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Background This study was designed to prospectively evaluate the efficacy of extracorporeal photopheresis (ECP) to attenuate the rate of decline of FEV1 in lung transplant recipients with refractory bronchiolitis obliterans. Due to an observed higher than expected early mortality, a preliminary analysis was performed. Study Design and Methods Subjects from 10 lung transplant centres were assigned to ECP treatment or to observation based on spirometric criteria, with potential crossover for those under observation. The primary endpoint of this study was to assess response to ECP (i.e., greater than a 50% decrease in the rate of FEV1 decline) before and 6 months after initiation of ECP. Mortality was also evaluated 6 and 12 months after enrolment as a secondary endpoint. Results Of 44 enrolled subjects, 31 were assigned to ECP treatment while 13 were initially assigned to observation on a non‐random basis using specific spirometric inclusion criteria (seven of the observation patients subsequently crossed over to receive ECP). Of evaluable patients, 95% of patients initially assigned to treatment responded to ECP with rates of FEV1 decline that were reduced by 93% in evaluable ECP‐treated patients. Mortality rates (percentages) at 6 and 12 months after enrolment was 32% and 41%, respectively. The most common (92%) primary cause of death was respiratory or graft failure. Significantly (p = 0.002) higher rates of FEV1 decline were observed in the non‐survivors (−212 ± 177 ml/month) when compared to the survivors (−95 ± 117 ml/month) 12 months after enrolment. In addition, 18 patients with bronchiolitis obliterans syndrome (BOS) diagnosis within 6 months of enrolment had lost 38% of their baseline lung function at BOS diagnosis and 50% of their lung function at enrolment. Conclusions These analyses suggest that earlier detection and treatment of BOS should be considered to appreciate improved outcomes with ECP.

Normalizing cardiovascular measurements for body size allows for comparison among children of different ages and for distinguishing pathologic changes from normal physiologic growth. Because of growing interest to use height for normalization, the aim of this study was to develop height-based normalization models and compare them to body surface area (BSA)-based normalization for aortic and left ventricular (LV) measurements. The study population consisted of healthy, non-obese children between 2 and 18 years of age enrolled in the Pediatric Heart Network Echo Z-Score Project. The echocardiographic study parameters included proximal aortic diameters at 3 locations, LV end-diastolic volume, and LV mass. Using the statistical methodology described in the original project, Z-scores based on height and BSA were determined for the study parameters and tested for any clinically significant relationships with age, sex, race, ethnicity, and body mass index (BMI). Normalization models based on height versus BSA were compared among underweight, normal weight, and overweight (but not obese) children in the study population. Z-scores based on height and BSA were calculated for the 5 study parameters and revealed no clinically significant relationships with age, sex, race, and ethnicity. Normalization based on height resulted in lower Z-scores in the underweight group compared to the overweight group, whereas normalization based on BSA resulted in higher Z-scores in the underweight group compared to the overweight group. In other words, increasing BMI had an opposite effect on height-based Z-scores compared to BSA-based Z-scores. Allometric normalization based on height and BSA for aortic and LV sizes is feasible. However, height-based normalization results in higher cardiovascular Z-scores in heavier children, and BSA-based normalization results in higher cardiovascular Z-scores in lighter children. Further studies are needed to assess the performance of these approaches in obese children with or without cardiac disease.

Genu varum in patients with achondroplasia is common and is often exacerbated by the associated generalized ligamentous laxity. Despite this, development of knee osteoarthritis is rare. There are only a few previously published case reports of total knee arthroplasty in this population. We present 2-year follow-up of a patient with achondroplasia who underwent staged bilateral primary total knee arthroplasties using hinged components. Technical considerations and careful preoperative planning are required in patients with achondroplasia given their small skeletal stature, metaphyseal deformities, and ligamentous laxity.

Importance and Objective The Covid pandemic is a timely opportunity to try to broaden our understanding of the links between education and health literacy and explore the vaccine-decision process with a view to identifying interventions that will positively influence vaccine uptake. Evidence Health and vaccine literacy encompass people’s knowledge, motivation, and competence to access, understand, appraise and apply health information in order to make judgements and take decisions in everyday life concerning health care, disease prevention and health promotion. Findings Appropriate vaccine communication, which depends greatly on personal and contextual determinants, as well as on societal and environmental circumstances, is essential to reassure people about vaccine efficacy, safety, and possible side effects. However, vaccine confidence is not solely a question of trust in the vaccine’s efficacy, safety. and individual protective benefit of vaccination. It also encompasses the mechanism(s) of vaccine activity, immunization schedules, organization and trust in the healthcare system that promotes and delivers the vaccines, and at what costs. When healthcare professionals as science brokers of vaccine knowledge attempt to increase vaccine knowledge and confidence, they must adjust their communication to the educational or health literacy level of their intended audience. Even if their messages are apparently clear and simple, they absolutely need to verify that they are properly understood. Relevance Specific vaccine communication training appears essential to increase vaccine communication skills among healthcare providers. Moreover, further randomized controlled studies are warranted to improve vaccine empowerment among different populations, from a variety of educational backgrounds.

Rationale: Hypertriglyceridemia and low HDL-C (high-density lipoprotein cholesterol), both of which are regulated by LpL (lipoprotein lipase) activity, associate with increased cardiovascular disease. Genetic regulators of LpL actions track with cardiovascular disease risk in humans. Whether this is due to changes in HDL-C or function or circulating triglyceride levels is unresolved. Objective: We created hypertriglyceridemia and HDL-C reduction in atherosclerotic mice to allow the assessment of how hypertriglyceridemia and reduced HDL-C affect regression of atherosclerosis and the phenotype of plaque macrophages. Methods and Results: Atherosclerosis regression was studied in control LpL floxed ( Lpl fl/fl ) mice and tamoxifen-inducible whole-body LpL knockout ( iLpl −/− ) mice with hypertriglyceridemia (≈500 mg/dL) and reduced HDL-C (≈50% reduction). Atherosclerosis regression was studied using 2 models in which advanced plaques resulting from hypercholesterolemia are exposed to normal LDL-C (low-density lipoprotein cholesterol) levels using aortic transplantation or treatments with oligonucleotides. In a subset of mice, we expressed hCETP (human cholesterol ester transfer protein) to humanize the relationship between apoB-lipoproteins and HDL. HDL particle number, cholesterol efflux capacity, and HDL proteome were measured in hypertriglyceridemia mice and humans. Surprisingly, hypertriglyceridemia and reduced HDL-C levels due to loss of LpL did not affect atherosclerosis lesion size or macrophage content (CD68+cells) in either model. Expression of hCETP and further reduction of HDL-C did not alter lesions. Sera from iLpl −/− mice had a decrease in total cholesterol efflux capacity, but not ABCA1 (ATP-binding cassette transporter A1)-mediated cholesterol efflux capacity. Hypertriglyceridemic humans, including those with LpL deficiency, had greater ABCA1-mediated cholesterol efflux capacity and total cholesterol efflux capacity per HDL particle number. Conclusions: Atherosclerosis regression in mice is driven by LDL-C reduction and is not affected by hypertriglyceridemia and plasma HDL-C levels.

Background: We previously showed that cardiomyocyte Krϋppel-like factor (KLF) 5 regulates cardiac fatty acid oxidation. As heart failure has been associated with altered fatty acid oxidation, we investigated the role of cardiomyocyte KLF5 in lipid metabolism and pathophysiology of ischemic heart failure. Methods: Using real-time polymerase chain reaction and Western blot, we investigated the KLF5 expression changes in a myocardial infarction (MI) mouse model and heart tissue from patients with ischemic heart failure. Using 2D echocardiography, we evaluated the effect of KLF5 inhibition after MI using pharmacological KLF5 inhibitor ML264 and mice with cardiomyocyte-specific KLF5 deletion (αMHC [α-myosin heavy chain]-KLF5 −/ − ). We identified the involvement of KLF5 in regulating lipid metabolism and ceramide accumulation after MI using liquid chromatography–tandem mass spectrometry, and Western blot and real-time polymerase chain reaction analysis of ceramide metabolism–related genes. We lastly evaluated the effect of cardiomyocyte-specific KLF5 overexpression (αMHC-rtTA [reverse tetracycline-controlled transactivator]-KLF5) on cardiac function and ceramide metabolism, and rescued the phenotype using myriocin to inhibit ceramide biosynthesis. Results: KLF5 mRNA and protein levels were higher in human ischemic heart failure samples and in rodent models at 24 hours, 2 weeks, and 4 weeks post–permanent left coronary artery ligation. αMHC-KLF5 −/− mice and mice treated with ML264 had higher ejection fraction and lower ventricular volume and heart weight after MI. Lipidomic analysis showed that αMHC-KLF5 −/ − mice with MI had lower myocardial ceramide levels compared with littermate control mice with MI, although basal ceramide content of αMHC-KLF5 −/ − mice was not different in control mice. KLF5 ablation suppressed the expression of SPTLC1 and SPTLC2 (serine palmitoyltransferase [SPT] long-chain base subunit ()1 2, respectively), which regulate de novo ceramide biosynthesis. We confirmed our previous findings that myocardial SPTLC1 and SPTLC2 levels are increased in heart failure patients. Consistently, αMHC-rtTA-KLF5 mice showed increased SPTLC1 and SPTLC2 expression, higher myocardial ceramide levels, and systolic dysfunction beginning 2 weeks after KLF5 induction. Treatment of αMHC-rtTA-KLF5 mice with myriocin that inhibits SPT, suppressed myocardial ceramide levels and alleviated systolic dysfunction. Conclusions: KLF5 is induced during the development of ischemic heart failure in humans and mice and stimulates ceramide biosynthesis. Genetic or pharmacological inhibition of KLF5 in mice with MI prevents ceramide accumulation, alleviates eccentric remodeling, and increases ejection fraction. Thus, KLF5 emerges as a novel therapeutic target for the treatment of ischemic heart failure.

Background Associations of diet with dilated cardiomyopathy are under investigation. Objectives That cardiac assessment would show abnormalities in healthy dogs eating grain‐free (GF) diets or diets with Food and Drug Administration (FDA)‐listed ingredients of concern (peas, lentils, or potatoes) as top 10 ingredients (FDA‐PLP), but not in dogs eating grain‐inclusive (GI) diets or diets without FDA‐listed ingredients of concern (PLP) in the top 10 ingredients (NoFDA‐PLP). Animals One hundred eighty‐eight healthy Doberman Pinschers, Golden Retrievers, Miniature Schnauzers, and Whippets. Methods This study was an observational cross‐sectional study. Echocardiograms, cardiac biomarkers, and blood and plasma taurine concentrations were compared between dogs eating GF (n = 26) and GI (n = 162) diets, and between FDA‐PLP (n = 39) and NoFDA‐PLP (n = 149) diets, controlling for age and breed. Demographic characteristics, murmurs, genetic status, and ventricular premature complexes (VPCs) during examination were compared between dogs eating different diet types. Results No differences in echocardiographic variables, N‐terminal pro‐B‐type natriuretic peptide or whole blood taurine were noted between dogs eating different diet types. Dogs eating GF diets had higher median high‐sensitivity cardiac troponin I (hs‐cTnI) (GF 0.076 ng/mL [Interquartile range (IQR), 0.028‐0.156] vs. GI 0.048 [IQR, 0.0026‐0.080]; P

ANGPTL3 has emerged as a therapeutic target whose inhibition results in profound reductions of plasma lipids, including atherogenic triglyceride-rich lipoproteins and low-density lipoprotein cholesterol. The identification of ANGPTL3 deficiency as a cause of familial combined hypolipidemia in humans hastened the development of anti-ANGPTL3 therapeutic agents, including evinacumab (a monoclonal antibody inhibiting circulating ANGPTL3), vupanorsen (an antisense oligonucleotide [ASO] targeting hepatic ANGPTL3 mRNA for degradation), and others. Advances have also been made in ANGPTL3 vaccination and gene editing strategies, with the former still in preclinical phases and the latter in preparation for Phase 1 trials. Here, we review the discovery of ANGPTL3 as an important regulator of lipoprotein metabolism, molecular characteristics of the protein, mechanisms by which it regulates plasma lipids, and the clinical development of anti-ANGPTL3 agents. The clinical success of therapies inhibiting ANGPTL3 highlights the importance of this target as a novel approach in treating refractory hypertriglyceridemia and hypercholesterolemia.

Motivation Novel machine learning and statistical modeling studies rely on standardized comparisons to existing methods using well-studied benchmark datasets. Few tools exist that provide rapid access to many of these datasets through a standardized, user-friendly interface that integrates well with popular data science workflows. Results This release of PMLB (Penn Machine Learning Benchmarks) provides the largest collection of diverse, public benchmark datasets for evaluating new machine learning and data science methods aggregated in one location. v1.0 introduces a number of critical improvements developed following discussions with the open-source community. Availability and implementation PMLB is available at https://github.com/EpistasisLab/pmlb. Python and R interfaces for PMLB can be installed through the Python Package Index and Comprehensive R Archive Network, respectively.

Lymphomatoid papulosis (LyP) type E is a rare variant of the primary cutaneous CD30+ lymphoproliferative disorders, characterized clinically by large necrotic eschar-like lesions and histopathologically by angiodestructive and angioinvasive infiltrates of CD30+ lymphocytes. As in other forms of lymphomatoid papulosis, type E lesions may undergo spontaneous regression after weeks, with frequent recurrences. We report a 21-year old male with an angiodestructive infiltrate of CD30+ lymphocytes manifesting as a papular eruption rather than ulceration, and suggest that this clinical phenotype might be related to the presence of CD4+ lymphocytes in the inflammatory cell infiltrate. This article is protected by copyright. All rights reserved.

Background Radiofrequency (RF) is commonly recognized treatment option for fat reduction, utilizing heat‐induced adipocyte deletion. HIFEM treatment has been proven to be an effective tool for body shaping. Objectives To document the structural changes in human subcutaneous tissue induced by the combination of RF treatment with the HIFEM procedure. Methods Four subjects (51.50 ± 6.35 years, 22.59 ± 3.21 kg/m2) received three 30‐minute abdominal treatments consisting of RF therapy and HIFEM. One subject (57 years, 23.60 kg/m2) served as a control. Punch biopsies were collected at baseline, 1‐week, and 1‐month post‐treatment. Samples were sliced and stained with H&E. Waist circumference, digital photographs, satisfaction, and therapy comfort were assessed. Subjects were monitored for any adverse event, and fat temperatures were measured. Results Baseline samples showed a healthy appearance of adipocytes, composed of round‐shaped unilocular cells of uniform size. At follow‐up, treated adipocytes demonstrated nuclear and shape changes with consequent fat reduction. Adipocytes were found to be flattened/shrunken and of smaller size (−33.5% at 1 week; −31.7% at 1‐month) along with occasional ruptures of the cytoplasmic membrane. In contrast to baseline, pyknotic nuclei with condensed nuclear chromatin were seen at 1‐week and 1‐month post‐treatment. The control samples showed no treatment‐related changes. Waist circumference decreased by an average of 2.20 cm in the treated patients. No adverse events were observed. The fat temperature reached 42‐45°C, during treatment; the therapy was comfortable with high patient satisfaction. Conclusions Results suggest the efficacy and safety of the therapy combining RF and HIFEM. The adipocyte deletion and shrinkage resulted in overall reduction of fat tissue.

Objective The aim of this study was to evaluate Scotland's national HIV preexposure prophylaxis (PrEP) programme in relation to PrEP uptake and associated population-level impact on HIV incidence among MSM. Design A retrospective cohort study within real-world implementation. Methods Comparison of HIV diagnoses from national surveillance data and HIV incidence within a retrospective cohort of HIV-negative MSM attending sexual health clinics from the National Sexual Health information system between the 2-year periods pre(July 2015-June 2017) and post(July 2017-June 2019) introduction of PrEP. Results Of 16 723 MSM attending sexual health services in the PrEP period, 3256 (19.5%) were prescribed PrEP. Between pre-PrEP and PrEP periods, new HIV diagnoses among MSM declined from 229 to 184, respectively [relative risk reduction (RRR): 19.7%, 95% confidence interval (95% CI) 2.5-33.8]; diagnosed recently acquired infections declined from an estimated 73 to 47, respectively (35.6%, 95% CI 7.1-55.4). Among MSM attending sexual health clinics, HIV incidence per 1000 person-years declined from 5.13 (95% CI 3.90-6.64) pre-PrEP to 3.25 (95% CI 2.30-4.47) in the PrEP period (adjusted IRR 0.57, 95% CI 0.37-0.87). Compared with the pre-PrEP period, incidence of HIV was lower in the PrEP period for those prescribed PrEP (aIRR 0.25, 95% CI 0.09-0.70) and for those not prescribed PrEP (aIRR 0.68, 95% CI 0.43-1.05). Conclusion We demonstrate national population-level impact of PrEP for the first time in a real-world setting. HIV incidence reduced in MSM who had been prescribed PrEP and, to a lesser extent, in those who had not. Promotion of the benefits of PrEP needs to extend to MSM who do not access sexual health clinics.

Background The adoption of low-carbohydrate diets can lead to weight loss in many patients. However, these now widespread diets also have the potential to exacerbate hypercholesterolemia. Objective The objective of this study is to display the potentially harmful effects of the ketogenic diet on cholesterol levels in patients with or without underlying hyperlipidemia. Methods We describe 5 patients who developed marked increases in plasma cholesterol on ketogenic diets and assessed whether they had a well-described underlying genetic hyperlipidemia. Results Three out of 5 patients had extraordinary increases of blood cholesterol levels to over 500 mg/dL. The other 2 patients more than doubled their low-density lipoprotein cholesterol levels on a ketogenic diet. One patient had an APOE E2/E2 genotype. A higher burden of common genetic polymorphisms was found in 2 patients, with no major mutations found. No potential genetic cause was seen in a fourth patient, and the fifth patient had no genetic testing. Three patients, including the one who was most hypercholesterolemic, had a marked reduction in cholesterol after reverting to a more liberal diet. One refused to change his diet but had a satisfactory low-density lipoprotein cholesterol reduction on ezetimibe. Conclusion These cases should serve as a caution that high-fat low-carbohydrate diets have the potential to exacerbate or cause hypercholesterolemia in patients with or without underlying genetic hyperlipidemia.

Objectives: Micro-elimination of hepatitis C virus (HCV) in people living with HIV (PLHIV) and co-infected with HCV has been proposed as a key contribution to the overall goal of HCV elimination. While other studies have examined micro-elimination in HIV-treated cohorts, few have considered HCV micro-elimination among those not treated for HIV or at a national level. Methods: Through data linkage of national and sentinel surveillance data, we examined the extent of HCV testing, diagnosis and treatment among a cohort of PLHIV in Scotland identified through the national database of HIV-diagnosed individuals, up to the end of 2017. Results: Of 5018 PLHIV, an estimated 797 (15%) had never been tested for HCV and 70 (9%) of these had undiagnosed chronic HCV. The odds of never having been tested for HCV were the highest in those not on HIV treatment [adjusted odds ratio (aOR) = 7.21, 95% confidence interval (CI): 5.15–10.10). Overall HCV antibody positivity was 11%, and it was at its highest among people who inject drugs (49%). Most of those with chronic HCV (91%) had attended an HCV treatment clinic but only half had been successfully treated (54% for those on HIV treatment, 12% for those not) by the end of 2017. The odds of never having been treated for HCV were the highest in those not on HIV treatment (aOR = 3.60, 95% CI: 1.59–8.15). Conclusions: Our data demonstrate that micro-elimination of HCV in PLHIV is achievable but progress will require increased effort to engage and treat those co-infected, including those not being treated for their HIV.

In November 2017, the donation service area (DSA) was removed as the primary unit of US donor lung allocation. Our primary objective was to evaluate the effect of this change on recipient characteristics, the use of pretransplant extracorporeal membrane oxygenation (ECMO), and on index hospitalization length of stay (LOS) and early posttransplant complications. We also assessed whether these outcomes differed in high and low competition centers, as defined by the Herfindahl-Hirschman Index. Following DSA removal, there was a 9-day decrease in median waitlist time (P = .001) and an increase in median lung allocation score (40 vs 42, P

Introduction: CHORD (CHOlesterol lowering and Residual Risk in Diabetes) is an ongoing, prospective, multicenter study designed to evaluate the effect of maximal cholesterol-lowering on cardiovascular (CV) risk. Aggressive lipid-lowering with HMG CoA-reductase inhibitors (e.g. statins), ezetimibe, and PCSK9 inhibitors (such as evolocumab) reduce atherothrombotic events. Statins reduce cholesterol dramatically and are also felt to have pleiotropic, anti-inflammatory properties. We compared the impact of statins and ezetimibe on thrombotic biomarkers after maximal lipid lowering with PCSK9 inhibition. Methods: CHORD enrolled subjects (n=57, mean age 52 ± 15 years, 44% male, 58% diabetes) with LDL-cholesterol >100mg/dl and treated with evolocumab (140mg every 2 weeks) plus either atorvastatin (80mg/day, n=27), or ezetimibe (10mg/day, n=30) for 30-days. High-sensitivity C-reactive protein (hs-CRP) and biomarkers of thrombosis (LEGENDplex Human Thrombosis Panel) were measured at baseline and follow-up. Results: Significant LDL-C reductions were observed in both the evolocumab + atorvastatin (130 mg/dl [123 - 145] to 31 mg/dl [27 - 39], pFigure 1). Conclusion: Despite similar levels of LDL-C reduction, statins plus evolocumab cause greater reductions in biomarkers of thrombosis and inflammation than ezetimibe and evolocumab. These data suggest that statins provide benefits over and above LDL-C reduction.

Background: Dyslipidemia induces a proinflammatory endothelium and vascular dysfunction. Lipid lowering therapy (LLT) consistently reduces cardiovascular (CV) events. Clinical studies suggest that statin-based LLT has pleiotropic anti-inflammatory effects beyond cholesterol reduction. However, the impact of statins or ezetimibe on top of potent cholesterol reduction is unknown. Thus, on a background of PCSK9 inhibition (with evolocumab), we analyzed the effect of LLT with atorvastatin or ezetimibe on the endothelium using a novel direct brachial vein (BV) endothelial cell (EC) harvesting technique. Methods: CHORD (CHOlesterol lowering and Residual Risk in Diabetes) is an ongoing, prospective study designed to evaluate the effect of maximal LLT on CV risk. Subjects with LDL-C >100mg/dl were treated with evolocumab (140mg/2 weeks) and either atorvastatin (80mg/day) or ezetimibe (10mg/day) for 30 days. In a subset of participants, EC harvesting was performed by inserting a J-wire into the BV, and ECs were isolated and analyzed using next generation RNA sequencing. Results: Among 20 participants (11 atorvastatin, 9 ezetimibe) undergoing EC RNASeq, median LDL-C (130 mg/dl, IQR [110, 147]) decreased by 75% [67, 81] on background PCSK9 inhibition with no significant difference in 30-day LDL-C between atorvastatin (27 mg/dl [20, 32]) and ezetimibe (41 mg/dl [26, 53]) groups (p=0.07). Following cholesterol reduction, 850 genes were upregulated and 2468 were downregulated (p Conclusions: Robust lipid lowering with PCSK9 inhibition plus statins, as opposed to ezetimibe has anti-inflammatory effects and suggests a preferred strategy to improve the endothelium and reduce CV risk.

Monocytes and macrophages are implicated in cardiovascular disease, including atherosclerotic plaque progression and regression. The scavenger receptor CD36, which is highly expressed in macrophages, mediates lipid uptake into macrophages and promotes clearance of apoptotic and dead cells. Moreover, CD36 as multi-ligand scavenger receptor binds both fatty acids and lipoproteins, which differ in their effects on macrophage phenotype. Some in vitro experiments have reported that CD36-mediated uptake of lipids convert macrophages to an inflammatory phenotype, whereas other studies show that lipid uptake converts macrophages to an alternatively activated state. To determine the role of this receptor in vivo where cells are exposed to both lipoproteins and free fatty acids, we created macrophage-specific CD36 knockout mice. Using zymosan-induced peritonitis to challenge immune cells, we found a broad heterogeneity of resident and infiltrated immune cells, primarily macrophages, in the peritoneum 72h after the initial stimuli. Macrophage CD36 deficient cells had increased expression of pathways related to innate immunity, antigen presentation and oxidative phosphorylation; whereas pathways related to efferocytosis adaptive immunity and B cell activation were downregulated. Gene signatures related to pro-inflammatory features were evident only in CD36 deficient macrophages. Macrophage efferocytosis capacity and B cell antibody production did not differ between control and CD36 depleted mice. Our data show that CD36 expression allows macrophages to convert to a less inflammatory state.

Despite the benefits of LDL-cholesterol-reducing medications, patients with type 1 diabetes (T1D) continue to have an increased risk of incident CVD. Preclinical and clinical observations indicate that triglyceride-rich lipoproteins (TRLs) and their remnants may contribute significantly to CVD risk in T1D. Recently, we have shown that diabetes increases levels of atherogenic TRL remnants and that improvement of remnant clearance halts atherosclerosis in a mouse model of T1D. Cholesteryl ester transfer protein (CETP), which is normally absent in mice, links metabolism of TRLs to that of HDL by mediating the transfer of cholesteryl ester from HDL to VLDL and other APOB-containing lipoproteins in exchange for triglycerides. We hypothesized that CETP impairs the atheroprotective effects of APOA1 by altering TRL and HDL metabolism in diabetes. To test this hypothesis, we developed a virally-induced T1D mouse model expressing the human APOA1 transgene ( APOA1 Tg , Ldlr –/– ). Cohorts of these mice were injected with a liver-targeted adeno-associated virus to express human CETP, and the effects on lipoproteins, plasma apolipoproteins, HDL particle concentrations (HDL-P), and atherosclerosis in the presence and absence of diabetes were determined. This mouse model exhibits an HDL profile similar to humans, with small, medium and large HDL-P, whereas wildtype ( Ldlr -/- ) littermates have only one sized HDL-P. Expression of the APOA1 transgene significantly suppressed diabetes-accelerated necrotic core expansion and accumulation of APOB and APOE in the aortic sinus (compared to wildtype Ldlr -/- mice), while CETP impaired the protective effect of APOA1 on these parameters in diabetic APOA1 Tg , Ldlr –/– mice (n= 22-30, p < 0.05). Further characterization of plasma lipoproteins and apolipoproteins by targeted mass spectrometry, FPLC and differential ion mobility analysis indicated that CETP leads to smaller TRL remnant particles, increases triglyceride content in HDL, lower levels of plasma APOA1 and reduction in large HDL-P under diabetic conditions (n= 8-10, p < 0.05). Our results are consistent with the proposal that inhibition of CETP might be cardioprotective in the setting of T1D and highlight the close links between TRL and HDL metabolism in diabetes.

The development of atherosclerosis is triggered by the endothelial crossing and subendothelial retention of apolipoprotein B (ApoB)-containing LDL and chylomicron remnants. LDL has been reported to cross the endothelial cell (EC) barrier via two receptors: scavenger receptor-B1 (SR-B1) and activin receptor-like kinase 1 (ALK1). We have shown that SR-B1 also mediates EC uptake of nascent chylomicrons, leading to the accumulation of lipid droplets (LD) within the aortic endothelium and skin macrophages of hyperchylomicronemic LpL-deficient mice. In vitro, chylomicron-exposed ECs induced LD accumulation in co-cultured macrophages in the absence of any other lipid source. Surprisingly, conditioned media from chylomicron-exposed ECs primarily contained phospholipids and diglycerides, rather than triglycerides and fatty acids. Electron microscopy analysis revealed the presence of small extracellular vesicles (sEVs), and filtration of the media to remove sEVs prevented LD accumulation in macrophages. To determine the molecular interaction of chylomicrons and SR-B1 we performed a series of competition experiments. At physiologic concentrations found in postprandial blood, chylomicrons blocked LDL uptake into cultured ECs. Moreover, chylomicron uptake was blocked by co-incubation with ApoB18, a lipid-free peptide comprising the 18% N-terminus of ApoB. To assess this in vivo, we used an adeno-associated virus to overexpress ApoB18 in LpL-deficient mice. ApoB18-expressing mice exhibited a ≈ 50% reduction in aortic EC LD content, suggesting that the peptide effectively inhibits chylomicron uptake in vivo. Further, ApoB18 blocked LDL uptake by ECs in culture. These results suggest that a) the N-terminus of ApoB harbors a binding sequence for SR-B1 and b) endothelial uptake of both chylomicrons and LDL can be blocked by competition with non-lipoprotein ApoB peptides.

Death from noncompressible torso hemorrhage (NCTH) may be preventable with improved prehospital care and shorter in-hospital times to hemorrhage control. We hypothesized that shorter times to surgical intervention for hemorrhage control would decrease mortality in hypotensive patients with NCTH.This was an AAST-sponsored multicenter, prospective analysis of hypotensive patients aged 15+ years who presented with NCTH from May 2018 to December 2020. Hypotension was defined as an initial systolic blood pressure (SBP) ≤ 90 mm Hg. Primary outcomes of interest were time to surgical intervention and in-hospital mortality.There were 242 hypotensive patients, of which 48 died (19.8%). Nonsurvivors had higher mean age (47.3 vs. 38.8; p = 0.02), higher mean New Injury Severity Score (38 vs. 29; p0.001), lower admit systolic blood pressure (68 vs. 79 mm Hg; p0.01), higher incidence of vascular injury (41.7% vs. 21.1%; p = 0.02), and shorter median (interquartile range, 25-75) time from injury to operating room start (74 minutes [48-98 minutes] vs. 88 minutes [61-128 minutes]; p = 0.03) than did survivors. Multivariable Cox regression showed shorter time from emergency department arrival to operating room start was not associated with improved survival (p = 0.04).Patients who died arrived to a trauma center in a similar time frame as did survivors but presented in greater physiological distress and had significantly shorter times to surgical hemorrhage intervention than did survivors. This suggests that even expediting a critically ill patient through the current trauma system is not sufficient time to save lives from NCTH. Civilian prehospital advance resuscitative care starting from the patient first contact needs special consideration.Prognostic/Epidemiologic, Level III.

Purpose: Although commonly used, HbA1c is insensitive for diagnosing prediabetes and diabetes. Glycemic variability (GV) or a 1-hour plasma glucose level (1-h PG) ≥ 155 mg/dL (8.6 mmol/L) during a 75-gram oral glucose tolerance test (OGTT) better identifies individuals with dysglycemia. The objectives were to (1) compare continuous glucose monitoring (CGM) with the OGTT for detecting dysglycemia in high-risk subjects with HbA1c < 5.7% (39 mmol/mol), and (2) correlate the 1-h PG with CGM-derived GV indices. Research Design and Methods: Subjects (n=15) with a HbA1c < 5.7% (39 mmol/mol) and at least one other risk factor for type 2 diabetes such as overweight, obesity, hypertension, or hyperlipidemia were recruited. A 2-h OGTT was performed within 3-7 days of CGM insertion, which was worn up to 14 days. Results: The average age was 50 ± 14 years, with the majority of participants being men (80%) and Caucasian (67%). The mean HbA1c was 5.3±0.2% (34 mmol/mol). The 1-h PG was highly correlated with 1-h CGM glucose levels (ρ=0.881, pConclusion: 1-h interstitial CGM glucose and 1-h PG can detect dysglycemia in high-risk subjects with HbA1c < 5.7% (39 mmol/mol). CGM may be an alternative screening tool for glucose disorders.

Interstitial lung disease is a known complication of rheumatoid arthritis, with a lifetime risk of developing the disease in any individual of 7·7%. We aimed to assess the safety, tolerability, and efficacy of pirfenidone for the treatment of patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD).TRAIL1 was a randomised, double-blind, placebo-controlled, phase 2 trial done in 34 academic centres specialising in interstitial lung disease in four countries (the UK, the USA, Australia, and Canada). Adults aged 18-85 years were eligible for inclusion if they met the 2010 American College of Rheumatology and European Alliance of Associations for Rheumatology criteria for rheumatoid arthritis and had interstitial lung disease on a high-resolution CT scan imaging and, when available, lung biopsy. Exclusion criteria include smoking, clinical history of other known causes of interstitial lung disease, and coexistant clinically significant COPD or asthma. Patients were randomly assigned (1:1) to receive 2403 mg oral pirfenidone (pirfenidone group) or placebo (placebo group) daily. The primary endpoint was the incidence of the composite endpoint of a decline from baseline in percent predicted forced vital capacity (FVC%) of 10% or more or death during the 52-week treatment period assessed in the intention-to-treat population. Key secondary endpoints included change in absolute and FVC% over 52 weeks, the proportion of patients with a decline in FVC% of 10% or more, and the frequency of progression as defined by Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02808871.From May 15, 2017, to March 31, 2020, 231 patients were assessed for inclusion, of whom 123 patients were randomly assigned (63 [51%] to the pirfenidone group and 60 [49%] to the placebo group). The trial was stopped early (March 31, 2020) due to slow recruitment and the COVID-19 pandemic. The difference in the proportion of patients who met the composite primary endpoint (decline in FVC% from baseline of 10% or more or death) between the two groups was not significant (seven [11%] of 63 patients in the pirfenidone group vs nine [15%] of 60 patients in the placebo group; OR 0·67 [95% CI 0·22 to 2·03]; p=0·48). Compared with the placebo group, patients in the pirfenidone group had a slower rate of decline in lung function, measured by estimated annual change in absolute FVC (-66 vs -146; p=0·0082) and FVC% (-1·02 vs -3·21; p=0·0028). The groups were similar with regards to the decline in FVC% by 10% or more (five [8%] participants in the pirfenidone group vs seven [12%] in the placebo group; OR 0·52 [95% CI 0·14-1·90]; p=0·32) and the frequency of progression as defined by OMERACT (16 [25%] in the pirfenidone group vs 19 [32%] in the placebo group; OR 0·68 [0·30-1·54]; p=0·35). There was no significant difference in the rate of treatment-emergent serious adverse events between the two groups, and there were no treatment-related deaths.Due to early termination of the study and underpowering, the results should be interpreted with caution. Despite not meeting the composite primary endpoint, pirfenidone slowed the rate of decline of FVC over time in patients with RA-ILD. Safety in patients with RA-ILD was similar to that seen in other pirfenidone trials.Genentech.

Three hundred thousand new cases of Lyme disease are diagnosed annually in the United States. The earliest manifestation of the disease, erythema migrans, occurs earlier than serologic conversion, and skin biopsies can be very helpful in suggesting the diagnosis. Histopathologic findings vary depending on where in the lesion the specimen is taken, but typically consist of a superficial and deep perivascular and interstitial lymphocytic infiltrate with eosinophils centrally and with histiocytes and plasma cells at the periphery. Rare cases with interstitial histiocytes and rare-to-sparse plasma cells exist. We present a 67-year-old man whose skin biopsy, taken on day 2 of his eruption, demonstrated a subtle perivascular and interstitial infiltrate of histiocytes without plasma cells. Dermatopathologists need to be aware of this pattern and consider the diagnosis of erythema migrans, despite negative initial serologic testing.

Let X be a topological space equipped with a complete positive σ -finite measure and T a subset of the reals with 0 as an accumulation point. Let a t x , y be a nonnegative measurable function on X × X which integrates to 1 in each variable. For a function f ∈ L 2 X and t ∈ T , define A t f x ≡ ∫ a t x , y f y d y . We assume that A t f converges to f in L 2 , as t ⟶ 0 in T . For example, A t is a diffusion semigroup (with T = 0 , ∞ ). For W a finite measure space and w ∈ W , select real-valued h w ∈ L 2 X , defined everywhere, with h w L 2 X ≤ 1 . Define the distance D by D x , y ≡ h w x − h w y L 2 W . Our main result is an equivalence between the smoothness of an L 2 X function f (as measured by an L 2 -Lipschitz condition involving a t · , · and the distance D ) and the rate of convergence of A t f to f .