Statins plus ezetimibe in the era of proprotein convertase subtilisin/kexin type-9 inhibitors

Statins are first-line agents in patients with dyslipidemia, with established benefits for reducing low-density-lipoprotein cholesterol (LDL-C) levels and cardiovascular events. However, a considerable number of statin-treated patients do not achieve target LDL-C levels, even at maximally tolerated statin doses, or are intolerant to intensive statin therapy. These patients can benefit from the addition of a non-statin lipid-lowering agent, and recent cholesterol guidelines have placed increased focus on combination lipid-lowering therapy. For patients that cannot achieve target treatment goals with statin therapy alone, the addition of the cholesterol absorption inhibitor ezetimibe leads to additional LDL-C reductions with good tolerability, and reductions in cardiovascular morbidity and mortality. The more recent Proprotein Convertase Subtilisin-Like/Kexin Type 9 (PCSK-9) inhibitors can lower LDL-C by an additional 45-65% and are also well tolerated with associated cardiovascular outcome data. These complementary approaches for LDL-C lowering in statin-treated patients lower LDL-C levels beyond that achieved with statin monotherapy. As no threshold level has been established below which LDL-C lowering benefits cease to occur, an early combination treatment strategy may lead to improved cardiovascular outcomes, particularly in high-risk patients. This review will examine the rationale, advantages and potential barriers to combination lipid-lowering therapy with reference to current guideline recommendations

Erythrocyte morphology automated analysis: proposal for a new prediction tool of essential hypertension diagnosis

Erythrocyte morphology has already been studied in essential hypertension (EH) and cell membrane alterations have been observed. Relationships among red cell rheological, biochemical, and morphological properties still appear complex and are not clearly understood

Assessment of body fluid balance and voluntary drinking in ultimate players during a match.

AIM: Ultimate is a sport played by hundreds of thousands of people in more than 42 countries; however, it is still mainly known as a recreational more than a team sport, and further studies are needed to define its physical load. Particularly, since no studies relating Ultimate to hydration have been performed, we aimed to determine body fluid balance, voluntary water intake and the most reliable method for assessing the hydration status of players after a typical 80-minute Ultimate match. METHODS: bioimpedance, urine specific gravity and body mass changes to asses the hydration level of the players were measured. RESULTS: It was observed that not all of the methods are adequate to determine dehydration in Ultimate players, and that measurement of body mass changes represents a reliable and accurate technique. CONCLUSIONS: These findings demonstrate that ultimate as an intense sport that can induce significant fluid loss, which is not always replaced by individual drinking

Left atrial trajectory impairment in hypertrophic cardiomyopathy disclosed by geometric morphometrics and parallel transport

The analysis of full Left Atrium (LA) deformation and whole LA deformational trajectory in time has been poorly investigated and, to the best of our knowledge, seldom discussed in patients with Hypertrophic Cardiomyopathy. Therefore, we considered 22 patients with Hypertrophic Cardiomyopathy (HCM) and 46 healthy subjects, investigated them by three-dimensional Speckle Tracking Echocardiography, and studied the derived landmark clouds via Geometric Morphometrics with Parallel Transport. Trajectory shape and trajectory size were different in Controls versus HCM and their classification powers had high AUC (Area Under the Receiving Operator Characteristic Curve) and accuracy. The two trajectories were much different at the transition between LA conduit and booster pump functions. Full shape and deformation analyses with trajectory analysis enabled a straightforward perception of pathophysiological consequences of HCM condition on LA functioning. It might be worthwhile to apply these techniques to look for novel pathophysiological approaches that may better define atrio-ventricular interaction

Management of toxicities associated with targeted therapies for HR-positive metastatic breast cancer: a multidisciplinary approach is the key to success

Purpose: Agents targeting HR-positive, HER2-negative locally advanced or metastatic breast cancer have improved patient outcomes compared with conventional single-agent endocrine therapy. Currently, approved targeted agents include everolimus and three CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib. Unlike the well-characterized and easily manageable safety profile of endocrine therapies, adverse events associated with targeted therapies are complex and potentially severe. Their prompt recognition and treatment, crucial for prolonged endocrine sensitivity and survival, may be challenging and requires a multidisciplinary effort and a good knowledge of drug interactions. Methods: We reviewed the current evidence on the drug safety of targeted agents for metastatic breast cancer currently used in clinical practice in Italy, supported by the clinical experience of Italian oncologists with expertise in the field. Results: All oncologists had used CDK4/6 inhibitors in clinical practice and/or within a clinical trial. The clinical management of toxicities, including dose adjustments, treatment interruptions, and concerns regarding special populations is discussed, and the management of relevant adverse events, related to individual agents and class-specific, toxicities is reviewed. Hematologic toxicities have the greatest impact on clinical management of the disease and on patients. Although toxicities associated with the new treatments result in more visits to the physician and more time and attention with patients, they are manageable, with no need for the oncologist to consult with specialist physicians. Conclusions: Based on the available evidence and current guidelines, we propose a series of practical recommendations for multidisciplinary clinical management of the various toxicities associated with the addition of targeted agents to endocrine therapy

Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4

The chemokine receptor, CXC chemokine receptor 4 (CXCR4), is selective for CXC chemokine ligand 12 (CXCL12), is broadly expressed in blood and tissue cells, and is essential during embryogenesis and hematopoiesis. CXCL14 is a homeostatic chemokine with unknown receptor selectivity and preferential expression in peripheral tissues. Here, we demonstrate that CXCL14 synergized with CXCL12 in the induction of chemokine responses in primary human lymphoid cells and cell lines that express CXCR4. Combining subactive concentrations of CXCL12 with 100–300 nM CXCL14 resulted in chemotaxis responses that exceeded maximal responses that were obtained with CXCL12 alone. CXCL14 did not activate CXCR4-expressing cells (i.e., failed to trigger chemotaxis and Ca2+ mobilization, as well as signaling via ERK1/2 and the small GTPase Rac1); however, CXCL14 bound to CXCR4 with high affinity, induced redistribution of cell-surface CXCR4, and enhanced HIV-1 infection by >3-fold. We postulate that CXCL14 is a positive allosteric modulator of CXCR4 that enhances the potency of CXCR4 ligands. Our findings provide new insights that will inform the development of novel therapeutics that target CXCR4 in a range of diseases, including cancer, autoimmunity, and HIV.—Collins, P. J., McCully, M. L., Mart´ınez-Muñoz, L., Santiago, C.,Wheeldon, J., Caucheteux, S., Thelen, S., Cecchinato, V., Laufer, J.M., Purvanov, V.,Monneau, Y. R., Lortat-Jacob, H., Legler, D. F., Uguccioni, M., Thelen, M., Piguet, V., Mellado, M., Moser, B. Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4. FASEB J. 31, 000–000 (2017). www.fasebj.or

Anti-chemokine antibodies after SARS-CoV-2 infection correlate with favorable disease course.

Infection by SARS-CoV-2 leads to diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse COVID-19 outcomes. Instead, we discovered that antibodies against specific chemokines are omnipresent after COVID-19, associated with favorable disease, and predictive of lack of long COVID symptoms at one year post infection. Anti-chemokine antibodies are present also in HIV-1 and autoimmune disorders, but they target different chemokines than those in COVID-19. Finally, monoclonal antibodies derived from COVID- 19 convalescents that bind to the chemokine N-loop impair cell migration. Given the role of chemokines in orchestrating immune cell trafficking, naturally arising anti-chemokine antibodies associated with favorable COVID-19 may be beneficial by modulating the inflammatory response and thus bear therapeutic potential. One-Sentence Summary Naturally arising anti-chemokine antibodies associate with favorable COVID-19 and are predictive of lack of long COVID

Macrophage death following influenza vaccination initiates the inflammatory response that promotes dendritic cell function in the draining lymph node

The mechanism by which inflammation influences the adaptive response to vaccines is not fully understood. Here, we examine the role of lymph node macrophages (LNMs) in the induction of the cytokine storm triggered by inactivated influenza virus vaccine. Following vaccination, LNMs undergo inflammasome-independent necrosis-like death that is reliant on MyD88 and Toll-like receptor 7 (TLR7) expression and releases pre-stored interleukin-1α (IL-1α). Furthermore, activated medullary macrophages produce interferon-β (IFN-β) that induces the autocrine secretion of IL-1α. We also found that macrophage depletion promotes lymph node-resident dendritic cell (LNDC) relocation and affects the capacity of CD11b+ LNDCs to capture virus and express co-stimulatory molecules. Inhibition of the IL-1α-induced inflammatory cascade reduced B cell responses, while co-administration of recombinant IL-1α increased the humoral response. Stimulation of the IL-1α inflammatory pathway might therefore represent a strategy to enhance antigen presentation by LNDCs and improve the humoral response against influenza vaccines