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Objectives/Goals: Osteoarthritis (OA) is a multifactorial disease where sustained gut inflammation is a continued source of inflammatory mediators driving degenerative processes in joints. The goal was to use spontaneous equine model to compare fecal and leukocyte microbiome and correlation to transcriptome in OA. Methods/Study Population: Seventy-six horses (31 OA, 45 controls) were enrolled by population-based sampling. Feces and peripheral blood mononuclear cells (PBMC) were collected. Horses were determined to have OA by clinical and radiographic evidence. Horses were excluded if they received medications or joint injections within two months. Fecal and circulating leukocyte bacterial microbial 16s-seq was performed. Bulk RNAseq of PBMC was performed by the Illumina platform. Gene expression data were mapped to the equine genome, and differential expression analysis was performed with DESeq2. Qiime2 was used for microbial analysis. Enrichment analysis was performed with a cluster profiler. Correlation analyses were performed between the datasets. Results/Anticipated Results: Beta and alpha microbial diversity differed in feces and PBMC of OA vs. healthy horses. Horses with OA had an increased Firmicutes to Bacteroidetes ratio compared with controls. The fecal microbiome of OA horses had significantly higher amounts of Firmicutes Oribacterium (q Discussion/Significance of Impact: These data suggest that altered microbiome and PBMC gene expression are associated with naturally occurring OA in the translational equine model. While Oribacterium has been detected in humans with rheumatoid arthritis, its role in OA warrants further proteomic and metabolomic profiling.

Multiple biological therapies for orthopedic injuries are marketed to veterinarians, despite a lack of rigorous comparative biological activity data to guide informed decisions in selecting a most effective compound. Therefore, the goal of this study was to use relevant bioassay systems to directly compare the anti-inflammatory and immunomodulatory activity of three commonly used orthobiological therapies (OTs): mesenchymal stromal cells (MSC), autologous conditioned serum (ACS), and platelet rich plasma (PRP). Equine monocyte-derived macrophages were used as the readout system to compare therapies, including cytokine production and transcriptomic responses. Macrophages were stimulated with IL-1ß and treated 24 h with OTs, washed and cultured an additional 24 h to generate supernatants. Secreted cytokines were measured by multiplex immunoassay and ELISA. To assess global transcriptomic responses to treatments, RNA was extracted from macrophages and subjected to full RNA sequencing, using an Illumina-based platform. Data analysis included comparison of differentially expressed genes and pathway analysis in treated vs. untreated macrophages. All treatments reduced production of IL-1ß by macrophages. Secretion of IL-10 was highest in MSC-CM treated macrophages, while PRP lysate and ACS resulted in greater downregulation of IL-6 and IP-10. Transcriptomic analysis revealed that ACS triggered multiple inflammatory response pathways in macrophages based on GSEA, while MSC generated significant downregulation of inflammatory pathways, and PRP lysate induced a mixed immune response profile. Key downregulated genes in MSC-treated cultures included type 1 and type 2 interferon response, TNF-α and IL-6. PRP lysate cultures demonstrated downregulation of inflammation-related genes IL-1RA, SLAMF9, ENSECAG00000022247 but concurrent upregulation of TNF-α, IL-2 signaling, and Myc targets. ACS induced upregulation of inflammatory IL-2 signaling, TNFα and KRAS signaling and hypoxia, but downregulation of MTOR signaling and type 1 interferon signaling. These findings, representing the first comprehensive look at immune response pathways for popular equine OTs, reveal distinct differences between therapies. These studies address a critical gap in our understanding of the relative immunomodulatory properties of regenerative therapies commonly used in equine practice to treat musculoskeletal disease and will serve as a platform from which further comparisons may build.

There is a need for implementation and maturation of an inclusive trauma system in every country in Europe, with patient centered care by dedicated surgeons. This process should be initiated by physicians and medical societies, based on the best available evidence, and supported and subsequently funded by the government and healthcare authorities. A systematic approach to organizing all aspects of trauma will result in health gain in terms of quality of care provided, higher survival rates, better functional outcomes and quality of life. In addition, it will provide reliable data for both research, quality improvement and prevention programs. Severely injured patients need surgeons with broad technical and non-technical competencies to provide holistic, inclusive and compassionate care. Here we describe the philosophy of the surgical approach and define the necessary skills for trauma, both surgical and other, to improve outcome of severely injured patients. As surgery is an essential part of trauma care, surgeons play an important role for the optimal treatment of trauma patients throughout and after their hospital stay, including the intensive care unit (ICU). However, in most European countries, it might not be obvious to either the general public, patients or even the physicians that the surgeon must assume this responsibility in the ICU to optimize outcomes. The aim of this paper is to define key elements in terms of trauma systems, trauma-specific surgical skills and active critical care involvement, to organize and optimize trauma care in Europe.

Background Integrating mental health services into primary care is a key strategy for reducing the mental healthcare treatment gap in low- and middle-income countries. We examined healthcare use and costs over time among individuals with depression and subclinical depressive symptoms in Chitwan, Nepal to understand the impact of integrated care on individual and health system resources. Methods Individuals diagnosed with depression at ten primary care facilities were randomized to receive a package of integrated care based on the Mental Health Gap Action Programme (treatment group; TG) or this package plus individual psychotherapy (TG + P); individuals with subclinical depressive symptoms received primary care as usual (UC). Primary outcomes were changes in use and health system costs of outpatient healthcare at 3- and 12-month follow up. Secondary outcomes examined use and costs by type. We used Poisson and log-linear models for use and costs, respectively, with an interaction term between time point and study group, and with TG as reference. Results The study included 192 primary care service users (TG = 60, TG +  P  = 60, UC = 72; 86% female, 24% formally employed, mean age 41.1). At baseline, outpatient visits were similar (− 11%, p  = 0.51) among TG + P and lower (− 35%, p  = 0.01) among UC compared to TG. Visits increased 2.30 times ( p  < 0.001) at 3 months among TG, with a 50% greater increase ( p  = 0.03) among TG + P, before returning to baseline levels among all groups at 12 months. Comparing TG + P to TG, costs were similar at baseline (− 1%, p  = 0.97) and cost changes did not significantly differ at three (− 16%, p  = 0.67) or 12 months (− 45%, p  = 0.13). Costs among UC were 54% lower than TG at baseline ( p  = 0.005), with no significant differences in cost changes over follow up. Post hoc analysis indicated individuals not receiving psychotherapy used less frequent, more costly healthcare. Conclusion Delivering psychotherapy within integrated services for depression resulted in greater healthcare use without significantly greater costs to the health system or individual. Previous research in Chitwan demonstrated psychotherapy determined treatment effectiveness for people with depression. While additional research is needed into service implementation costs, our findings provide further evidence supporting the inclusion of psychotherapy within mental healthcare integration in Nepal and similar contexts.

Whilst the link between physical factors and risk of high altitude (HA)-related illness and acute mountain sickness (AMS) have been extensively explored, the influence of psychological factors has been less well examined. In this study we aimed to investigate the relationship between 'anxiety and AMS risk during a progressive ascent to very HA. Eighty health adults were assessed at baseline (848m) and over 9 consecutive altitudes during a progressive trek to 5140m. HA-related symptoms (Lake Louise [LLS] and AMS-C Scores) and state anxiety (State-Trait-Anxiety-Score [STAI Y-1]) were examined at each altitude with trait anxiety (STAI Y-2) at baseline. The average age was 32.1 ± 8.3 years (67.5% men). STAI Y-1 scores fell from 848m to 3619m, before increasing to above baseline scores (848m) at ≥4072m (p = 0.01). STAI Y-1 scores correlated with LLS (r = 0.31; 0.24-0.3; P<0.0001) and AMS-C Scores (r = 0.29; 0.22-0.35; P<0.0001). There was significant main effect for sex (higher STAI Y-1 scores in women) and altitude with no sex-x-altitude interaction on STAI Y-1 Scores. Independent predictors of significant state anxiety included female sex, lower age, higher heart rate and increasing LLS and AMS-C scores (p<0.0001). A total of 38/80 subjects (47.5%) developed AMS which was mild in 20 (25%) and severe in 18 (22.5%). Baseline STAI Y-2 scores were an independent predictor of future severe AMS (B = 1.13; 1.009-1.28; p = 0.04; r2 = 0.23) and STAI Y-1 scores at HA independently predicted AMS and its severity. Trait anxiety at low altitude was an independent predictor of future severe AMS development at HA. State anxiety at HA was independently associated with AMS and its severity.

Background Existing implementation measures developed in high-income countries may have limited appropriateness for use within low- and middle-income countries (LMIC). In response, researchers at Johns Hopkins University began developing the Mental Health Implementation Science Tools (mhIST) in 2013 to assess priority implementation determinants and outcomes across four key stakeholder groups—consumers, providers, organization leaders, and policy makers—with dedicated versions of scales for each group. These were field tested and refined in several contexts, and criterion validity was established in Ukraine. The Consumer and Provider mhIST have since grown in popularity in mental health research, outpacing psychometric evaluation. Our objective was to establish the cross-context psychometric properties of these versions and inform future revisions. Methods We compiled secondary data from seven studies across six LMIC—Colombia, Myanmar, Pakistan, Thailand, Ukraine, and Zambia—to evaluate the psychometric performance of the Consumer and Provider mhIST. We used exploratory factor analysis to identify dimensionality, factor structure, and item loadings for each scale within each stakeholder version. We also used alignment analysis (i.e., multi-group confirmatory factor analysis) to estimate measurement invariance and differential item functioning of the Consumer scales across the six countries. Results All but one scale within the Provider and Consumer versions had Cronbach’s alpha greater than 0.8. Exploratory factor analysis indicated most scales were multidimensional, with factors generally aligning with a priori subscales for the Provider version; the Consumer version has no predefined subscales. Alignment analysis of the Consumer mhIST indicated a range of measurement invariance for scales across settings ( R 2 0.46 to 0.77). Several items were identified for potential revision due to participant nonresponse or low or cross- factor loadings. We found only one item, which asked consumers whether their intervention provider was available when needed, to have differential item functioning in both intercept and loading. Conclusion We provide evidence that the Consumer and Provider versions of the mhIST are internally valid and reliable across diverse contexts and stakeholder groups for mental health research in LMIC. We recommend the instrument be revised based on these analyses and future research examine instrument utility by linking measurement to other outcomes of interest.

Background Age‐related muscle decline (sarcopenia) associates with numerous health risk factors and poor quality of life. Drugs that counter sarcopenia without harmful side effects are lacking, and repurposing existing pharmaceuticals could expedite realistic clinical options. Recent studies suggest bisphosphonates promote muscle health; however, the efficacy of bisphosphonates as an anti‐sarcopenic therapy is currently unclear. Methods Using Caenorhabditis elegans as a sarcopenia model, we treated animals with 100 nM, 1, 10, 100 and 500 μM zoledronic acid (ZA) and assessed lifespan and healthspan (movement rates) using a microfluidic chip device. The effects of ZA on sarcopenia were examined using GFP‐tagged myofibres or mitochondria at days 0, 4 and 6 post‐adulthood. Mechanisms of ZA‐mediated healthspan extension were determined using combined ZA and targeted RNAi gene knockdown across the life‐course. Results We found 100 nM and 1 μM ZA increased lifespan (P < 0.001) and healthspan [954 ± 53 (100 nM) and 963 ± 48 (1 μM) vs. 834 ± 59% (untreated) population activity AUC, P < 0.05]. 10 μM ZA shortened lifespan (P < 0.0001) but not healthspan (758.9 ± 37 vs. 834 ± 59, P > 0.05), whereas 100 and 500 μM ZA were larval lethal. ZA (1 μM) significantly improved myofibrillar structure on days 4 and 6 post‐adulthood (83 and 71% well‐organized myofibres, respectively, vs. 56 and 34% controls, P < 0.0001) and increased well‐networked mitochondria at day 6 (47 vs. 16% in controls, P < 0.01). Genes required for ZA‐mediated healthspan extension included fdps‐1/FDPS‐1 (278 ± 9 vs. 894 ± 17% population activity AUC in knockdown + 1 μM ZA vs. untreated controls, respectively, P < 0.0001), daf‐16/FOXO (680 ± 16 vs. 894 ± 17%, P < 0.01) and agxt‐2/BAIBA (531 ± 23 vs. 552 ± 8%, P > 0.05). Life/healthspan was extended through knockdown of igdb‐1/FNDC5 (635 ± 10 vs. 523 ± 10% population activity AUC in gene knockdown vs. untreated controls, P < 0.01) and sir‐2.3/SIRT‐4 (586 ± 10 vs. 523 ± 10%, P < 0.05), with no synergistic improvements in ZA co‐treatment vs. knockdown alone [651 ± 12 vs. 635 ± 10% (igdb‐1/FNDC5) and 583 ± 9 vs. 586 ± 10% (sir‐2.3/SIRT‐4), both P > 0.05]. Conversely, let‐756/FGF21 and sir‐2.2/SIRT‐4 were dispensable for ZA‐induced healthspan [630 ± 6 vs. 523 ± 10% population activity AUC in knockdown + 1 μM ZA vs. untreated controls, P < 0.01 (let‐756/FGF21) and 568 ± 9 vs. 523 ± 10%, P < 0.05 (sir‐2.2/SIRT‐4)]. Conclusions Despite lacking an endoskeleton, ZA delays Caenorhabditis elegans sarcopenia, which translates to improved neuromuscular function across the life course. Bisphosphonates might, therefore, be an immediately exploitable anti‐sarcopenia therapy.

Background Ferroptosis is a type of cell death induced by iron dysregulation. It is characterized by mitochondrial abnormalities such as smaller size, outer membrane rupture, dense membranes, reduction in mitochondrial crista, and reduced mitochondrial membrane potential. Recent literature has identified ferroptosis as a mechanism contributing to neuronal death and the progression of neurological disorders such as Alzheimer's disease (AD). Ferroptosis has been primarily studied on neurons or neuron‐like cells, but limited research has been conducted using astrocytes. Astrocytes are glial cells recognized, among other functions, for maintaining the blood‐brain barrier, regulating synapses, repairing tissue, and recently have been acknowledged as significant players in the onset and progression of neurological disorders including AD. Methods In this work, we evaluated the effects of N2, N7‐dicyclohexyl‐9‐(hydroxyimino)‐9H‐fluorene‐2,7‐disulfonamide (FIN56) and two free iron sources (FeCl2 and FeCl3) as ferroptosis inducing agents on the biological behavior of adult human astrocytes. The response of the cells to FIN56 and free iron species at different concentrations, and exposure times was evaluated for cell viability, cell morphology, reactive oxygen species (ROS) production, and mitochondrial function. Results Initial results showed that human astrocyte viability was not significantly affected by the presence of free iron up to 50 μM. In addition, JC‐1 measurements revealed that mitochondrial activity was enhanced in human astrocytes cultured in free iron supplemented medium. On the other hand, the presence of FIN56 in the culture medium appeared fatal to cells event at low concentrations. This cell death was linked to significantly reduced mitochondrial membrane potential caused by FIN56. Conclusion At the same molar concentration, we observed a stronger and detrimental impact on astrocyte survival and mitochondrial function with the use of FIN56 relative to free iron species.

New Delhi metallo-β-lactamases (NDMs) are major contributors to the spread of carbapenem resistance globally. In Australia, NDMs were previously associated with international travel, but from 2019 we noted increasing incidence of NDM-positive clinical isolates. We investigated the clinical and genomic epidemiology of NDM carriage at a tertiary-care Australian hospital from 2016 to 2021. We identified 49 patients with 84 NDM-carrying isolates in an institutional database, and we collected clinical data from electronic medical record. Short- and long-read whole genome sequencing was performed on all isolates. Completed genome assemblies were used to assess the genetic setting of genes and to compare NDM plasmids. Of 49 patients, 38 (78%) were identified in 2019-2021 and only 11 (29%) of 38 reported prior travel, compared with 9 (82%) of 11 in 2016-2018 ( .037). In patients with NDM infection, the crude 7-day mortality rate was 0% and the 30-day mortality rate was 14% (2 of 14 patients). NDMs were noted in 41 bacterial strains (ie, species and sequence type combinations). Across 13 plasmid groups, 4 NDM variants were detected: , , , and . We noted a change from a diverse NDM plasmid repertoire in 2016-2018 to the emergence of conserved IncN and IncX3 epidemic plasmids, with interstrain spread in 2019-2021. These plasmids were noted in 19 (50%) of 38 patients and 35 (51%) of 68 genomes in 2019-2021. Increased NDM case numbers were due to local circulation of 2 epidemic plasmids with extensive interstrain transfer. Our findings underscore the challenges of outbreak detection when horizontal transmission of plasmids is the primary mode of spread.

Objectives:New Delhi metallo-β-lactamases (NDMs) are major contributors to the spread of carbapenem resistance globally. In Australia, NDMs were previously associated with international travel, but from 2019 we noted increasing incidence of NDM-positive clinical isolates. We investigated the clinical and genomic epidemiology of NDM carriage at a tertiary-care Australian hospital from 2016 to 2021.Methods:We identified 49 patients with 84 NDM-carrying isolates in an institutional database, and we collected clinical data from electronic medical record. Short- and long-read whole genome sequencing was performed on all isolates. Completed genome assemblies were used to assess the genetic setting of blaNDM genes and to compare NDM plasmids.Results:Of 49 patients, 38 (78%) were identified in 2019–2021 and only 11 (29%) of 38 reported prior travel, compared with 9 (82%) of 11 in 2016–2018 (P = .037). In patients with NDM infection, the crude 7-day mortality rate was 0% and the 30-day mortality rate was 14% (2 of 14 patients). NDMs were noted in 41 bacterial strains (ie, species and sequence type combinations). Across 13 plasmid groups, 4 NDM variants were detected: blaNDM-1, blaNDM-4, blaNDM-5, and blaNDM-7. We noted a change from a diverse NDM plasmid repertoire in 2016–2018 to the emergence of conserved blaNDM-1 IncN and blaNDM-7 IncX3 epidemic plasmids, with interstrain spread in 2019–2021. These plasmids were noted in 19 (50%) of 38 patients and 35 (51%) of 68 genomes in 2019–2021.Conclusions:Increased NDM case numbers were due to local circulation of 2 epidemic plasmids with extensive interstrain transfer. Our findings underscore the challenges of outbreak detection when horizontal transmission of plasmids is the primary mode of spread.