Age-modified risk factors for mortality of non-elderly adult kidney transplant recipients: a retrospective database analysis.

PURPOSE: We aimed to investigate the role of the recipient's age strata in modifying the associations between risk factors and mortality in non-elderly adult kidney transplant (KT) recipients (KTR). METHODS: We stratified 108,695 adult KTRs between 2000 and 2016 with conditional 1-year survival after KT into cohorts based on age at transplant: 18-49 years and 50-64 years. We excluded KTRs aged < 18 years or > / = 65 years. KTRs were observed for 5 years during the 2nd through 6th years post-KT for the outcome, all-cause mortality. RESULTS: Increasing recipient age strata (18-49-year-old and 50-64-year-old) correlated with decreasing 6-year post-KT survival rates conditional on 1-year survival (79% and 57%, respectively, p < 0.0001). Middle adult age stratum was associated with a higher risk of all-cause mortality than young adult age stratum in KTRs of Hispanic/Latino and other races [HR = 1.23, 95% CI = 1.04-1.45 and HR = 1.51, 95% CI = 1.16-1.97, respectively] and with a primary native renal diagnosis of hypertension or glomerulonephritis [HR = 1.32, 95% CI = 1.12-1.55 and HR = 1.29, 95% CI = 1.10-151, respectively]. When compared with the young adult age stratum, the middle adult age stratum had a mitigating effect on the higher risk of mortality associated with sirolimus-mycophenolate or sirolimus-tacrolimus than the standard calcineurin inhibitor-mycophenolate regimen [HR = 0.75, 95% CI = 0.57-0.99 and HR = 0.71, 95% CI = 0.57-0.89, respectively]. CONCLUSION: Among adult non-elderly KTRs, the age strata, 18-49 years, and 50-64 years, have varying modifying effects on the strength and direction of associations between some specific risk factors and all-cause mortality.

Cholesterol accumulation impairs HIF-1α-dependent immunometabolic reprogramming of LPS-stimulated macrophages by upregulating the NRF2 pathway.

Lipid accumulation in macrophages (Mφs) is a hallmark of atherosclerosis. Yet, how lipid loading modulates Mφ inflammatory responses remains unclear. We endeavored to gain mechanistic insights into how pre-loading with free cholesterol modulates Mφ metabolism upon LPS-induced TLR4 signaling. We found that activities of prolyl hydroxylases (PHDs) and factor inhibiting HIF (FIH) are higher in cholesterol loaded Mφs post-LPS stimulation, resulting in impaired HIF-1α stability, transactivation capacity and glycolysis. In RAW264.7 cells expressing mutated HIF-1α proteins resistant to PHDs and FIH activities, cholesterol loading failed to suppress HIF-1α function. Cholesterol accumulation induced oxidative stress that enhanced NRF2 protein stability and triggered a NRF2-mediated antioxidative response prior to and in conjunction with LPS stimulation. LPS stimulation increased NRF2 mRNA and protein expression, but it did not enhance NRF2 protein stability further. NRF2 deficiency in Mφs alleviated the inhibitory effects of cholesterol loading on HIF-1α function. Mutated KEAP1 proteins defective in redox sensing expressed in RAW264.7 cells partially reversed the effects of cholesterol loading on NRF2 activation. Collectively, we showed that cholesterol accumulation in Mφs induces oxidative stress and NRF2 stabilization, which when combined with LPS-induced NRF2 expression leads to enhanced NRF2-mediated transcription that ultimately impairs HIF-1α-dependent glycolytic and inflammatory responses.

Plasma S1P Orchestrates the Reverse Transendothelial Migration of Aortic Intimal Myeloid Cells in Mice.

BACKGROUND: Myeloid cells (MCs) reside in the aortic intima at regions predisposed to atherosclerosis. Systemic inflammation triggers reverse transendothelial migration (RTM) of intimal MCs into the arterial blood, which orchestrates a protective immune response that clears intracellular pathogens from the arterial intima. Molecular pathways that regulate RTM remain poorly understood. S1P (sphingosine-1-phosphate) is a lipid mediator that regulates immune cell trafficking by signaling via 5 G-protein-coupled receptors (S1PRs [S1P receptors]). We investigated the role of S1P in the RTM of aortic intimal MCs. METHODS: Intravenous injection of lipopolysaccharide was used to model a systemic inflammatory stimulus that triggers RTM. CD11c+ intimal MCs in the lesser curvature of the ascending aortic arch were enumerated by en face confocal microscopy. Local gene expression was evaluated by transcriptomic analysis of microdissected intimal cells. RESULTS: In wild-type C57BL/6 mice, lipopolysaccharide induced intimal cell expression of S1pr1, S1pr3, and Sphk1 (a kinase responsible for S1P production). Pharmacological modulation of multiple S1PRs blocked lipopolysaccharide-induced RTM and modulation of S1PR1 and S1PR3 reduced RTM in an additive manner. Cre-mediated deletion of S1pr1 in MCs blocked lipopolysaccharide-induced RTM, confirming a role for myeloid-specific S1PR1 signaling. Global or hematopoietic deficiency of Sphk1 reduced plasma S1P levels, the abundance of CD11c+ MCs in the aortic intima, and blunted lipopolysaccharide-induced RTM. In contrast, plasma S1P levels, the abundance of intimal MCs, and lipopolysaccharide-induced RTM were rescued in Sphk1-/- mice transplanted with Sphk1+/+ or mixed Sphk1+/+ and Sphk1-/- bone marrow. Stimulation with lipopolysaccharide increased endothelial permeability and intimal MC exposure to circulating factors such as S1P. CONCLUSIONS: Functional and expression studies support a novel role for S1P signaling in the regulation of lipopolysaccharide-induced RTM and the homeostatic maintenance of aortic intimal MCs. Our data provide insight into how circulating plasma mediators help orchestrate intimal MC dynamics.

Oxidized Low-Density Lipoprotein Accumulation in Macrophages Impairs Lipopolysaccharide-Induced Activation of AKT2, ATP Citrate Lyase, Acetyl-Coenzyme A Production, and Inflammatory Gene H3K27 Acetylation.

The accumulation of lipid and the formation of macrophage foam cells is a hallmark of atherosclerosis, a chronic inflammatory disease. To better understand the role of macrophage lipid accumulation in inflammation during atherogenesis, we studied early molecular events that follow the accumulation of oxidized low-density lipoprotein (oxLDL) in cultured mouse macrophages. We previously showed that oxLDL accumulation downregulates the inflammatory response in conjunction with downregulation of late-phase glycolysis. In this study, we show that within hours after LPS stimulation, macrophages with accumulated oxLDL maintain early-phase glycolysis but selectively downregulate activation of AKT2, one of three AKT isoforms. The inhibition of AKT2 activation reduced LPS-induced ATP citrate lyase activation, acetyl-CoA production, and acetylation of histone 3 lysine 27 (H3K27ac) in certain inflammatory gene promoters. In contrast to oxLDL, multiple early LPS-induced signaling pathways were inhibited in macrophages with accumulated cholesterol, including TBK1, AKT1, AKT2, MAPK, and NF-κB, and early-phase glycolysis. The selective inhibition of LPS-induced AKT2 activation was dependent on the generation of mitochondrial oxygen radicals during the accumulation of oxLDL in macrophages prior to LPS stimulation. This is consistent with increased oxidative phosphorylation, fatty acid synthesis, and oxidation pathways found by comparative transcriptomic analyses of oxLDL-loaded versus control macrophages. Our study shows a functional connection between oxLDL accumulation, inactivation of AKT2, and the inhibition of certain inflammatory genes through epigenetic changes that occur soon after LPS stimulation, independent of early-phase glycolysis.

Oxidized Low-Density Lipoprotein Accumulation Suppresses Glycolysis and Attenuates the Macrophage Inflammatory Response by Diverting Transcription from the HIF-1α to the Nrf2 Pathway.

Lipid accumulation in macrophages (Mφs) is a hallmark of atherosclerosis, yet how lipid accumulation affects inflammatory responses through rewiring of Mφ metabolism is poorly understood. We modeled lipid accumulation in cultured wild-type mouse thioglycolate-elicited peritoneal Mφs and bone marrow-derived Mφs with conditional (Lyz2-Cre) or complete genetic deficiency of Vhl, Hif1a, Nos2, and Nfe2l2. Transfection studies employed RAW264.7 cells. Mφs were cultured for 24 h with oxidized low-density lipoprotein (oxLDL) or cholesterol and then were stimulated with LPS. Transcriptomics revealed that oxLDL accumulation in Mφs downregulated inflammatory, hypoxia, and cholesterol metabolism pathways, whereas the antioxidant pathway, fatty acid oxidation, and ABC family proteins were upregulated. Metabolomics and extracellular metabolic flux assays showed that oxLDL accumulation suppressed LPS-induced glycolysis. Intracellular lipid accumulation in Mφs impaired LPS-induced inflammation by reducing both hypoxia-inducible factor 1-α (HIF-1α) stability and transactivation capacity; thus, the phenotype was not rescued in Vhl-/- Mφs. Intracellular lipid accumulation in Mφs also enhanced LPS-induced NF erythroid 2-related factor 2 (Nrf2)-mediated antioxidative defense that destabilizes HIF-1α, and Nrf2-deficient Mφs resisted the inhibitory effects of lipid accumulation on glycolysis and inflammatory gene expression. Furthermore, oxLDL shifted NADPH consumption from HIF-1α- to Nrf2-regulated apoenzymes. Thus, we postulate that repurposing NADPH consumption from HIF-1α to Nrf2 transcriptional pathways is critical in modulating inflammatory responses in Mφs with accumulated intracellular lipid. The relevance of our in vitro models was established by comparative transcriptomic analyses, which revealed that Mφs cultured with oxLDL and stimulated with LPS shared similar inflammatory and metabolic profiles with foamy Mφs derived from the atherosclerotic mouse and human aorta.

Role of standard HLA mismatch in modifying associations between non-pharmacologic risk factors and solid organ malignancy after kidney transplantation.

BACKGROUND: Human leukocyte antigen mismatch(es) (HLA-mm) between donors and recipients has not been extensively studied either as a risk factor for solid organ malignancy (SOM) or as a modifier of associations between nonpharmacologic risk factors and SOM in kidney transplant recipients (KTRs). METHODS: In a secondary analysis from a previous study, 166,256 adult KTRs in 2000-2018 who survived the first 12 months post-transplant free of graft loss or malignancy were classified into 0, 1-3, and 4-6 standard HLA-mm cohorts. Multivariable cause-specific Cox regressions analyzed the risks of SOM and all-cause mortality (ac-mortality) in 5 years following the first KT year. Comparisons of associations between SOM and risk factors in HLA mismatch cohorts were made by estimating the ratios of adjusted hazard ratios. RESULTS: Compared with 0 HLA-mm, 1-3 HLA-mm was not associated, and 4-6 HLA-mm was equivocally associated with increased risk of SOM [hazard ratio, (HR) = 1.05, 95%, confidence interval (CI) = 0.94-1.17 and HR = 1.11, 95% CI = 1.00-1.34, respectively]. Both 1-3 HLA-mm and 4-6 HLA-mm were associated with increased risk of ac-mortality compared with 0 HLA mm [hazard ratio (HR) = 1.12, 95%, Confidence Interval (CI) = 1.08-1.18) and (HR = 1.16, 95% CI = 1.09-1.22), respectively]. KTR's history of pre-transplant cancer, age 50-64, and >/=65 years were associated with increased risks of SOM and ac-mortality in all HLA mismatch cohorts. Pre-transplant dialysis >2 years, diabetes as the primary renal disease, and expanded or standard criteria deceased donor transplantation were risk factors for SOM in the 0 and 1-3 HLA-mm cohorts and of ac-mortality in all HLA-mm cohorts. KTRs male sex or history of previous kidney transplant was a risk factor for SOM in the 1-3 and 4-6 HLA-mm cohorts and of ac-mortality in all HLA-mm cohorts. CONCLUSION: Direct association between SOM and the degree of HLA mismatching is equivocal and limited to the 4-6 HLA-mm stratum; however, the degree of HLA mismatching has significant modifying effects on the associations between specific nonpharmacologic risk factors and SOM in KTRs.

Replacing Plain Radiograph with ultra-low dose CT thorax in cystic fibrosis (CF) in the era of CFTR modulation and its impact on cumulative effective dose.

BACKGROUND: Medical radiation exposure is of increasing concern in patients with cystic fibrosis (PWCF) due to improving life expectancy. We aimed to assess and quantify the cumulative effective dose (CED) in PWCF in the context of CFTR-modulator therapy and the advancement of dose reduction techniques. METHODS: We performed a retrospective observational study in a single University CF centre over a 11-year period. We included PWCF, aged over 18 years who exclusively attended our institution. Relevant clinical data (demographics, transplantation history and modulator status) and radiological data (modality, quantity, and radiation exposure measured as CED) were collected. For those on modulator therapy the quantified imaging and radiation data was dichotomised into pre-and-post therapy periods. RESULTS: The study included 181 patients: 139 on CFTR modulator therapy, 15 transplant recipients and 27 with neither exposure. 82% of patients received <25 mSv over the study period. Mean study duration was 6.9 ± 2.6 years pre-modulation and 4.2 ± 2.6 years post-modulation. Pre-modulation CT contributed 9.6% of total chest imaging (n = 139/1453) and 70.9% of the total CED. Post-modulation CT use increased contributing 42.7% of chest imaging (n = 444/1039) and comprised 75.8% of CED. Annual CED was 1.55 mSv pre and 1.36 mSv post modulation (p = 0.41). Transplant recipients had an annual CED of 64 ± 36.1mSv. CONCLUSION: Chest CT utilisation for PWCF is rising in our institution, replacing chest radiography amidst CFTR-modulation. Despite the increasing use of CT, no significant radiation dose penalty was observed with a reduction in mean annual CED, primarily due to the influence of CT dose reduction strategies.

Common predictors of adverse outcomes in adult deceased donor kidney transplant recipients with varying sensitization.

OBJECTIVE: Our objective was to identify consistent predictors of multiple adverse outcomes of adult deceased donor (DD) kidney transplant recipients (KTRs) of varying sensitization status. METHODS: We used the national transplant database in studying 62037 adult DD-KTRs between Dec. 2007 and Jun. 2015 stratified into sensitization cohorts based on calculated panel reactive antibody (CPRA) of <10%, 10%-79%, and ≥80%. We used multivariable logistic regressions for the analysis of risks for delayed graft function (DGF), and of acute rejection (AR) and hospitalization in the first year of transplant, and Cox hazard regression for 5-year overall graft loss (OAGL) and death. RESULTS: The kidney donor risk index (KDRI) highest two quartiles ≥1.45 and 1.15-1.44 were the most consistent predictors for 100% of adverse outcomes (OAGL, death, DGF, AR, and hospitalization) with high significance (P<0.0001) across all sensitization cohorts. The two risk factors that were consistently associated with 80% of adverse outcomes across sensitization cohorts were: (1) pre-transplant dialysis duration >2 years was significantly associated with increased risks of overall graft loss, death, DGF, and hospitalization; and (2) Black KTR race was significantly associated with increased risks of DGF, AR, and hospitalization, and decreased risk of death. Diabetes and KTR age >65 (years) were significant risk factors for overall loss and death across sensitization cohorts. CONCLUSIONS: The two highest KDRI quartiles, pre-transplant dialysis duration >2 years, and African American recipient race are consistent predictors of multiple adverse outcomes in adult DDKTRs across sensitization strata and should be among the factors considered in clinical decision-making and research models in kidney transplantation.

Individualized approach to elexacaftor/tezacaftor/ivacaftor dosing in cystic fibrosis, in response to self-reported anxiety and neurocognitive adverse events: A case series.

The prevalence of mental health disorders is high among people with Cystic Fibrosis. The psychological symptoms in CF are associated with poor adherence, worse treatment outcomes, and greater health utilization/cost. Mental health and neurocognitive Adverse Events (AEs) have been reported with all available Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators in small groups of patients. We report our experience with a dose reduction strategy in 10 of our patients on elexacaftor/tezacaftor/ivacaftor (7.9% of total number of patients) who self-reported developing intense anxiety, irritability, sleep disturbance and/or mental slowness after initiation of full dose treatment. Standard dose elexacaftor/tezacaftor/ivacaftor resulted in 14.3 points improvement in mean Percent Predicted Forced Expiratory Volume in 1 s (ppFEV1), and a mean difference in sweat chloride of -39.3 mmol/L. We initially discontinued and/or reduced therapy according to the AEs severity, with a subsequent planned dose escalation every 4-6 weeks guided by sustainability of clinical effectiveness, absence of AEs recurrence, and patients' preferences. Clinical parameters including lung function and sweat chloride were monitored for up to 12 weeks to assess ongoing clinical response to the reduced dose regimen. Dose reduction resulted in resolution of self-reported mental/psychological AEs, without loss of clinical effectiveness (ppFEV1 was 80.7% on standard dose, and 83.4% at 12 weeks on reduced dose; sweat chloride was 33.4 and 34 mmol/L on standard and reduced dose, respectively). Furthermore, in a subgroup of patients who completed 24 weeks of the reduced dose regimen, repeat low dose Computed Tomography imaging showed a significant response when compared to pre-initiation of elexacaftor/tezacaftor/ivacaftor.

Telehealth in Cystic Fibrosis. A systematic review incorporating a novel scoring system and expert weighting to identify a 'top 10 manuscripts' to inform future best practices implementation.

The ongoing development and integration of telehealth within CF care has been accelerated in response to the Covid-19 pandemic, with many centres publishing their experiences. Now, as the restrictions of the pandemic ease, the use of telehealth appears to be waning, with many centres returning to routine traditional face-to-face services. For most, telehealth is not integrated into clinical care models, and there is a lack of guidance on how to integrate such a service into clinical care. The aims of this systematic review were to first identify manuscripts which may inform best CF telehealth practices, and second, to analyse these finding to determine how the CF community may use telehealth to improve care for patients, families, and Multidisciplinary Teams into the future. To achieve this, the PRISMA review methodology was utilised, in combination with a modified novel scoring system that consolidates expert weighting from key CF stakeholders, allowing for the manuscripts to be placed in a hierarchy in accordance with their scientific robustness. From the 39 found manuscripts, the top ten are presented and further analysed. The top ten manuscripts are exemplars of where telehealth is used effectively within CF care at this time, and demonstrate specific use cases of its potential best practices. However, there is a lack of guidance for implementation and clinical decision making, which remains an area for improvement. Thus, it is suggested that further work explores and provides guidance for standardised implementation into CF clinical practice.

Single Use or Disposable Flexible Bronchoscopes: Bench Top and Preclinical Comparison of Currently Available Devices.

BACKGROUND: Data regarding the risk of infection related to reusable bronchoscopes, the global drive toward disposable technology and the COVID-19 pandemic have led to an increase in the use and production of single use or disposable bronchoscopes. An in-depth comparison of all available devices has not been published. METHODS: A benchtop comparison of the Ambu®aScopeTM, Boston Scientific® EXALTTM Model B, the Surgical Company Broncoflex© Vortex, Pentax® Medical ONE Pulmo™, and Vathin® H-SteriscopeTM (all 2.8 mm inner dimension other than the Pentax single-use flexible bronchoscope (3 mm)) was undertaken including measurement of maximal flexion and extension angles, thumb force required and suction with and without biopsy forceps. Thereafter, preclinical assessment was performed with data collected including experience, gender, hand size, and scope preference. RESULTS: The Vathin single-use flexible bronchoscope had the biggest range of tip movement from flexion to extension with and without forceps. The Boston single-use flexible bronchoscope required the maximal thumb force but had the least reduction of tip movement with forceps. The Boston single-use flexible bronchoscope significantly outperformed all other scopes including the standard Pentax scope and was the only scope capable of suctioning pseudo-mucus around the forceps. Although there was no significant difference in preference in the overall group, females and those with smaller hand size preferred the Pentax and males the Broncoflex single-use flexible bronchoscope. CONCLUSIONS: Currently available single-use flexible bronchoscopes differ in several factors other than scope sizes and monitor including suction, turning envelope, and handle size. Performance in the clinical setting will be key to their success.

Factors related to upstaging of clinical stage T2 organ-confined bladder cancer following radical cystectomy: A multicenter study.

Aims: This study aimed to detect possible risk factors related to upstaging of clinical stage T2 organ-confined (OC) to non-OC (nOC) bladder cancer (BC) following radical cystectomy (RC). Settings and Design: This was a prospective multicenter study. Subjects and Methods: This is a multicenter prospective study including 196 Egyptian BC patients undergoing RC from January 2017 to February 2019 at Cairo University, Fayoum University, and Menoufia University. Only patients with muscle invasive BC (T2) were included in the study. Patients' characteristics, preoperative clinical data (including Hydronephrosis), cystoscopy data, and biopsy pathological data were recorded. Preoperative clinical staging is compared to postoperative pathological staging, to determine upstaged cases. The occurrence of upstaging in correspondence to each preoperative factor is recorded and statistically analyzed. Results: Among 196 BC patients of our study, upstaging from OC T2 to nOC occurred in 88 (44.9%) patients. Statistical analysis showed that the factors related to upstaging are older age (P ≤ 0.001), large tumor size (P = 0.048), lymphovascular invasion (LVI) (P ≤ 0.001), and multifocal tumor (P ≤ 0.001). On the other hand, the following factors were not related to upstaging: gender (P = 0.159), smoking (P = 0.286), preoperative hydronephrosis (P = 0.242), and presence of carcinoma in situ (P = 0.349). Conclusions: The difference between clinical and pathological staging of BC patients following RC is a frequent problem with no clear guidelines to overcome it. Several factors including age of the patient, large tumor size, LVI, and multifocal tumor are predictors of upstaging in OC BC. A good concern must be taken in these patients to achieve an optimum treatment plan for them.

Natural Garlic Organosulfur Compounds Prevent Metabolic Disorder of Lipid and Glucose by Increasing Gut Commensal Bacteroides acidifaciens.

A number of reports of the effects of garlic on gut microbiota revealed that the active garlic organosulfur compounds (OSCs) are destabilized by the action of alliinase during garlic preparation. In this study, garlic alliinase was deactivated to obtain stable garlic OSCs. Experiments with C57BL/6J mice fed with lipid and glucose metabolic disorder-inducing Western diet (WD) revealed that stable garlic OSCs prevented the disorder by increasing the relative abundance of gut Bacteroides acidifaciens. Molecular analysis indicated that garlic OSCs inhibited dyslipidemia and fatty liver by increasing taurine and subsequently promoting hepatic fatty acid ß-oxidation. In parallel, garlic OSCs could meliorate glucose homeostasis by inhibiting dipeptidyl peptidase-4 (DPP-4) and hepatic gluconeogenesis. In vitro bacterial culture experiments revealed that garlic OSCs directly increased the growth of gut Bacteroides acidifaciens. The results of this study demonstrate that the molecular mechanism of the preventive effect of garlic OSCs on the WD-induced metabolic disorder is attributed to the enhanced growth of Bacteroides acidifaciens and the consequent increase in taurine.

Highly efficient protein expression of Plasmodium vivax surface antigen, Pvs25, by silkworm and its biochemical analysis.

Plasmodium vivax ookinete surface protein, Pvs25, is a candidate for a transmission-blocking vaccine (TBV) for malaria. Pvs25 has four EGF-like domains containing 22 cysteine residues forming 11 intramolecular disulfide bonds, a structural feature that makes its recombinant protein expression difficult. In this study, we report the high expression of recombinant Pvs25 as a soluble form in silkworm, Bombyx mori. The Pvs25 protein was purified from hemolymphs of larvae and pupae by affinity chromatography. In the Pvs25 expressed by silkworm, no isoforms with inappropriate disulfide bonds were found, requiring no further purification step, which is necessary in the case of Pichia pastoris-based expression systems. The Pvs25 from silkworm was confirmed to be molecularly uniform by sodium dodecyl sulfate gel electrophoresis and size-exclusion chromatography. To examine the immunogenicity, the Pvs25 from B. mori was administered to BALB/c mice subcutaneously with oil adjuvant. The Pvs25 produced by silkworm induced potent and robust immune responses, and the induced antisera correctly recognized P. vivax ookinetes in vitro, demonstrating the potency of Pvs25 from silkworm as a candidate for a malaria TBV. To the best of our knowledge, this is the first study to construct a system for mass-producing malaria TBV antigens using silkworm.

Radiation Impacts Early Atherosclerosis by Suppressing Intimal LDL Accumulation.

RATIONALE: Bone marrow transplantation (BMT) is used frequently to study the role of hematopoietic cells in atherosclerosis, but aortic arch lesions are smaller in mice after BMT. OBJECTIVE: To identify the earliest stage of atherosclerosis inhibited by BMT and elucidate potential mechanisms. METHODS AND RESULTS: Ldlr-/- mice underwent total body γ-irradiation, bone marrow reconstitution, and 6-week recovery. Atherosclerosis was studied in the ascending aortic arch and compared with mice without BMT. In BMT mice, neutral lipid and myeloid cell topography were lower in lesions after feeding a cholesterol-rich diet for 3, 6, and 12 weeks. Lesion coalescence and height were suppressed dramatically in mice post-BMT, whereas lateral growth was inhibited minimally. Targeted radiation to the upper thorax alone reproduced the BMT phenotype. Classical monocyte recruitment, intimal myeloid cell proliferation, and apoptosis did not account for the post-BMT phenotype. Neutral lipid accumulation was reduced in 5-day lesions, thus we developed quantitative assays for LDL (low-density lipoprotein) accumulation and paracellular leakage using DiI-labeled human LDL and rhodamine B-labeled 70 kD dextran. LDL accumulation was dramatically higher in the intima of Ldlr-/- relative to Ldlr+/+ mice, and was inhibited by injection of HDL mimics, suggesting a regulated process. LDL, but not dextran, accumulation was lower in mice post-BMT both at baseline and in 5-day lesions. Since the transcript abundance of molecules implicated in LDL transcytosis was not significantly different in the post-BMT intima, transcriptomics from whole aortic arch intima, and at single-cell resolution, was performed to give insights into pathways modulated by BMT. CONCLUSIONS: Radiation exposure inhibits LDL entry into the aortic intima at baseline and the earliest stages of atherosclerosis. Single-cell transcriptomic analysis suggests that LDL uptake by endothelial cells is diverted to lysosomal degradation and reverse cholesterol transport pathways. This reduces intimal accumulation of lipid and impacts lesion initiation and growth.

Autorotation of the Mandible as Sequelae to Maxillary Intrusion: A Systematic Review.

BACKGROUND: Autorotation of the mandible is a normally anticipated phenomenon following a surgical superior repositioning of the maxilla in clinical situations where patients have an excessive gummy smile. Prediction of the surgical treatment outcome following a presurgical orthodontic treatment is a critical element in the surgical treatment planning. MATERIALS AND METHODS: The relevant articles were selected by hand search and electronic media (Google Scholar, PubMed, Science Direct, Medline, Embase, and Cochrane) from 1982 to 2020. All the relevant articles were properly screened, and findings were extracted from the articles. RESULTS: It was observed that, following maxillary intrusion, mandible would eventually autorotate to take a new occlusion. Mandibular autorotation as a result of maxillary intrusion would lead to minimal shortening of the lower lip in the vertical plane. It was observed that the amount of mandibular autorotation correlates with the extent of maxillary impaction. Studies have shown that there is a passive soft-tissue response which may be attributed to the fact that no muscular detachment had been affected in the lower lip and soft-tissue chin region during the maxillary surgery. CONCLUSION: It is observed that there is a definite influence on the mandibular and chin positions as a result of maxillary intrusion and autorotation of the mandible. Every 1 mm of maxillary superior impaction, the chin moved 0.6 mm vertically and 0.2 mm horizontally. There is an appreciable shortening of the lower lip length.

Coronavirus Disease and New-Onset Atrial Fibrillation: Two Cases.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in a considerable amount of morbidity and mortality worldwide since December 2019. Patients with coronavirus disease (COVID-19) most commonly present with respiratory manifestations, while cardiac manifestations were reported as a complication and seldom as a presenting feature. We report two cases of new-onset atrial fibrillation occurring in middle-aged men with no significant past medical history. The first patient presented with symptomatic atrial fibrillation; however, during his hospitalization course, he developed a fever, which led to the diagnosis of infection with SARS-CoV-2. The second patient presented from urgent care after being diagnosed with COVID-19 associated with newly diagnosed atrial fibrillation. Both patients were treated symptomatically for COVID-19 and discharged home after reverting to sinus rhythm. Physicians should be aware of the variable clinical presentations of COVID-19, especially in new or worsening cardiac illnesses, in order to practice the appropriate personal protection practices. More studies are needed to identify the viral mechanisms leading to the dysregulation of cardiac rhythm.

Outcomes of induction antibody therapies in the nonbroadly sensitized adult deceased donor kidney transplant recipients: a retrospective cohort registry analysis.

The outcomes of lymphocyte-depleting antibody induction therapy (LDAIT), [thymoglobulin (ATG) or alemtuzumab (ALM)] versus interleukin-2 receptor antagonist (IL-2RA) in the nonbroadly-sensitized [pretransplant calculated panel reactive antibody (cPRA), <80%] adult deceased donor kidney transplant recipients (adult-DDKTRs) are understudied. In this registry, study of 55 593 adult-DD-KTRs, outcomes of LDAIT [(ATG, N = 32 985) and (ALM, N = 9429)], and IL-2RA (N = 13 179) in <10% and 10-79% cPRA groups was analyzed. Adjusted odds ratio (aOR) of one-year biopsy-proven acute rejection (BPAR) was lower; while, aOR of 1-year composite of re-hospitalization, graft loss, or death was higher with LDAIT than IL2-RA in both cPRA groups. Adjusted odds ratio (aOR) of delayed graft function was higher with LDAIT than IL-2RA in the <10% cPRA group. Adjusted hazard ratio (aHR) of 5-year death-censored graft loss (DCGL) in both <80% cPRA groups seemed higher with ALM than other inductions [(<10% cPRA: ALM versus IL2RA, aHR = 1.11, 95% CI = 1.00-1.23 and ATG versus ALM: aHR = 0.84, 95% CI = 0.77-0.91; 10-79% cPRA: ALM versus IL2RA, aHR = 1.29, 95% CI = 1.02-1.64; and ATG versus ALM, aHR = 0.83, 95% CI = 0.70-0.98)]. Five-year aHR of death did not differ among induction therapies in both cPRA groups. In nonbroadly sensitized adult-DDKTRs, LDAIT is more protective against 1-year BPAR (not 5-year mortality) than IL-2RA; the trend of a higher 5-year DCGL risk with ALM than ATG or IL-2RA needs further investigation.