Human microglia maturation is underpinned by specific gene regulatory networks.

Microglia phenotypes are highly regulated by the brain environment, but the transcriptional networks that specify the maturation of human microglia are poorly understood. Here, we characterized stage-specific transcriptomes and epigenetic landscapes of fetal and postnatal human microglia and acquired corresponding data in induced pluripotent stem cell (iPSC)-derived microglia, in cerebral organoids, and following engraftment into humanized mice. Parallel development of computational approaches that considered transcription factor (TF) co-occurrence and enhancer activity allowed prediction of shared and state-specific gene regulatory networks associated with fetal and postnatal microglia. Additionally, many features of the human fetal-to-postnatal transition were recapitulated in a time-dependent manner following the engraftment of iPSC cells into humanized mice. These data and accompanying computational approaches will facilitate further efforts to elucidate mechanisms by which human microglia acquire stage- and disease-specific phenotypes.

Effects of L1 adhesion molecule agonistic mimetics on signal transduction in neuronal functions.

The L1 cell adhesion molecule plays an essential role in neural development and repair. It is not only a 'lock and key' recognition molecule, but an important signal transducer that stimulates regenerative-beneficial cellular functions such as neurite outgrowth, neuronal cell migration, survival, myelination, and synapse formation. Triggering L1 functions after neurotrauma improves functional recovery. In addition, loss-of-function mutations in the L1 gene lead to the L1 syndrome, a rare, X-linked neurodevelopmental disorder with an incidence of approximately 1:30,000 in newborn males. To use L1 for beneficial functions, we screened small compound libraries for L1 agonistic mimetics that trigger L1 functions and improve conditions in animal models of neurotrauma and the L1 syndrome. To understand the mechanisms underlying these functions, it is important to gain a better understanding of L1-dependent cellular signaling that is triggered by the L1 agonistic mimetics. We tested the cell signaling features of L1 agonistic mimetics that contribute to neurite outgrowth and neuronal migration. Our findings indicates that L1 agonistic mimetics trigger the same cell signaling pathways underlying neurite outgrowth, but only the L1 mimetics tacrine, polydatin, trimebutine and honokiol trigger neuronal migration. In contrast, the mimetics crotamiton and duloxetine did not affect neuronal migration, thus limiting their use in increasing neuronal migration, leaving open the question of whether this is a desired or not desired feature in the adult.

Tools for studying human microglia: In vitro and in vivo strategies.

Microglia may only represent 10% of central nervous system (CNS) cells but they perform critical roles in development, homeostasis and neurological disease. Microglia are also environmentally regulated, quickly losing their transcriptomic and epigenetic signature after leaving the CNS. This facet of microglia biology is both fascinating and technically challenging influencing the study of the genetics and function of human microglia in a manner that recapitulates the CNS environment. In this review we provide a comprehensive overview of existing in vitro and in vivo methodology to study human microglia, such as immortalized cells lines, stem cell-derived microglia, cerebral organoids and xenotransplantation. Since there is currently no single method that completely recapitulates all hallmarks of human ex vivo adult homeostatic microglia, we also discuss the advantages and limitations of each existing model as a practical guide for researchers.

Increased Peripheral Blood Neutrophil Activation Phenotypes and Neutrophil Extracellular Trap Formation in Critically Ill Coronavirus Disease 2019 (COVID-19) Patients: A Case Series and Review of the Literature.

BACKGROUND: Increased inflammation has been well defined in coronavirus disease 2019 (COVID-19), while definitive pathways driving severe forms of this disease remain uncertain. Neutrophils are known to contribute to immunopathology in infections, inflammatory diseases, and acute respiratory distress syndrome, a primary cause of morbidity and mortality in COVID-19. Changes in neutrophil function in COVID-19 may give insight into disease pathogenesis and identify therapeutic targets. METHODS: Blood was obtained serially from critically ill COVID-19 patients for 11 days. Neutrophil extracellular trap formation (NETosis), oxidative burst, phagocytosis, and cytokine levels were assessed. Lung tissue was obtained immediately postmortem for immunostaining. PubMed searches for neutrophils, lung, and COVID-19 yielded 10 peer-reviewed research articles in English. RESULTS: Elevations in neutrophil-associated cytokines interleukin 8 (IL-8) and interleukin 6, and general inflammatory cytokines IFN-inducible protien-19, granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin 1ß, interleukin 10, and tumor necrosis factor, were identified both at first measurement and across hospitalization (P < .0001). COVID-19 neutrophils had exaggerated oxidative burst (P < .0001), NETosis (P < .0001), and phagocytosis (P < .0001) relative to controls. Increased NETosis correlated with leukocytosis and neutrophilia, and neutrophils and NETs were identified within airways and alveoli in lung parenchyma of 40% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected lungs available for examination (2 of 5). While elevations in IL-8 and absolute neutrophil count correlated with disease severity, plasma IL-8 levels alone correlated with death. CONCLUSIONS: Literature to date demonstrates compelling evidence of increased neutrophils in the circulation and lungs of COVID-19 patients. Importantly, neutrophil quantity and activation correlates with severity of disease. Similarly, our data show that circulating neutrophils in COVID-19 exhibit an activated phenotype with enhanced NETosis and oxidative burst.

Mediterranean diet adherence and metabolic syndrome in US adolescents.

The Mediterranean diet (MD) has been found to lower the risk of heart disease, stroke, and diabetes in adults. Little is known about its acceptance and relationship to cardiovascular risk markers in US adolescents. Using data from the National Health and Nutrition Examination Survey, years 2007-2014, we performed a cross-sectional analysis of adherence to the Mediterranean diet among a representative sample of US adolescents (n = 4223), factors that influence adherence, and whether adherence is associated with cardiometabolic risk factors including metabolic syndrome. MD adherence was calculated using the KIDMED scoring system. We found that overall MD adherence was very low among US adolescents, with Mexican American youths having higher adherence compared to other groups. Higher income was associated with greater adherence. There was low intake of key MD foods including olive oil and finfish. The unadjusted prevalence of metabolic syndrome was 6.6%. MD adherence was not associated with metabolic syndrome.

Data-Driven Insights on the Effects of COVID-19 on Aesthetics: Part I (Passive Analysis).

BACKGROUND: Since COVID-19 was declared to be a worldwide pandemic and US national emergency in March (week 11), it has significantly changed aesthetic plastic surgery. As plastic surgeons now move towards reopening practices, understanding public interest in medical aesthetics will be critical to maximize efforts and resource allocation in procedures and treatments that patients want. OBJECTIVES: In this study, the authors sought to passively query public interest in aesthetics utilizing Google Trends search data. METHODS: Google Trends was utilized to quantify relative search volumes over the past 4 years for a variety of categories: patient-related, surgery-related, injectables, breast procedures, face procedures, and body procedures. Data were deseasonalized and represented graphically. Z-scores of each time-point differing from the expected values were determined utilizing least squares regression. RESULTS: Of the 204 significantly anomalous search term data points in 2020, 172 (84.0%) occurred after week 11 (pandemic/national emergency declaration). Sixty percent of searches in all time-points after week 11 significantly differed, and 25/26 (96.0%) search terms experienced significant changes after week 11. There was decreased interest for 18 terms with variable recovery. Procedural nadirs for decreased search volume troughs occurred between weeks 11 and 14. Six patient-related chief complaints saw increased search interest after COVID-19, with peak interest between weeks 11 and 17. CONCLUSIONS: This is the first study, to the authors' knowledge, to assess real-time, national data about the impact of COVID-19 on public interest in aesthetics.

Data-Driven Insights on the Effects of COVID-19 on Public Interest in Medical Aesthetics: Part II (Active Analysis).

BACKGROUND: The COVID-19 pandemic significantly affected financial and psychosocial factors that influence plastic surgery demand. OBJECTIVES: The authors sought to actively assess public interest changes and the reasons underlying these shifts. METHODS: Using Amazons' Mechanical Turk, we crowdsourced public opinions regarding aesthetic interventions from April 30 to May 3, 2020. The survey assessed prior experience with and interest in 6 aesthetic interventions before and during the pandemic and reasons for changing interest. United States residents aged 18 years and over who passed the attention check were included. RESULTS: We included 704 of 838 total responses. One-half of respondents were female; the median age group was 25 to 34 years. During the pandemic, 21% of respondents had increased and 33% decreased interest in at least one intervention. Non-invasive procedures (7.3%), facial aesthetic surgery (6.6%), and medical-grade skincare (5.9%) elicited the greatest interest increase. Seeing themselves in the mirror more often (43.2%), desire to look better after the crisis (41.8%), and increased time on social media (40.4%) were the top reasons for increased interest. The most common reasons for decreased interest were changing spending priorities (58%), focusing on other health aspects (49.8%), and worrying about infection in medical facilities (46.3%). Almost one-half of respondents considered virtual consultations for interventions of increased interest. CONCLUSIONS: The COVID-19 pandemic significantly affected interest in medical aesthetics. Offering telemedicine and discussing detailed COVID-19 infection control policies with patients will be critical to address patient needs and concerns. These findings can be used to improve patient outreach, advertisement, and counseling as practices focus on reopening.

Prevention of Umbilical Sagging After Medium Definition Liposuction.

BACKGROUND: The loss of the umbilical vertical axis, causing a horizontal shape deformity after liposuction, is a current aesthetic issue. The use of energy devices, such as LASER and VASER, has been advocated as an option for improving skin retraction, but no data are available on the prevention of umbilical sagging. OBJECTIVES: The authors sought to describe a technique for preventing umbilical deformities after medium definition liposuction employing suction-assisted liposuction. METHODS: Over a period of 31 months, 62 patients underwent medium definition liposuction with direct needle fixation of the umbilical stalk to prevent horizontal umbilical deformities. All patients underwent surgery performed by a single surgeon (G.B.). All patients underwent objective measurements of the umbilical shape before and after the procedure utilizing digital image measurements by Mirror Image software, version 6.0 (Fairfield, NJ). Statistical analysis was performed with IBM SPSS Statistics V26. The mean age of the patients was 28.8 years. The follow-up evaluation was performed 2 weeks and 9 months postoperatively. RESULTS: Over a period of 31 months, 60 patients (96.7%) who underwent abdominal etching liposuction showed maintenance of (n = 9, 14.5%) or improvements in the umbilical shape 9 months postoperatively (n = 51, 82.2%, P < 0.05). Two patients (3.2%) experienced worsening of the umbilical shape after surgery despite suture fixation. CONCLUSIONS: Horizontal shape deformities of the umbilicus after liposuction can be improved by utilizing direct needle fixation of the umbilical stalk. The approach has been shown to be effective, safe, and reproducible for the prevention of umbilical sagging in selected patients.

Safety of a Protective Funnel in Primary Breast Augmentation: A Retrospective Analysis of 380 Multicenter Cases in the United States.

BACKGROUND: Protective funnel devices are commonly used to deliver implants in primary breast augmentation (BA) yet there is a paucity of evidence-based data describing their safety in the literature. OBJECTIVES: The purpose of this study was to assess the safety of protective funnels in primary BA within the first 30 days postoperatively. METHODS: This multicenter, Level 3 study retrospectively reviewed the surgical records of 380 consecutive patients (760 breasts) who underwent primary BA by 9 board-certified plastic surgeons using the iNPLANT Funnel (Proximate Concepts LLC, Allendale, NJ) for implant delivery between November 2019 and December 2020. Data were collected pertaining to demographics, implant information, surgery details, and postoperative complications. RESULTS: The mean patient age was 33 years and 76% of patients had a BMI <25 kg/m2. Of this cohort, 11.4% were smokers, 0.8% had diabetes, and 83% were ASA Class 1. All patients received smooth implants with a median volume of 375 cc. A total of 8 (2.1%) complications were reported, including 3 hematomas (0.79%), 1 seroma (0.26%), and 1 superficial infection (0.26%). No patient required explantation. We identified ASA class, BMI, surgery duration, and implant size as potential risk factors. CONCLUSIONS: The data suggest that the use of protective funnels, such as the iNPLANT Funnel, in primary BA is a safe option when these are utilized according to the manufacturer's Instructions for Use. The use of this device led to a low infection rate (0.26%) and a complication rate of (2.1%) consistent with the average reported in the literature (2%-2.5%).1 Implications for clinical practice are encouraging and future research will include a prospective analysis with a larger case series and potentially a control group.

Oestrogen receptor β ligand acts on CD11c+ cells to mediate protection in experimental autoimmune encephalomyelitis.

Oestrogen treatments are neuroprotective in a variety of neurodegenerative disease models. Selective oestrogen receptor modifiers are needed to optimize beneficial effects while minimizing adverse effects to achieve neuroprotection in chronic diseases. Oestrogen receptor beta (ERβ) ligands are potential candidates. In the multiple sclerosis model chronic experimental autoimmune encephalomyelitis, ERβ-ligand treatment is neuroprotective, but mechanisms underlying this neuroprotection remain unclear. Specifically, whether there are direct effects of ERβ-ligand on CD11c+ microglia, myeloid dendritic cells or macrophages in vivo during disease is unknown. Here, we generated mice with ERβ deleted from CD11c+ cells to show direct effects of ERβ-ligand treatment in vivo on these cells to mediate neuroprotection during experimental autoimmune encephalomyelitis. Further, we use bone marrow chimeras to show that ERβ in peripherally derived myeloid cells, not resident microglia, are the CD11c+ cells mediating this protection. CD11c+ dendritic cell and macrophages isolated from the central nervous system of wild-type experimental autoimmune encephalomyelitis mice treated with ERβ-ligand expressed less iNOS and T-bet, but more IL-10, and this treatment effect was lost in mice with specific deletion of ERβ in CD11c+ cells. Also, we extend previous reports of ERβ-ligand’s ability to enhance remyelination through a direct effect on oligodendrocytes by showing that the immunomodulatory effect of ERβ-ligand acting on CD11c+ cells is necessary to permit the maturation of oligodendrocytes. Together these results demonstrate that targeting ERβ signalling pathways in CD11c+ myeloid cells is a novel strategy for regulation of the innate immune system in neurodegenerative diseases. To our knowledge, this is the first report showing how direct effects of a candidate neuroprotective treatment on two distinct cell lineages (bone marrow derived myeloid cells and oligodendrocytes) can have complementary neuroprotective effects in vivo.awx315media15688130498001.

Nut consumption and metabolic syndrome in US adolescents.

OBJECTIVE: To determine whether nut intake is associated with the prevalence of metabolic syndrome in US adolescents. DESIGN: A cross-sectional analysis of data from the National Health and Nutrition Examination Survey (NHANES) years 2003-2012. Anthropometric measurements, blood tests, 24 h diet recalls and demographic data were retrieved for participating adolescents. Metabolic syndrome was defined according to paediatric-modified Adult Treatment Panel III criteria. The exposure was defined as a nut intake ≥5 g/d. SETTING: USA. SUBJECTS: Individuals aged 12-19 years (n 2805). RESULTS: Nut consumption was associated with lower odds for metabolic syndrome (crude OR=0·25; 95 % CI 0·11, 0·55; P≤0·001). This effect was independent of age, sex, race/ethnicity and family income:poverty ratio (adjusted OR=0·27; 95 % CI 0·12, 0·61; P=0·002), and was stable after controlling for nutritional covariates including intake of sugar and total energy consumption (OR=0·36; 95 % CI 0·16, 0·81; P=0·014). CONCLUSION: Nut consumption of ≥5 g/d is independently associated with lower odds for metabolic syndrome in US adolescents.

A screen in mice uncovers repression of lipoprotein lipase by microRNA-29a as a mechanism for lipid distribution away from the liver.

UNLABELLED: Identification of microRNAs (miRNAs) that regulate lipid metabolism is important to advance the understanding and treatment of some of the most common human diseases. In the liver, a few key miRNAs have been reported that regulate lipid metabolism, but since many genes contribute to hepatic lipid metabolism, we hypothesized that other such miRNAs exist. To identify genes repressed by miRNAs in mature hepatocytes in vivo, we injected adult mice carrying floxed Dicer1 alleles with an adenoassociated viral vector expressing Cre recombinase specifically in hepatocytes. By inactivating Dicer in adult quiescent hepatocytes we avoided the hepatocyte injury and regeneration observed in previous mouse models of global miRNA deficiency in hepatocytes. Next, we combined gene and miRNA expression profiling to identify candidate gene/miRNA interactions involved in hepatic lipid metabolism and validated their function in vivo using antisense oligonucleotides. A candidate gene that emerged from our screen was lipoprotein lipase (Lpl), which encodes an enzyme that facilitates cellular uptake of lipids from the circulation. Unlike in energy-dependent cells like myocytes, LPL is normally repressed in adult hepatocytes. We identified miR-29a as the miRNA responsible for repressing LPL in hepatocytes, and found that decreasing hepatic miR-29a levels causes lipids to accumulate in mouse livers. CONCLUSION: Our screen suggests several new miRNAs are regulators of hepatic lipid metabolism. We show that one of these, miR-29a, contributes to physiological lipid distribution away from the liver and protects hepatocytes from steatosis. Our results, together with miR-29a's known antifibrotic effect, suggest miR-29a is a therapeutic target in fatty liver disease.

Immunosuppression With FTY720 Reverses Cardiac Dysfunction in Hypomorphic ApoE Mice Deficient in SR-BI Expression That Survive Myocardial Infarction Caused by Coronary Atherosclerosis.

AIMS: We recently reported that immunosuppression with FTY720 improves cardiac function and extends longevity in Hypomorphic ApoE mice deficient in scavenger receptor Type-BI expression, also known as the HypoE/SR-BI(­/­) mouse model of diet-induced coronary atherosclerosis and myocardial infarction (MI). In this study, we tested the impact of FTY720 on cardiac dysfunction in HypoE/SR-BI(­/­) mice that survive MI and subsequently develop chronic heart failure. METHODS/RESULTS: HypoE/SR-BI(­/­) mice were bred to Mx1-Cre transgenic mice, and offspring were fed a high-fat diet (HFD) for 3.5 weeks to provoke hyperlipidemia, coronary atherosclerosis, and recurrent MIs. In contrast to our previous study, hyperlipidemia was rapidly reversed by inducible Cre-mediated gene repair of the HypoE allele and switching mice to a normal chow diet. Mice that survived the period of HFD were subsequently given oral FTY720 in drinking water or not, and left ventricular (LV) function was monitored using serial echocardiography for up to 15 weeks. In untreated mice, LV performance progressively deteriorated. Although FTY720 treatment did not initially prevent a decline of heart function among mice 6 weeks after Cre-mediated gene repair, it almost completely restored normal LV function in these mice by 15 weeks. Reversal of heart failure did not result from reduced atherosclerosis as the burden of aortic and coronary atherosclerosis actually increased to similar levels in both groups of mice. Rather, FTY720 caused systemic immunosuppression as assessed by reduced numbers of circulating T and B lymphocytes. In contrast, FTY720 did not enhance the loss of T cells or macrophages that accumulated in the heart during the HFD feeding period, but it did enhance the loss of B cells soon after plasma lipid lowering. Moreover, FTY720 potently reduced the expression of matrix metalloproteinase-2 and genes involved in innate immunity-associated inflammation in the heart. CONCLUSIONS: Our data demonstrate that immunosuppression with FTY720 prevents postinfarction myocardial remodeling and chronic heart failure.

Inducible ApoE gene repair in hypomorphic ApoE mice deficient in the low-density lipoprotein receptor promotes atheroma stabilization with a human-like lipoprotein profile.

OBJECTIVE: To study atherosclerosis regression in mice after plasma lipid reduction to moderately elevated apolipoprotein B (apoB)-lipoprotein levels. APPROACH AND RESULTS: Chow-fed hypomorphic Apoe mice deficient in low-density lipoprotein receptor expression (Apoe(h/h)Ldlr(-/-)Mx1-cre mice) develop hyperlipidemia and atherosclerosis. These mice were studied before and after inducible cre-mediated Apoe gene repair. By 1 week, induced mice displayed a 2-fold reduction in plasma cholesterol and triglyceride levels and a decrease in the non-high-density lipoprotein:high-density lipoprotein-cholesterol ratio from 87%:13% to 60%:40%. This halted atherosclerotic lesion growth and promoted macrophage loss and accumulation of thick collagen fibers for up to 8 weeks. Concomitantly, blood Ly-6C(high) monocytes were decreased by 2-fold but lesional macrophage apoptosis was unchanged. The expression of several genes involved in extracellular matrix remodeling and cell migration was changed in lesional macrophages 1 week after Apoe gene repair. However, mRNA levels of numerous genes involved in cholesterol efflux and inflammation were not significantly changed at this time point. CONCLUSIONS: Restoring apoE expression in Apoe(h/h)Ldlr(-/-)Mx1-cre mice resulted in lesion stabilization in the context of a human-like ratio of non-high-density lipoprotein:high-density lipoprotein-cholesterol. Our data suggest that macrophage loss derived in part from reduced blood Ly-6C(high) monocytes levels and genetic reprogramming of lesional macrophages.

The immunosuppressant FTY720 prolongs survival in a mouse model of diet-induced coronary atherosclerosis and myocardial infarction.

FTY720, an analogue of sphingosine-1-phosphate, is cardioprotective during acute injury. Whether long-term FTY720 affords cardioprotection is unknown. Here, we report the effects of oral FTY720 on ischemia/reperfusion injury and in hypomorphic apoE mice deficient in SR-BI receptor expression (ApoeR61(h/h)/SRB1(-/- mice), a model of diet-induced coronary atherosclerosis and heart failure. We added FTY720 (0.3 mg·kg(-1)·d(-1)) to the drinking water of C57BL/6J mice. After ex vivo cardiac ischemia/reperfusion injury, these mice had significantly improved left ventricular (LV) developed pressure and reduced infarct size compared with controls. Subsequently, ApoeR61(h/h)/SRB1(-/-) mice fed a high-fat diet for 4 weeks were treated or not with oral FTY720 (0.05 mg·kg(-1)·d(-1)). This sharply reduced mortality (P < 0.02) and resulted in better LV function and less LV remodeling compared with controls without reducing hypercholesterolemia and atherosclerosis. Oral FTY720 reduced the number of blood lymphocytes and increased the percentage of CD4+Foxp3+ regulatory T cells (Tregs) in the circulation, spleen, and lymph nodes. FTY720-treated mice exhibited increased TGF-ß and reduced IFN-γ expression in the heart. Also, CD4 expression was increased and strongly correlated with molecules involved in natural Treg activity, such as TGF-ß and GITR. Our data suggest that long-term FTY720 treatment enhances LV function and increases longevity in mice with heart failure. These benefits resulted not from atheroprotection but from systemic immunosuppression and a moderate reduction of inflammation in the heart.

Pharmacological PINK1 activation ameliorates Pathology in Parkinson's Disease models.

PINK1 loss-of-function mutations and exposure to mitochondrial toxins are causative for Parkinson's disease (PD) and Parkinsonism, respectively. We demonstrate that pathological α-synuclein deposition, the hallmark pathology of idiopathic PD, induces mitochondrial dysfunction, and impairs mitophagy as evidenced by the accumulation of the PINK1 substrate pS65-Ubiquitin (pUb). We discovered MTK458, a brain penetrant small molecule that binds to PINK1 and stabilizes its active complex, resulting in increased rates of mitophagy. Treatment with MTK458 mediates clearance of accumulated pUb and α-synuclein pathology in α-synuclein pathology models in vitro and in vivo. Our findings from preclinical PD models suggest that pharmacological activation of PINK1 warrants further clinical evaluation as a therapeutic strategy for disease modification in PD.

Apolipoprotein E4 domain interaction accelerates diet-induced atherosclerosis in hypomorphic Arg-61 apoe mice.

OBJECTIVE: Apolipoprotein (apo) E4 is an established risk factor for atherosclerosis, but the structural components underlying this association remain unclear. ApoE4 is characterized by 2 biophysical properties: domain interaction and molten globule state. Substituting Arg-61 for Thr-61 in mouse apoE introduces domain interaction without molten globule state, allowing us to delineate potential proatherogenic effects of domain interaction in vivo. METHODS AND RESULTS: We studied atherosclerosis susceptibility of hypomorphic Apoe mice expressing either Thr-61 or Arg-61 apoE (ApoeT(h/h) or ApoeR(h/h)mice). On a chow diet, both mouse models were normolipidemic with similar levels of plasma apoE and lipoproteins. However, on a high-cholesterol diet, ApoeR(h/h) mice displayed increased levels of total plasma cholesterol and very-low-density lipoprotein as well as larger atherosclerotic plaques in the aortic root, arch, and descending aorta compared with ApoeT(h/h) mice. In addition, evidence of cellular dysfunction was identified in peritoneal ApoeR(h/h) macrophages which released lower amounts of apoE in culture medium and displayed increased expression of major histocompatibility complex class II molecules. CONCLUSIONS: These data indicate that domain interaction mediates proatherogenic effects of apoE4 in part by modulating lipoprotein metabolism and macrophage biology. Pharmaceutical targeting of domain interaction could lead to new treatments for atherosclerosis in apoE4 individuals.

ApoE suppresses atherosclerosis by reducing lipid accumulation in circulating monocytes and the expression of inflammatory molecules on monocytes and vascular endothelium.

OBJECTIVE: We investigated atheroprotective properties of apolipoprotein (apo) E beyond its ability to lower plasma cholesterol. We hypothesized that apoE reduces atherosclerosis by decreasing lipid accumulation in circulating monocytes and the inflammatory state of monocytes and the vascular endothelium. METHODS AND RESULTS: We developed mice with spontaneous hyperlipidemia with and without plasma apoE. Hypomorphic apoE mice deficient in low-density lipoprotein receptor (Apoe(h/h)Ldlr(-/-)) were compared to Apoe(-/-)Ldlr(-/-) mice. Despite 4-fold more plasma apoE than WT mice, Apoe(h/h)Ldlr(-/-) mice displayed similar plasma cholesterol as Apoe(-/-) Ldlr(-/-) mice but developed 4-fold less atherosclerotic lesions by 5 months of age. The aortic arch of Apoe(h/h)Ldlr(-/-) mice showed decreased endothelial expression of ICAM-1, PECAM-1, and JAM-A. In addition, Apoe(h/h)Ldlr(-/-) mice had less circulating leukocytes and proinflammatory Ly6C(high) monocytes. These monocytes had decreased neutral lipid content and reduced surface expression of ICAM-1, VLA-4, and L-Selectin. Apoe(h/h)Ldlr(-/-) mice displayed increased levels of apoA1-rich HDL that were potent in promoting cellular cholesterol efflux. CONCLUSIONS: Our findings suggest that apoE reduces atherosclerosis in the setting of hyperlipidemia by increasing plasma apoA1-HDL that likely contribute to reduce intracellular lipid accumulation and thereby the activation of circulating leukocytes and the vascular endothelium.

Artificial Intelligence Versus Expert Plastic Surgeon: Comparative Study Shows ChatGPT "Wins" Rhinoplasty Consultations: Should We Be Worried?

Introduction: Large language models, such as ChatGPT, hold tremendous promise to bridge gaps in patient education and enhance the decision-making resources available online for patients seeking nasal surgery. Objective: To compare the performance of ChatGPT in answering preoperative and postoperative patient questions related to septorhinoplasty. Methods: Two sets of responses were collected for the questions: one from an expert rhinoplasty surgeon with over two decades of experience, and the other from ChatGPT-3.5. Seven expert rhinoplasty surgeons, blinded to the source of responses, independently assessed the responses using a 5-point Likert scale in four performance areas: empathy, accuracy, completeness, and overall quality. Results: ChatGPT outperformed physician responses in three of the four performance areas, earning significantly higher ratings in accuracy, completeness, and overall quality (p < 0.001). In addition, ChatGPT was overwhelmingly preferred over physician responses (p < 0.001), with evaluators favoring ChatGPT in 80.95% of instances. Conclusions: ChatGPT has demonstrated its remarkable ability to deliver accurate, complete, and high-quality responses to preoperative and postoperative patient questions. Although certain improvements are warranted, this artificial intelligence tool has shown its potential to effectively counsel and educate prospective septorhinoplasty patients at a level comparable with or exceeding that of an expert surgeon.