Bone infection, also called osteomyelitis, can result when bacteria invade a bone. Treatment of osteomyelitis usually requires surgical debridement and prolonged antimicrobial therapy. The rising incidence of infection with multidrug-resistant bacteria, in particular methicillin-resistant staphylococcus aureus (MRSA), however, limits the antimicrobial treatment options available. Silver is well known for its antimicrobial properties and is highly toxic to a wide range of microorganisms. We previously reported our development of biocompatible, biodegradable, nanofibrous scaffolds that released silver ions in a controlled manner. The objective of this study was to determine the efficacy of these scaffolds in treating or preventing osteomyelitis. To achieve this objective, antimicrobial efficacy was determined using a 3D coculture system of human adipose-derived stem cells (hASC) and MRSA. Human ASC were seeded on the scaffolds and induced to undergo osteogenic differentiation in both the absence and presence of MRSA. Our results indicated that the silver ion-releasing scaffolds not only inhibited biofilm formation, but also supported osteogenesis of hASC. Our findings suggest that these biocompatible, degradable, silver ion-releasing scaffolds can be used at an infection site to treat osteomyelitis and/or to coat bone implants as a preventative measure against infection postsurgery.

Background: In the last decades, cardiovascular diseases (CVD) have remained the first leading cause of mortality and morbidity in the world. Although several therapeutic approaches have been introduced in the past, the development of novel treatments remains an important research goal, which is hampered by the lack of understanding of key mechanisms and targets. Emerging evidences in recent years indicate the involvement of misfolded proteins aggregation and the derailment of protein quality control in the pathogenesis of cardiovascular diseases. Several potential interventions targeting protein quality control have been translated from the bench to the bedside to effectively employ the misfolded proteins as promising therapeutic targets for cardiac diseases, but with trivial results. Design: In this review, we describe the recent progresses in preclinical and clinical studies of protein misfolding and compromised protein quality control by selecting and reporting studies focusing on cardiovascular diseases including cardiomyopathies, cardiac amyloidosis, atherosclerosis, atrial fibrillation and thrombosis. Results: In preclinical models, modulators of several molecular targets (eg heat shock proteins, unfolded protein response, ubiquitin protein system, autophagy and histone deacetylases) have been tested in various conditions with promising results although lacking an adequate transition towards clinical setting. Conclusions: At present, no therapeutic strategies have been reported to attenuate proteotoxicity in patients with CVD due to a lack of specific biomarkers for pinpointing upstream events in protein folding defects at a subclinical stage of the diseases requiring an intensive collaboration between basic scientists and clinicians. K E Y W O R D Samyloid, cardiovascular diseases, oligomer, protein misfolding, therapy, unfolded protein responses 2 of 17 | DITEEPENG ET al.

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ObjectiveTrimethylamine-N-oxide (TMAO) is a metabolite derived from the microbial processing of dietary phosphatidylcholine and carnitine and the subsequent hepatic oxidation. Due to its prothrombotic and inflammatory mechanisms, we aimed to assess its role in the prediction of adverse events in a susceptible population, namely patients with atrial fibrillation.MethodsBaseline TMAO plasma levels were measured by liquid chromatography-tandem mass spectrometry in 2379 subjects from the ongoing Swiss Atrial Fibrillation cohort. 1722 underwent brain MRI at baseline. Participants were prospectively followed for 4 years (Q1–Q3: 3.0–5.0) and stratified into baseline TMAO tertiles. Cox proportional hazards and linear and logistic mixed effect models were employed adjusting for risk factors.ResultsSubjects in the highest TMAO tertile were older (75.4±8.1 vs 70.6±8.5 years, p<0.01), had poorer renal function (median glomerular filtration rate: 49.0 mL/min/1.73 m2(35.6–62.5) vs 67.3 mL/min/1.73 m2(57.8–78.9), p<0.01), were more likely to have diabetes (26.9% vs 9.1%, p<0.01) and had a higher prevalence of heart failure (37.9% vs 15.8%, p<0.01) compared with patients in the lowest tertile. Oral anticoagulants were taken by 89.1%, 94.0% and 88.2% of participants, respectively (from high to low tertiles). Cox models, adjusting for baseline covariates, showed increased total mortality (HR 1.65, 95% CI 1.17 to 2.32, p<0.01) as well as cardiovascular mortality (HR 1.86, 95% CI 1.21 to 2.88, p<0.01) in the highest compared with the lowest tertile. When present, subjects in the highest tertile had more voluminous, large, non-cortical and cortical infarcts on MRI (log-transformed volumes; exponentiated estimate 1.89, 95% CI 1.11 to 3.21, p=0.02) and a higher chance of small non-cortical infarcts (OR 1.61, 95% CI 1.16 to 2.22, p<0.01).ConclusionsHigh levels of TMAO are associated with increased risk of cardiovascular mortality and cerebral infarction in patients with atrial fibrillation.Trial registration numberNCT02105844.

Introduction Trimethylamine-N-oxide (TMAO) is a well characterized pro-atherogenic metabolite derived from the microbial processing of phosphatidylcholine and carnitine (usually present in red meat) and subsequent hepatic oxydation, which promotes endothelial dysfunction, platelet activation and thrombosis initiation. Its role concerning cerebral and cardiovascular adverse events has been assessed in various patient subpopulations but not for long term in patients with atrial fibrillation. Methods Baseline TMAO plasma levels were measured by high-performance liquid chromatography/mass spectrometry in plasmas of 2,379 subjects from our multicentric study. Among them, 1,722 participants at time of recruitment underwent brain MRI. Participants were stratified into TMAO tertiles and Cox PH models, linear mixed effect models or logistic mixed effect models were employed adjusting for several risk factors (age, sex, BMI, active and past smoke habit, cystatin c levels, heart failure, diabetes mellitus, hypertension, coronary artery disease and history of TIA/stroke). Subjects were prospectively followed with a median observation time of 4 years. Results Subjects in the highest tertile of TMAO were older (75.4 vs. 70.6 years in low tertile p&lt;0.001) and had significantly more often comorbidities, (26.9% of subjects were diabetic vs. 9.1% in low tertile p&lt;0.001), with higher BMI (28.1 vs 27.0, p&lt;0.001) and worse renal function as assessed by serum cystatin C (1.46 vs 1.07, mg/dl; p&lt;0.001). Heart failure was present in 37.9% participants in the upper compared to 15.8% in the lower tertile. (p&lt;0.001). As shown in Figure 1, Kaplan Meier estimates showed increased cardiovascular mortality with increasing TMAO tertiles (p&lt;0.0001). After adjustment for the abovementioned factors the upper tertile (T3) had an increased hazard ratio (HR) compared to the lowest one (HR 2.36 95% CI 1.56–3.58 p&lt;0.01). Similar trends for global and ischemic stroke occurrences were not found although TMAO levels positively weakly correlated with NIHSS severity (Spearman's coefficient 0.31 p=0.02). Concerning brain MRI findings, TMAO tertiles identified individuals with different prevalence of small non-cortical infarcts (30.5%, 18.1% and 17.4% in high, middle and low tertiles respectively; p&lt;0.001) and when present, larger white matter lesions volumes (5061 mm3, 4158 mm3 and 2970 mm3; p&lt;0.001). After adjustment, the association with small non-cortical infarcts with TMAO levels remained significant in the highest tertile (T3) (OR 1.48 95% CI 1.07–2.05; p=0.02) and a trend towards larger white matter lesions volumes was observed (estimate 1307 95% CI −90–2705; p=0.07). Conclusions TMAO represents a robust prognostic independent biomarker identifying multimorbid, high risk patients for cardiovascular mortality and brain damage. FUNDunding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Swiss National Science Foundation (SNSF) and Theodor und Ida Herzog-Egli Foundation Figure 1. CV mortality according to TMAO Figure 2. Brain lesions assessment

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Background Amyloid plaques and neurofibrillary tangles, the molecular lesions that characterize Alzheimer’s disease (AD) and other forms of dementia, are emerging as determinants of proteinopathies ‘beyond the brain’. This study aims to establish tau’s putative pathophysiological mechanistic roles and potential future therapeutic targeting of tau in heart failure (HF). Methods and results A mouse model of tauopathy and human myocardial and brain tissue from patients with HF, AD, and controls was employed in this study. Tau protein expression was examined together with its distribution, and in vitro tau-related pathophysiological mechanisms were identified using a variety of biochemical, imaging, and functional approaches. A novel tau-targeting immunotherapy was tested to explore tau-targeted therapeutic potential in HF. Tau is expressed in normal and diseased human hearts, in contradistinction to the current oft-cited observation that tau is expressed specifically in the brain. Notably, the main cardiac isoform is high-molecular-weight (HMW) tau (also known as big tau), and hyperphosphorylated tau segregates in aggregates in HF and AD hearts. As previously described for amyloid-beta, the tauopathy phenotype in human myocardium is of diastolic dysfunction. Perturbation in the tubulin code, specifically a loss of tyrosinated microtubules, emerged as a potential mechanism of myocardial tauopathy. Monoclonal anti-tau antibody therapy improved myocardial function and clearance of toxic aggregates in mice, supporting tau as a potential target for novel HF immunotherapy. Conclusion The study presents new mechanistic evidence and potential treatment for the brain–heart tauopathy axis in myocardial and brain degenerative diseases and ageing.

Introduction Since patients with atrial fibrillation (AF) are predisposed to suffer from major adverse cerebrovascular events (MACE), they are more likely to suffer MACE linked sequelae, such as cognitive impairment. We hypothesised that the gut microbiome derivate trimethylamine N-oxide (TMAO) may amplify this pathomechanism given its hypercoagulative, proinflammatory and proatherogenic effects. Methods Patients of the Swiss-AF cohort with determined TMAO plasma levels, cognitive scores (n=2'379) and cerebral magnetic resonance imaging (cMRI) (n=1'722) collected at baseline were included. TMAO levels were measured by liquid chromatography-mass spectrometry (HPLC). Overall cognitive performance was evaluated using the Cognitive Construct (CoCo) score reflecting different cognitive functions measured by four validated neuropsychological assessments, namely the Montreal Cognitive Assessment (MoCA), Trail Making Test (TMT parts A and B), Semantic Fluency Test (SFT) and Digital Symbol Substitution Test (DSST). The scores were compared with the quartiles of patients' TMAO plasma levels (Q1: 0.6–4, Q2: 4–5.8, Q3: 5.8–9.1, Q4: 9.1–164μmol/l) in linear effect models. All models were adjusted for multiple covariates correlating with this association: For TMAO (overall meat consumption &gt;3 times per week, physical activity, glomerular filtration rate, presence of diabetes mellitus), cognitive function (EQ-5D-5L score, geriatric depression scale, education level) and cerebral affects (white matter lesions volume and total brain volume in cMRI). The relevance of high TMAO plasma levels in different stroke groups in cMRI (i.e., clinically overt, silent, or no stroke) were analysed in a subgroup analysis. The subgroups were additionally adjusted for total brain volume to eliminate the effect of simultaneous decrease of cerebral white matter. Results After multivariable adjustment, AF patients in the highest quartile of TMAO levels performed significantly poorer in the global cognitive score (CoCo: estimate −0.11, 95% CI [−0.17, −0.05], p=0.002) compared to patients in the lowest quartile. This was observed also in the MoCA, SFT, DSST, TMT-A and TMT-B. In the subgroup analysis, an association between the highest TMAO quartile (compared with the lowest quartile) and lower CoCo score was found in the group of patients with overt strokes (−0.18, 95% CI [−0.33, −0.04], p=0.012). Weak evidence of the same association was found in the group of patients with silent strokes (−0.13, 95% CI [−0.25, 0.002], p=0.053) and patients with no strokes (−0.08, 95% CI [−0.16, 0.01], p=0.07). After adjustment for decreased brain volume, the association remained for silent strokes (−0.14, 95% CI [−0.28, −0.01], p=0.036) indicating the impact of TMAO in this subgroup. Conclusion TMAO plasma levels were associated with cognitive impairment in patients with AF. Longitudinal data will clarify dynamics and likely causality between TMAO and cognitive impairment. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Swiss National Science Foundation