S100a8/9 (S100 Calcium Binding Protein a8/9) Promotes Cardiac Hypertrophy Via Upregulation of FGF23 (Fibroblast Growth Factor 23) in Mice.

BACKGROUND: S100a8/9 (S100 calcium binding protein a8/9) belongs to the S100 family and has gained a lot of interest as a critical regulator of inflammatory response. Our previous study found that S100a8/9 homolog promoted aortic valve sclerosis in mice with chronic kidney disease. However, the role of S100a8/9 in pressure overload-induced cardiac hypertrophy remains unclear. The present study was to explore the role of S100a8/9 in cardiac hypertrophy. METHODS AND RESULTS: Cardiomyocyte-specific S100a9 loss or gain of function was achieved using an adeno-associated virus system, and the model of cardiac hypertrophy was established by aortic banding-induced pressure overload. The results indicate that S100a8/9 expression was increased in response to pressure overload. S100a9 deficiency alleviated pressure overload-induced hypertrophic response, whereas S100a9 overexpression accelerated cardiac hypertrophy. S100a9-overexpressed mice showed increased FGF23 (fibroblast growth factor 23) expression in the hearts after exposure to pressure overload, which activated calcineurin/NFAT (nuclear factor of activated T cells) signaling in cardiac myocytes and thus promoted hypertrophic response. A specific antibody that blocks FGFR4 (FGF receptor 4) largely abolished the prohypertrophic response of S100a9 in mice. CONCLUSIONS: In conclusion, S100a8/9 promoted the development of cardiac hypertrophy in mice. Targeting S100a8/9 may be a promising therapeutic approach to treat cardiac hypertrophy.

Conversation, discourse and linguistic analysis in dental communication: valuable but under-used approaches.

According to Dental Protection, 'good dentists are good communicators, it's that simple!' Unfortunately, dental communication is an under-researched field, so it is not yet clear exactly what good communication in this context entails. The dominant method of researching dental communication to date has followed a 'process approach' where the focus has been on evaluating the communicative competence of the clinician using a checklist of communicative functions; for example, 'the clinician explains the condition'. Conversation analysis, discourse analysis and linguistic analysis are discursive approaches that bring precision by analysing the actual language/discourses being used by patients and providers in interactions. These discursive approaches can be used to capture exactly how, for example, patient engagement is maintained in routine dental consultations, patient reassurance is achieved during invasive procedures and which communication strategies are the most likely to result in enhanced treatment outcomes in paediatric dentistry. In addition to shedding new light on the unique nature of dental communication, discursive approaches provide targeted new tools for developing needs-based training packages for dental professionals.

An assessment of the current medical management of thoracic aortic disease: A patient-centered scoping literature review.

Thoracic aortic aneurysm and dissection are complex diagnoses that require management by multidisciplinary providers using a variety of medical therapies, surgical interventions, and lifestyle modifications. Pharmacological agents, such as ß-blockers (atenolol) and angiotensin II type 1 receptor blockers (losartan), have been mainstay treatments for several years, and research from the past decade has continued to evaluate these and other medication classes to further improve patient morbidity and mortality. Combination ß- and renin-aldosterone-angiotensin blockade, statins, metformin, antioxidants, and vitamins have been evaluated as therapeutics in both thoracic and abdominal aortic aneurysms, as well as the effects of various antibiotics (ie, fluoroquinolones and tetracyclines) and benefits of lifestyle modifications (eg, diet and exercise) and enhanced patient-centered care and treatment adherence. In addition, as our understanding of the genetic, biochemical, and pathophysiological mechanisms behind these diseases expands, so do potential targets for future therapeutic research (eg, interleukins, matrix metalloproteases, and mast cells). This review incorporates the major meta-analyses, systematic and generalized reviews, and clinical trials published from 2010 through 2021 that focus on these topics in thoracic aortic aneurysms (and abdominal aneurysms when thoracic literature is scarce). Several key ongoing clinical trials, case studies, and in vivo/in vitro studies are also mentioned. Furthermore, we discuss current gaps in the literature and the abundance of clinical evidence for some interventions in abdominal aneurysms with few thoracic correlates, thus indicating a need for investigation of these subjects in the latter.

Impact of the influenza vaccine on COVID-19 infection rates and severity.

BACKGROUND: With a unique influenza season occurring in the midst of a pandemic, there is interest in assessing the role of the influenza vaccine in COVID-19 susceptibility and severity. METHODS: In this retrospective cohort study, patients receiving a laboratory test for COVID-19 were identified. The primary outcome was comparison of positive COVID-19 testing in those who received the influenza vaccine versus those who did not. Secondary end points in patients testing positive for COVID-19 included mortality, need for hospitalization, length of stay, need for intensive care, and mechanical ventilation. RESULTS: A total of 27,201 patients received laboratory testing for COVID-19. The odds of testing positive for COVID-19 was reduced in patients who received an influenza vaccine compared to those who did not (odds ratio 0.76, 95% CI 0.68-0.86; P < .001). Vaccinated patients testing positive for COVID-19 were less likely to require hospitalization (odds ratio, 0.58, 95% CI 0.46-0.73; P < .001), or mechanical ventilation (odds ratio, 0.45, 95% CI 0.27-0.78; P = .004) and had a shorter hospital length of stay (risk ratio, 0.76, 95% CI 0.65-0.89; P < .001). CONCLUSION: Influenza vaccination is associated with decreased positive COVID-19 testing and improved clinical outcomes and should be promoted to reduce the burden of COVID-19.

A framework for scaffolding academic reflective writing in dentistry.

INTRODUCTION: Being able to demonstrate reflection on clinical practice is a key competency required of undergraduate dental students and registrants alike. Academic reflective writing (ARW) is an increasingly widely used genre of writing which evidences reflective practice. ARW is complex, as students need to achieve balance from a challenging mix of personal, academic and evaluative writing. The aim of this study is to analyse four student ARW tasks from a UK Dental School in order to make recommendations regarding the systematic development of student ARW through the dental curriculum. METHODS: In this study, a detailed linguistic analysis of high-scoring examples of two first year and two fourth year ARW tasks was undertaken, complemented by comments from interviews with markers of the tasks. RESULTS: The linguistic analysis of high-scoring student ARW revealed five consistent reflective aspects common to all tasks, viz description, feelings, analysis, evaluation and conclusion and action planning. Entry-level and final-year ARW showed a different balance between reflective aspects. Markers' expectations in the lower years were found to equate to high-quality technical reflection, whereas markers in the higher years expected students to have shifted their perspectives to achieve critical reflection. CONCLUSION: Whilst this study is limited in its generalisability due to its small-scale exploratory nature, it is hoped that the five reflective aspects, and the categories of reflection put forward here will be useful in stimulating discussion about how to scaffold the development of student ARW (and associated reflective thinking) longitudinally through the dental curriculum.

Clinician and Patient Factors Influencing Treatment Decisions: Ethnographic Study of Antibiotic Prescribing and Operative Procedures in Out-of-Hours and General Dental Practices.

Operative treatment is indicated for most toothache/dental abscesses, yet antibiotics instead of procedures are often prescribed. This ethnographic study aimed to identify clinician and patient factors influencing urgent dental care for adults during actual appointments; and to identify elements sensitive to context. Appointments were observed in out-of-hours and general dental practices. Follow-up interviews took place with dentists, dental nurses, and patients. Dentist and patient factors were identified through thematic analysis of observation records and appointment/interview transcripts. Dentist factors were based on a published list of factors influencing antibiotic prescribing for adults with acute conditions across primary health care and presented within the Capability-Opportunity-Motivation-Behaviour model. Contextually sensitive elements were revealed by comparing the factors between settings. In total, thirty-one dentist factors and nineteen patient factors were identified. Beliefs about antibiotics, goals for the appointment and access to dental services were important for both dentists and patients. Dentist factors included beliefs about the lifetime impact of urgent dental procedures on patients. Patient factors included their communication and negotiation skills. Contextual elements included dentists' concerns about inflicting pain on regular patients in general dental practice; and patients' difficulties accessing care to complete temporary treatment provided out of hours. This improved understanding of factors influencing shared decisions about treatments presents significant opportunity for new, evidence-based, contextually sensitive antibiotic stewardship interventions.

Higher admission rates and in-hospital mortality for acute type A aortic dissection during Influenza season: a single center experience.

Triggering events for acute aortic dissections are incompletely understood. We sought to investigate whether there is an association between admission for acute type A aortic dissection (ATAAD) to the University of Michigan Medical Center and the reported annual influenza activity by the Michigan Department of Health and Human Services. From 1996-2019 we had 758 patients admitted for ATAAD with 3.1 admissions per month during November-March and 2.5 admissions per month during April-October (p = 0.01). Influenza reporting data by the Michigan Department of Health and Human Services became available in 2009. ATAAD admissions for the period 2009-2019 (n = 455) were 4.8 cases/month during peak influenza months compared to 3.5 cases/month during non-peak influenza months (p = 0.001). ATAAD patients admitted during influenza season had increased in-hospital mortality (11.0% vs. 5.8%, p = 0.024) and increased 30-day mortality (9.7 vs. 5.4%, p = 0.048). The results point to higher admission rates for ATAAD during months with above average influenza rates. Future studies need to investigate whether influenza virus infection affects susceptibility for aortic dissection, and whether this risk can be attenuated with the annual influenza vaccine in this patient population.

Update on Clinical Trials of Losartan With and Without ß-Blockers to Block Aneurysm Growth in Patients With Marfan Syndrome: A Review.

Importance: Thoracic aortic aneurysms leading to acute aortic dissections are a major cause of morbidity and mortality despite significant advances in surgical treatment, which remains the main intervention to prevent type A dissections. In the past 2 decades progress has been made toward a better understanding of molecular mechanisms that lead to aneurysm formation and dissections of the thoracic aorta. This focused review emphasizes the results of clinical trials using ß-blocker, losartan potassium, and irbesartan in patients with Marfan syndrome and comments briefly on mechanisms of aortic remodeling, including fibrosis and transforming growth factor ß signaling. Observation: The major risk factors for the disease are increased hemodynamic forces, typically owing to poorly controlled hypertension, and heritable genetic variants. The altered genes predisposing to thoracic aortic disease have been shown or are predicted to decrease vascular smooth muscle cell contraction, decrease transforming growth factor ß signaling, or alter the extracellular matrix. Preclinical models of Marfan syndrome showed promising results for losartan as a potential therapy to attenuate aortic dilation in mice. However, several clinical trials did not conclusively confirm that losartan attenuated aortic aneurysm expansion better than ß-blockers. Most importantly, clinical trials assessing whether losartan therapy not only reduces aortic growth but also improves adverse aortic outcomes, including dissection, need for surgery, and death, have not been conducted. The largest trial to date to our knowledge, the Pediatric Heart Network trial, sponsored by the National Heart, Lung, and Blood Institute, showed a nonsignificant increase in adverse aortic outcomes, with almost a doubling of adverse events in patients randomized to losartan treatment compared with ß-blockers, suggesting that this study was underpowered to assess adverse aortic outcomes. On the other hand, the evidence for ß-blocker therapy to reduce morbidity and mortality in Marfan syndrome is limited to a single small, prospective randomized and nonblinded clinical trial. Conclusions and Relevance: Taken together, these data emphasize the need for clinical trials adequately powered to assess both aortic aneurysm growth and adverse aortic outcomes to identify effective medical therapies for Marfan syndrome and other aortopathies.

S100/RAGE-Mediated Inflammation and Modified Cholesterol Lipoproteins as Mediators of Osteoblastic Differentiation of Vascular Smooth Muscle Cells.

Arterial calcification is a feature of atherosclerosis and shares many risk factors including diabetes, dyslipidemia, chronic kidney disease, hypertension, and age. Although there is overlap in risk factors, anti-atherosclerotic therapies, including statins, fail to reduce arterial, and aortic valve calcifications. This suggests that low density lipoprotein (LDL) may not be the main driver for aortic valve disease and arterial calcification. This review focuses on modified LDLs and their role in mediating foam cell formation in smooth muscle cells (SMCs), with special emphasis on enzyme modified non-oxidized LDL (ELDL). In vivo, ELDL represents one of the many forms of modified LDLs present in the atherosclerotic vessel. Phenotypic changes of macrophages and SMCs brought about by the uptake of modified LDLs overlap significantly in an atherosclerotic milieu, making it practically impossible to differentiate between the effects from oxidized LDL, ELDL, and other LDL modification. By studying in vitro-generated modifications of LDL, we were able to demonstrate marked differences in the transcriptome of human coronary artery SMCs (HCASMCs) upon uptake of ELDL, OxLDL, and native LDL, indicating that specific modifications of LDL in atherosclerotic plaques may determine the biology and functional consequences in vasculature. Enzyme-modified non-oxidized LDL (ELDL) induces calcification of SMCs and this is associated with reduced mRNA levels for genes protective for calcification (ENPP1, MGP) and upregulation of osteoblastic genes. A second focus of this review is on the synergy between hyperlipidemia and accelerated calcification In vivo in a mouse models with transgenic expression of human S100A12. We summarize mechanisms of S100A12/RAGE mediated vascular inflammation promoting vascular and valve calcification in vivo.

Enzyme-modified non-oxidized LDL (ELDL) induces human coronary artery smooth muscle cell transformation to a migratory and osteoblast-like phenotype.

Enzyme modified non-oxidative LDL (ELDL) is effectively taken up by vascular smooth muscle cells (SMC) and mediates transition into foam cells and produces phenotypic changes in SMC function. Our data show that incubation of human coronary artery SMC (HCASMC) with low concentration of ELDL (10 µg/ml) results in significantly enhanced foam cell formation compared to oxidized LDL (200 µg/ml; p < 0.01) or native LDL (200 µg/ml; p < 0.01). Bioinformatic network analysis identified activation of p38 MAPK, NFkB, ERK as top canonical pathways relevant for biological processes linked to cell migration and osteoblastic differentiation in ELDL-treated cells. Functional studies confirmed increased migration of HCASMC upon stimulation with ELDL (10 µg/ml) or Angiopoietin like protein 4, (ANGPTL4, 5 µg/ml), and gain in osteoblastic gene profile with significant increase in mRNA levels for DMP-1, ALPL, RUNX2, OPN/SPP1, osterix/SP7, BMP and reduction in mRNA for MGP and ENPP1. Enhanced calcification of HCASMC by ELDL was demonstrated by Alizarin Red staining. In summary, ELDL is highly potent in inducing foam cells in HCASMC and mediates a phenotypic switch with enhanced migration and osteoblastic gene profile. These results point to the potential of ELDL to induce migratory and osteoblastic effects in human smooth muscle cells with potential implications for migration and calcification of SMCs in human atherosclerosis.

Aortic Valve Replacement for Moderate Aortic Stenosis with Severe Calcification and Left Ventricualr Dysfunction-A Case Report and Review of the Literature.

A 55-year-old man with a history of erosive, seropositive rheumatoid arthritis (RA), and interstitial lung disease presented with shortness of breath. Echocardiography showed new-onset severe left ventricular (LV) dysfunction with an ejection fraction (EF) of 15% and moderately increased mean aortic valve gradient of 20 mmHg in a trileaflet aortic valve with severe sclero-calcific degeneration. Coronary angiography revealed no significant obstructive coronary disease. Invasive hemodynamic studies and dobutamine stress echocardiography were consistent with moderate aortic stenosis. Guideline directed medical therapy for heart failure with reduced EF was initiated; however, diuretics and neurohormonal blockade (beta-blocker and angiotensin receptor blocker) provided minimal improvement, and the patient remained functionally limited. Of interest, echocardiography performed 1 year prior to his presentation showed normal LV EF and mild aortic leaflet calcification with moderate stenosis, suggesting a rapid progressing of calcific aortic valve disease. Subsequently, the patient underwent surgical aortic valve replacement and demonstrated excellent postsurgical recovery of LV EF (55%). Calcific aortic valve disease is commonly associated with aging, bicuspid aortic valve, and chronic kidney disease. Pathophysiological mechanism for valvular calcification is incompletely understood but include osteogenic transformation of valvular interstitial cells mediated by local and systemic inflammatory processes. Several rheumatologic diseases including RA are associated with premature atherosclerosis and arterial calcification, and we speculated a similar role of RA accelerating calcific aortic valve disease. We present a case of accelerated aortic valve calcification with (only) moderate stenosis, complicated by a rapid decline in LV systolic performance. Guidelines for AVR in moderate stenosis without concomitant cardiac surgery are not well established, although it should be considered in selected patients.

Enzymatically Modified Low-Density Lipoprotein Promotes Foam Cell Formation in Smooth Muscle Cells via Macropinocytosis and Enhances Receptor-Mediated Uptake of Oxidized Low-Density Lipoprotein.

OBJECTIVE: Enzyme-modified nonoxidized low-density lipoprotein (ELDL) is present in human atherosclerotic lesions. Our objective is to understand the mechanisms of ELDL uptake and its effects on vascular smooth muscle cells (SMC). APPROACH AND RESULTS: Transformation of murine aortic SMCs into foam cells in response to ELDL was analyzed. ELDL, but not acetylated or oxidized LDL, was potent in inducing SMC foam cell formation. Inhibitors of macropinocytosis (LY294002, wortmannin, amiloride) attenuated ELDL uptake. In contrast, inhibitors of receptor-mediated endocytosis (dynasore, sucrose) and inhibitor of caveolae-/lipid raft-mediated endocytosis (filipin) had no effect on ELDL uptake in SMC, suggesting that macropinocytosis is the main mechanism of ELDL uptake by SMC. Receptor for advanced glycation end products (RAGE) is not obligatory for ELDL-induced SMC foam cell formation, but primes SMC for the uptake of oxidized LDL in a RAGE-dependent manner. ELDL increased intracellular reactive oxygen species, cytosolic calcium, and expression of lectin-like oxidized LDL receptor-1 in wild-type SMC but not in RAGE(-/-) SMC. The macropinocytotic uptake of ELDL is regulated predominantly by intracellular calcium because ELDL uptake was completely inhibited by pretreatment with the calcium channel inhibitor lacidipine in wild-type and RAGE(-/-) SMC. This is in contrast to pretreatment with PI3 kinase inhibitors which completely prevented ELDL uptake in RAGE(-/-) SMC, but only partially in wild-type SMC. CONCLUSIONS: ELDL is highly potent in inducing foam cells in murine SMC. ELDL endocytosis is mediated by calcium-dependent macropinocytosis. Priming SMC with ELDL enhances the uptake of oxidized LDL.