modulation of buffalo peripheral blood mononuclear cells by two asparaginyl endopeptidases from Fasciola gigantica
Authors: Wu Dong-Qi , Guo Yan-Feng , Zou Yu , Tang Xiao-Ting , Zhang Wei-Yu , Di Wen-Da
Published: December 2024

Background

Fascioliasis is a zoonotic parasitic disease caused by Fasciola hepatica and Fasciola gigantica, which poses a serious threat to global public health and livestock farming. Fasciola gigantica secretes and excretes various components to manipulate the immune response, thereby enhancing its invasion, migration, and survival in vivo. However, the roles of specific components in immune modulation, such as asparagine endopeptidase, remain unknown.

Methods

The transcriptional abundance of members of the asparagine endopeptidase family (also known as the legumain family) from F. gigantica was analyzed. Two highly transcribed asparagine endopeptidases in metacercariae, juveniles and adults were cloned, and their recombinant proteins—recombinant F. gigantica legumain (rFgLGMN-1) and (rFgLGMN-2)—were expressed in prokaryotic expression system. Their regulatory effects on buffalo peripheral blood mononuclear cells (PBMCs), including proliferation, migration, total nitric oxide (NO) production, cytokine secretion, and phagocytosis were explored in vitro.

Results

Ten members of the legumain family were detected in F. gigantica, among of which FgLGMN-1 and FgLGMN-2 exhibited high transcription levels in juveniles and adults. The isolation of sequences indicated that FgLGMN-1 encodes 409 amino acids, while FgLGMN-2 encodes 403 amino acids. Both recombinant FgLGMN-1 (rFgLGMN-1) and rFgLGMN-2 were recognized by serum from buffaloes infected with F. gigantica. Both rFgLGMN-1 and rFgLGMN-2 inhibited the proliferation of PBMCs, and rFgLGMN-1 also inhibited the migration of PBMCs. While rFgLGMN-1 increased the production of total NO, rFgLGMN-2 decreased NO production. Both rFgLGMN-1 and rFgLGMN-2 increased the transcription of the cytokines interleukin-10 and transforming growth factor β. The effect of rFgLGMN-1 and rFgLGMN-2 on the phagocytosis of PBMCs varied depending on their concentrations.

Conclusions

rFgLGMN-1 and rFgLGMN-2 modulate several cellular and immunological functions of PBMCs, and exhibited distinct regulatory effects on these in vitro, which indicated that they may play roles in immune modulation and facilitate fluke development. However, due to uncertainties associated with in vitro experiments, further studies are necessary to elucidate the precise functions of these legumains.

Graphical Abstract
Preventive efficacy of six monthly doses of NexGard® PLUS or Simparica Trio® against a macrocyclic lactone-resistant isolate (JYD-34) of Dirofilaria immitis and of a single dose of NexGard PLUS against a susceptible isolate
Authors: Prullage Joseph , Frost Justin , DiCosty Utami , Martin Elizabeth , Dumont Pascal , Yoon Stephen , Süssenberger Ricarda
Published: December 2024

Background

Two studies were conducted assessing the efficacy of NexGard® PLUS (NP) in preventing heartworm disease. Study 1 evaluated the efficacy of six monthly doses of NP or Simparica Trio® (ST) against a macrocyclic lactone-resistant isolate of heartworm, Dirofilaria immitis, and study 2 evaluated the efficacy of a single dose of NP against a susceptible isolate.

Methods

In two studies, dogs that were negative for heartworms by antigen test and modified Knott’s test were used. In study 1, dogs were randomly allocated into three treatment groups (n = 6/group): negative control, NP per label instructions, and ST per label instructions. Dogs were inoculated with 50 third-stage D. immitis larvae (JYD-34 isolate) on day −30. NP and ST were administered orally on days 0, 30, 60, 90, 120, and 150. A necropsy was performed on day 180 for adult heartworm recovery. In study 2, dogs were randomly allocated into two treatment groups (n = 10/group): negative control and NP. Dogs were inoculated with 50 third-stage larvae (SC-20 isolate) on day −30. NP was administered orally once on day 0 to target the minimum moxidectin label dose. A necropsy was performed on day 120 for adult heartworm recovery.

Results

For study 1, all control dogs had adult heartworms at necropsy (geometric mean, 39.7; range, 28–48). Two of the NP-treated dogs had one live worm, and one of the ST-treated dogs had one live worm. Both treated groups were significantly different from the control group with an efficacy of 99.5% for NP and 99.8% for ST (P < 0.0001). There was no significant difference (P = 0.8797) between the groups treated with NP and ST. For study 2, all control dogs had adult heartworms (geometric mean, 34.5; range 26–43). None of the dogs treated with NP had live adult worms (efficacy of 100%, P < 0.0001).

Conclusions

The results of study 1 demonstrated that NexGard® PLUS and Simparica Trio® administered at the label dose provided comparable efficacy against a macrocyclic lactone-resistant isolate of D. immitis. The results of study 2 demonstrated that NexGard® PLUS administered once near the minimum label dose was 100% effective against a susceptible isolate.

Graphical Abstract
Epigenetic regulation on left atrial function and disease recurrence after catheter ablation in atrial fibrillation
Authors: Han Mi-Ryung , Jeong Joo Hee , Kim Yun Gi , Yang Hyun-Ho , Seo Chang-Ok , Kim Yeji , Lee Hyoung Seok , Shim Jaemin , Kim Young-Hoon , Choi Jong-Il
Published: December 2024

Background

Genetic variation and modifiable risk factors play a significant role in the pathogenesis of atrial fibrillation (AF). The influence of epigenetic modification on AF remains to be elucidated. We investigated the role of DNA methylation in the etiology of AF. Epigenetic evaluation was performed in 115 AF patients who underwent radiofrequency catheter ablation in a single institution. We measured methylation at approximately 850,000 bp cytosine-phosphate-guanine (CpG) sites in the 115 samples. The degree of methylation was compared across seven classification criteria: type of AF, late recurrence, impaired left atrium (LA) function, late gadolinium enhancement, LA diameter, LA volume, and flow velocity of the LA appendage.

Results

The four most significantly methylated genes were DEFB104B, C3, TANC1, and TMEM9B. The DEFB104B gene (cg20223677 in the transcription start site), which encodes β-defensin 104B, was hypomethylated in three groups: AF patients with late recurrence, impaired LA function, and impaired LAA flow velocity. Enriched functional annotation of the differentially methylated datasets revealed that five out of the seven AF groups in this cohort were associated with genes involved in the cell movement of endothelial cell lines, sprouting angiogenesis by endothelial cell lines, or migration of endothelial cell lines.

Conclusions

Epigenetic profiling revealed that epigenetic modification might affect important characteristics of AF. Our results suggest that the pathogenesis of AF might be affected by not only genetic variation or modifiable factors but also by epigenetic modulation.
Identification of Brucella RS15060 as a novel type IV secretion system effector associated with bacterial virulence
Authors: Yin Yi , Tian Mingxing , Zhang Guangdong , Hu Hai , Ding Chan , Yu Shengqing
Published: December 2024

Brucella is an intracellular parasitic pathogen that causes the worldwide zoonotic disease brucellosis. The type IV secretion system (T4SS) is utilized to secrete various effectors to help Brucella form Brucella-containing vacuoles within the cell and accomplish intracellular trafficking and replication. Brucella has fewer recognized effector proteins than other intracellular parasites in the Proteobacteria, indicating that Brucella may contain a large number of unidentified effector proteins. In this study, the optimal conditions for inducing protein secretion from Brucella were screened, and the secreted proteins of 2308 and the T4SS-deficient mutant SV123 under optimal conditions were collected for comparative proteomics analysis. By label-free quantitative proteomics, we identified 15 differential proteins. Through the β-lactamase TEM1 assay and indirect immunofluorescence assay, we identified RS15060 and RS10635 as novel T4SS effectors. Furthermore, by constructing mutation strains and performing cell/mouse infection experiments, we found that deletion of the rs15060 gene reduced the capacity of Brucella to replicate in cells and cause chronic infection in mice. In conclusion, a novel Brucella T4SS effector protein, RS15060, was identified to be associated with virulence in this study, and the discovery of effector proteins is conducive to a more comprehensive elucidation of T4SS function as well as to uncovering the cryptic strategies of Brucella survival in cells.
Insights into genetic determinants of piglet survival during a PRRSV outbreak
Authors: Tarrés Joaquim , Jové-Juncà Teodor , Hernández-Banqué Carles , González-Rodríguez Olga , Ganges Llilianne , Gol Sofia , Díaz Marta , Reixach Josep , Pena Ramona N. , Quintanilla Raquel , Ballester Maria
Published: December 2024

Breeding animals to produce more robust and disease-resistant pig populations becomes a complementary strategy to the more conventional methods of biosecurity and vaccination. The objective of this study was to explore the ability of a panel of genetic markers and immunity parameters to predict the survival rates during a natural PRRSV outbreak. Ten-week-old female Duroc pigs (n = 129), obtained from 61 sows and 20 boars, were naturally infected with a highly pathogenic PRRSV genotype 1 strain. Prior to infection, piglets were screened for immunity parameters (IgG levels in plasma and SOX13 mRNA expression in blood) and genetic markers previously associated to PRRSV immune response and immunity traits. Additionally, the 20 boars were genotyped with a panel of 132 single nucleotide polymorphisms (SNPs). Survival analysis showed that mortality was significantly higher for animals with low basal IgG levels in plasma and/or high SOX13 mRNA expression in blood. The genotypes of sires for SNPs associated with IgG plasma levels, CRP in serum, percentage of γδ T cells, lymphocyte phagocytic capacity, total number of lymphocytes and leukocytes, and MCV and MCH were significantly associated with the number of surviving offspring. Furthermore, CD163 and GBP5 markers were also associated to piglet survival. The effects of these SNPs were polygenic and cumulative, survival decreased from 94 to 21% as more susceptible alleles were accumulated for the different markers. Our results confirmed the existence of genetic variability in survival after PRRSV infection and provided a set of genetic markers and immunity traits associated with PRRS resistance.
Revealing novel and conservative CD8+T-cell epitopes with MHC B2 restriction on ALV-J
Authors: Li Xueqing , Li Ziwei , Ma Mulin , Yang Na , Du Shanyao , Liao Ming , Dai Manman
Published: December 2024

MHC B2 haplotype chickens have been reported to induce strong immune response against various avian pathogens. However, little is known about the CD8+T-cell epitope with MHC B2-restricted on subgroup J avian leukosis virus (ALV-J). In this study, we explored the ALV-J-induced cellular immune response in B2 haplotype chickens in vivo. We found that ALV-J infection significantly increased the proportion of CD8+T cells in chickens and up-regulated the expression of cytotoxic genes like Granzyme A and antiviral genes like IFIT5 at 14 days post-infection (dpi). We selected 32 candidate peptides based on the peptide-binding motif and further identified three MHC B2-restricted CD8+T epitopes on ALV-J, including Pol652−660, Gag374−382, and Gag403−411 which induced significant levels of chicken IFN-γ production in splenocytes from ALV-J infected chickens using the ELISpot assay. In addition, we also verified that the three identified epitopes stimulated memory splenocytes elevating TNF-α and IL-2 protein expression. Importantly, we found that the three positive peptides were highly conserved among ALV-A, ALV-B, ALV-E, ALV-J, and ALV-K. Taken together, we identified three MHC B2-restricted CD8+T cell epitopes on ALV-J, providing a foundation for developing effective T cell epitope vaccines targeting conserved internal viral proteins.
The predominant role of FliC contributes to the flagella-related pathogenicity of ST34 S. Typhimurium monophasic variant
Authors: Hong Yaming , Hou Qilong , Liu Hui , Wang Xiaojie , Gu Jiaojie , Wang Zhenyu , Jiao Xinan , Li Qiuchun
Published: December 2024

Over the past two decades, the monophasic variant of Salmonella enterica serovar Typhimurium (S. Typhimurium) has rapidly emerged and increased worldwide. This upsurge is especially true for the European clone of the ST34 S. Typhimurium monophasic variant. The key distinction between ST34 S. Typhimurium and its monophasic variant is that the genes that encode for second-phase flagellin (FljB) and the regions around it have been replaced with various multidrug resistance cassettes. To determine if the loss of fljB or the retention of fliC,-the gene coding for first-phase flagellin (FliC)-, would impact its pathogenicity, we constructed various mutations, including deletions of fljB, fliC, fliC/fljB, and strains where fliC was replaced with fljB. Our results showed that the loss of fljB in ST34 S. Typhimurium and its monophasic variant does not affect bacterial motility, cell infection ability, survival in macrophages, induced pro-inflammatory cytokines secretion, virulence, or persistent infection in mice. However, the deletion of fliC caused a significant decrease in these outcomes for both strains, while the replacement of fliC with fljB only partially restored these capabilities. Consequently, we determined that FliC is predominant in the flagellar expression of ST34 S. Typhimurium other than FljB. This finding demonstrates that replacing the fljB gene with various resistance regions in ST34 S. Typhimurium monophasic variants can enhance bacterial survival under specific antibiotic farming practices and spread globally.
Leveraging Lactobacillus plantarum probiotics to mitigate diarrhea and Salmonella infections in broiler chickens
Authors: Mirsalami Seyed Mehrdad , Mirsalami Mahsa
Published: December 2024

Anaerobic bacteria, such as Lactobacillus plantarum (LP), are known to play a significant role in maintaining gut health and protecting against enteric pathogens in animals. The present study aimed to develop a safe, affordable, and eco-friendly method for producing LP-based probiotics and evaluate their efficacy in mitigating Salmonella-induced diarrhea in broiler chickens. The study employed three different culture media (MRS, TSB, and Baird Parker) to grow LP, which was then dried using a spray-drying technique to produce a stable probiotic formulation. When administered to broiler chickens, the LP probiotic derived from the MRS medium significantly improved body weight gain (4.147-fold increase over 4 weeks) compared to the other two culture conditions. Importantly, the LP probiotic treatment could substantially reduce the diarrhea index in broilers, with up to an 86.45% improvement in Salmonella-induced enteric infections. The beneficial effects were attributed to the ability of LP to modulate the gut microbiome, enhance the integrity of the intestinal mucosa, and mitigate the pathogenic effects of Salmonella. These findings demonstrate the potential of anaerobic Lactobacillus plantarum as a safe and effective probiotic intervention for controlling enteric diseases and improving production outcomes in poultry farming. The developed method provides a sustainable approach to harness the beneficial properties of this anaerobic bacterium for animal health and welfare.

Graphical abstract
Gender-based opportunity structure in the energy sector: a literature review on women’s networking and mentoring
Authors: Lazoroska Daniela , Palm Jenny , Kojonsaari Anna-Riikka
Published: December 2024

Background

While the energy system is recognized as the largest contributor to climate disruption, the bulk of the sustainability-oriented interventions are made through technologies rather than employment equity and social justice issues. Emergent research points to the critical role of increasing the number of women and other minoritized groups in the energy sector, which could have a cultural, economic, and environmental impact. Nevertheless, how inclusion and diversity in the sector are to be achieved is not clear.

Main text

This article is a result of a structured literature review of earlier research focusing on gender in professional networks and mentoring programs within the energy sector. Professional networks and mentoring have been identified as some of the tools employed for increasing gender diversity in the sector. We seek to understand how gender has been integrated, what the main barriers and enablers for women are, and what strategies organizations have applied to achieve gender balance so that men and women face equal opportunities to partake in and influence decisions concerning the energy system.

Conclusion

We found that women’s exclusion is not recognized as a problem that needs to be acknowledged, monitored, or addressed by the energy sector or policymakers. Professional mentoring and networking have largely been employed to fill the career advancement and diversity gaps left untackled by the energy sector or policymakers. Opportunities for women to be meaningfully included in energy systems decision-making are still limited and fragmented. Furthermore, this lack of recognition is mirrored in energy research. We identified a concerning lack of evidence-based findings on the topic of women’s networking and mentoring in the energy sector. We thus call for in-depth, qualitative, and critical examinations of how opportunities for women and other minoritized groups are generated on both the policy and practice level.
Innovations to the ECHO model to enhance reach and network-building among addiction clinicians in Western Canada
Authors: Robinson Samantha , Brohman Isabella , Draanen Jenna van , Kushner Rivka , Fairbairn Nadia , Glegg Stephanie
Published: December 2024

Background

Building capacity for evidence-based treatment and support for people with substance use disorders (SUD) is an urgent priority in the context of the toxic drug poisoning crisis. We implemented the first substance use-focused Project Extension for Community Healthcare Outcomes (ECHO) in Western Canada for health care providers, to enhance their clinical addiction skills and knowledge, facilitate practice change, and foster a supportive community of practice. The aims of this article are to describe our innovations to the Project ECHO model in British Columbia (BC) and Yukon, and present key program outcomes.

Methods

A pragmatic multi-methods program evaluation employed observational records of BC ECHO on Substance Use session attendance, cross-sectional and longitudinal participant surveys, and qualitative interviews with participants to assess satisfaction, relevance, and preparation to use evidence-based approaches, practice change intentions, and actual behaviours.

Results

The 52 ECHO sessions (from June 2019 to July 2022) attracted 2134 unique registrants with 5089 attendances (mean 124/session), 2132 newsletter subscribers, and 5842 podcast downloads. The evaluation included 844 post-session survey respondents and 53 interview participants. The program included ECHO sessions with rolling attendance; widely accessed supplemental formats (e.g., newsletter, podcast, clinical tools, archived presentation recordings); variable, regional hub representation; and evidence-based content developed by medical writers. These features contributed to broad geographic and discipline reach, high-quality program content, and high mean session satisfaction ratings (4.2/5). Key qualitative themes emerged, related to knowledge and skill acquisition, gaining confidence in providing SUD care, facilitating shared decision-making, increasing compassion for patients, consolidating learning and applying it to practice, and reducing isolation through expanded networks.

Conclusions

The ECHO model is an effective way to improve capacity in SUD care for physicians and nurse practitioners, while offering benefits for interprofessional attendees. Our findings can inform innovations in other ECHO programs to enhance reach, engagement, and impact.
The burden of left ventricular assist device (LVAD) infections on costs, lengths of stay, antimicrobial consumption and resistance: a prospective case control approach
Authors: Ficinski Matthew , West Jennifer , Glassman Shannon , Wojciechowski Katrina , Gutowski Jennifer , Laguio-Vila Maryrose , Feitell Scott , Lesho Emil
Published: December 2024

Background

Congestive heart failure has reached pandemic levels, and left-ventricular assist devices (LVAD) are increasingly used to treat refractory heart failure. Infection is a leading complication of LVADs. Despite numerous reports (most being retrospective), several knowledge gaps pertaining to the epidemiology and burden of an LVAD-associated infection (LVADi) remain. We sought to address these gaps using a prospective, case-control design.

Methods

All patients who received an LVAD from November 1, 2018 to August 31, 2023 (n = 110) were included and prospectively monitored until death. Data were extracted from clinical encounters and medical records in real-time or near real-time and imported to Excel and REDcap electronic data capture tools. An LVADi was ascertained using definitions from the mechanical circulatory support academic research consortium in conjunction with and the U.S. National Health Safety Network. All meeting those definitions were included as ‘cases.’ Patients with no LVADi were controls. Excess lengths-of-stays (LOS) and direct costs were calculated from billing records using a commercial cost accounting software platform (Strata®, Chicago, IL).

Results

The amount of healthcare contact before implantation and discharge to a rehabilitation or skilled nursing facility instead of home were the primary risks for infection, resulting in mean excesses of 25 hospital and 60 antibiotic-days and $43,000 per event. One-third occurred > 1 year after implantation. 35% developed > 1 infection. Gram-negative, fungal, and antimicrobial-resistant organisms predominated deep or repeat infections. 7.2% developed ≥ 3 infections. Organisms became increasingly antimicrobial resistant with subsequent infections, leading to extensive or pan-drug resistance in 4.5% of patients. The burden of an LVADi was 1862 excess hospital days, 3960 excess antibiotic days, and $3.4 million.

Conclusions

Patients with LVADis had significant increases in costs, LOS, readmissions, and antibiotic usage. Antimicrobial resistance varied directly with the number of repeat infections and antibiotic exposure. Identification of factors associated with LVADi, and quantification of the burden of LVADi can inform prevention efforts and lead to reduced infection rates. As preventing infections in the first place is also important for limiting the emergence of antimicrobial resistance, we offer strategies to avoid LVADis.

Trial registry

Not applicable.