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Background: Cell phenotype switching is increasingly being recognized in atherosclerosis. However, our understanding of the exact stimuli for such cellular transformations and their significance for human atherosclerosis is still evolving. Intraplaque hemorrhage is thought to be a major contributor to plaque progression in part by stimulating the influx of CD163 + macrophages. Here, we explored the hypothesis that CD163 + macrophages cause plaque progression through the induction of proapoptotic endothelial-to-mesenchymal transition (EndMT) within the fibrous cap., Methods: Human coronary artery sections from CVPath's autopsy registry were selected for pathological analysis. Athero-prone ApoE -/- and ApoE -/- /CD163 -/- mice were used for in vivo studies. Human peripheral blood mononuclear cell-induced macrophages and human aortic endothelial cells were used for in vitro experiments., Results: In 107 lesions with acute coronary plaque rupture, 55% had pathological evidence of intraplaque hemorrhage in nonculprit vessels/lesions. Thinner fibrous cap, greater CD163 + macrophage accumulation, and a larger number of CD31/FSP-1 (fibroblast specific protein-1) double-positive cells and TUNEL (terminal deoxynucleotidyl transferase-dUTP nick end labeling) positive cells in the fibrous cap were observed in nonculprit intraplaque hemorrhage lesions, as well as in culprit rupture sections versus nonculprit fibroatheroma sections. Human aortic endothelial cells cultured with supernatants from hemoglobin/haptoglobin-exposed macrophages showed that increased mesenchymal marker proteins (transgelin and FSP-1) while endothelial markers (VE-cadherin and CD31) were reduced, suggesting EndMT induction. Activation of NF-κB (nuclear factor kappa β) signaling by proinflammatory cytokines released from CD163 + macrophages directly regulated the expression of Snail, a critical transcription factor during EndMT induction. Western blot analysis for cleaved caspase-3 and microarray analysis of human aortic endothelial cells indicated that apoptosis was stimulated during CD163 + macrophage-induced EndMT. Additionally, CD163 deletion in athero-prone mice suggested that CD163 is required for EndMT and plaque progression. Using single-cell RNA sequencing from human carotid endarterectomy lesions, a population of EndMT was detected, which demonstrated significant upregulation of apoptosis-related genes., Conclusions: CD163 + macrophages provoke EndMT, which may promote plaque progression through fibrous cap thinning., Competing Interests: R. Virmani and A.V. Finn have received institutional research support from R01 HL141425 Leducq Foundation Grant, the National Institutes of Health Grant (NIH; HL141425), the Amazon Web Services Coronavirus Disease 2019 Diagnostic Development Initiative Grant, 480 Biomedical, 4C Medical, 4Tech, Abbott Vascular, Ablative Solutions, Absorption Systems, Advanced NanoTherapies, Aerwave Medical, Alivas, Amgen, Asahi Medical, Aurios Medical, Avantec Vascular, BD, Biosensors, Biotronik, Biotyx Medical, Bolt Medical, Boston Scientific, Canon, Cardiac Implants, Cardiawave, CardioMech, Cardionomic, Celonova, Cerus EndoVascular, Chansu Vascular Technologies, Childrens National, Concept Medical, Cook Medical, Cooper Health, Cormaze, CRL, Croivalve, Cardiovascular Systems, Inc. (CSI), Dexcom, Edwards Lifesciences, Elucid Bioimaging, eLum Technologies, Emboline, Endotronix, Envision, Filterlex, Imperative Care, Innovalve, Innovative, Cardiovascular Solutions, Intact Vascular, Interface Biologics, Intershunt Technologies, Invatin, Lahav, Limflow, L&J Bio, Lutonix, Lyra Therapeutics, Mayo Clinic, Maywell, MDS, MedAlliance, Medanex, Medtronic, Mercator, Microport, Microvention, Neovasc, Nephronyx, Nova Vascular, Nyra Medical, Occultech, Olympus, Ohio Health, OrbusNeich, Ossiso, Phenox, Pi-Cardia, Polares Medical, Polyvascular, Profusa, ProKidney, LLC, Protembis, Pulse Biosciences, Qool Therapeutics, Recombinetics, Recor Medical, Regencor, Renata Medical, Restore Medical, Ripple Therapeutics, Rush University, Sanofi, Shockwave, SMT, SoundPipe, Spartan Micro, Spectrawave, Surmodics, Terumo Corporation, The Jacobs Institute, Transmural Systems, Transverse Medical, TruLeaf, University of California, San Francisco (UCSF), University of Pittsburgh Medical Center (UPMC), Vascudyne, Vesper, Vetex Medical, Whiteswell, WL Gore, and Xeltis. A.V. Finn received honoraria from Abbott Vascular, Biosensors, Boston Scientific, Celonova, Cook Medical, CSI, Lutonix Bard, Sinomed, and Terumo Corporation and is a consultant for Amgen, Abbott Vascular, Boston Scientific, Celonova, Cook Medical, Lutonix Bard, and Sinomed. R. Virmani received honoraria from Abbott Vascular, Biosensors, Boston Scientific, Celonova, Cook Medical, Cordis, CSI, Lutonix Bard, Medtronic, OrbusNeich Medical, CeloNova, SINO Medical Technology, ReCore, Terumo Corporation, W. L. Gore, and Spectranetics and is a consultant for Celonova, Cook Medical, CSI, Edwards Lifesciences, Bard BD, Medtronic, OrbusNeich Medical, ReCor Medical, SinoMedical Sciences Technology, Surmodics, Terumo Corporation, W. L. Gore, and Xeltis. L. Guo is supported by NIH (grant HL141425) and the Leducq Foundation Grant. M. Mori, A. Sakamoto, and K. Kawai are supported by the Leducq Foundation Grant. The other authors report no conflicts.

Competing Interests: Disclosures A.V. Finn and R. Virmani have received institutional research support from 480 Biomedical, 4C Medical, 4Tech, Abbott, Accumedical, Amgen, Biosensors, Boston Scientific, Cagent Vascular, Cardiac Implants, CeloNova, Claret Medical, Concept Medical, Cook, Cardiovascular Systems, Inc, DuNing, Inc, Edwards LifeSciences, Emboline, Endotronix, Envision Scientific, Gateway, Leducq Foundation Grant, Lifetech, Limflo, Lutonix/Bard, MedAlliance, Medtronic, Mercator, Meril, Microport Medical, Microvention, Mitraalign, Mitra Assist, North American Science Associates, LLC, Nanova, Neovasc, National Institutes of Health (HL141425), Nipro, Novogate, Occlutech, OrbusNeich Medical, Phenox, Profusa, Protembis, Qool, Recor, Senseonics, Shockwave, Sinomed, Spectranetics, Surmodics, Symic, Vesper, W.L. Gore, and Xeltis. A.V. Finn has received honoraria from Abbott Vascular, Biosensors, Boston Scientific, Celonova, Cook Medical, CSI, Lutonix Bard, Sinomed, Terumo Corporation; and is a consultant to Amgen, Abbott Vascular, Boston Scientific, Celonova, Cook Medical, Lutonix Bard, and Sinomed. R. Virmani has received honoraria from Abbott Vascular, Biosensors, Boston Scientific, CeloNova, Cook Medical, Cordis, CSI, Lutonix Bard, Medtronic, OrbusNeich Medical, ReCor, Sino Medical Technology, Spectranetics, Terumo Corporation, and W.L. Gore, and is a consultant for Abbott Vascular, Boston Scientific, CeloNova, Cook Medical, Cordis, Cardiovascular Solutions, Inc, Edwards Lifesciences, Lutonix Bard, Medtronic, OrbusNeich Medical, ReCor, Sino Medical Sciences Technology, Spectranetics, Surmodics, Terumo Corporation, W.L. Gore, and Xeltis. The other authors report no conflicts.

Background: Laparoscopic colon surgery frequently requires performing maneuvers under mirror-images conditions; the complexity differs depending on the surgical site location in the abdominal cavity. However, no previous reports have examined this., Methods: Eleven surgeons participated in this study. Operations were performed on 25 points placed at the bottom and sides of a laparoscopic training box under mirror-image conditions. The mean time-point required to operate at each point and variation between surgeons were evaluated., Results: When the right hand was used, time-points to touch the right side-superficial ends were 0.50 to 0.58 and 0.27 to 0.45 for the other sites. With the left hand, time-points to touch the left side-superficial ends were 0.58 to 0.63 and 0.28 to 0.51 for the other sites, indicating that the most difficult manipulation was at the proximal site of the surgical port. The variation in the difficulty according to the spots increased with a decrease in the surgeon's experience (right hand, r =-0.248; left hand, r =-0.491)., Conclusions: In performing laparoscopic surgery under mirror-image conditions, the technical difficulty varies by location, and operating in locations close to the forceps port is the most difficult., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Bleeding rates on dual antiplatelet therapy (DAPT) within 1 month after percutaneous coronary intervention (PCI) remain high in clinical practice, particularly in patients with acute coronary syndrome or high bleeding risk. Aspirin-free strategy might result in lower bleeding early after PCI without increasing cardiovascular events, but its efficacy and safety have not yet been proven in randomized trials., Methods: We randomly assigned 6002 patients with acute coronary syndrome or high bleeding risk just before PCI either to prasugrel (3.75 mg/day) monotherapy or to DAPT with aspirin (81-100 mg/day) and prasugrel (3.75 mg/day) after loading of 20 mg of prasugrel in both groups. The coprimary end points were major bleeding (Bleeding Academic Research Consortium 3 or 5) for superiority and cardiovascular events (a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or ischemic stroke) for noninferiority with a relative 50% margin., Results: The full analysis set population consisted of 5966 patients (no-aspirin group, 2984 patients; DAPT group, 2982 patients; age, 71.6±11.7 years; men, 76.6%; acute coronary syndrome, 75.0%). Within 7 days before randomization, aspirin alone, aspirin with P2Y12 inhibitor, oral anticoagulants, and intravenous heparin infusion were given in 21.3%, 6.4%, 8.9%, and 24.5%, respectively. Adherence to the protocol-specified antiplatelet therapy was 88% in both groups at 1 month. At 1 month, the no-aspirin group was not superior to the DAPT group for the coprimary bleeding end point (4.47% and 4.71%; hazard ratio, 0.95 [95% CI, 0.75-1.20]; P superiority =0.66). The no-aspirin group was noninferior to the DAPT group for the coprimary cardiovascular end point (4.12% and 3.69%; hazard ratio, 1.12 [95% CI, 0.87-1.45]; P non inferiority =0.01). There was no difference in net adverse clinical outcomes and each component of coprimary cardiovascular end point. There was an excess of any unplanned coronary revascularization (1.05% and 0.57%; hazard ratio, 1.83 [95%CI, 1.01-3.30]) and subacute definite or probable stent thrombosis (0.58% and 0.17%; hazard ratio, 3.40 [95% CI, 1.26-9.23]) in the no-aspirin group compared with the DAPT group., Conclusions: The aspirin-free strategy using low-dose prasugrel compared with the DAPT strategy failed to attest superiority for major bleeding within 1 month after PCI but was noninferior for cardiovascular events within 1 month after PCI. However, the aspirin-free strategy was associated with a signal suggesting an excess of coronary events., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04609111., Competing Interests: Disclosures Dr Natsuaki reports honoraria from Abbott Medical Japan, Daiichi Sankyo, Medtronic, Terumo, Japan Lifeline, Asahi Intecc, Bristol-Myers Squibb, Otsuka, Amgen, Sanofi, Takeda and Bayer. Dr Watanabe reports personal fees from Abbott Medical Japan during the conduct of the study, and personal fees from Daiichi Sankyo, Kowa, Abiomed, Bayer, Pfizer, Bristol-Myers Squibb, and Otsuka, as well, outside the submitted work. Dr Morimoto reports lecturer’s fees from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Pfizer and Tsumura; manuscript fees from Bristol-Myers Squibb and Pfizer; advisory board for Novartis and Teijin. Dr Suwa reports personal fees from Abbott Medical Japan and Daiichi Sankyo outside the submitted work. Dr Ogita reports personal fees from Daiichi Sankyo, Abbott Medical Japan, and Japan Lifeline outside the submitted work. Dr Suzuki reports grants from Abbott Medical Japan during the conduct of the study. Dr Morishima reports honoraria from Abbott Medical Japan and Daiichi Sankyo. Dr Kimura reports grants from Abbott Medical Japan and Boston Scientific and being an advisory board member of Abbott Medical Japan and Terumo Japan. The remaining authors reported no conflicts.

Coronary artery calcification (CAC) accompanies the development of advanced atherosclerosis. Its role in atherosclerosis holds great interest because the presence and burden of coronary calcification provide direct evidence of the presence and extent of coronary artery disease; furthermore, CAC predicts future events independently of concomitant conventional cardiovascular risk factors and to a greater extent than any other noninvasive biomarker of this disease. Nevertheless, the relationship between CAC and the susceptibility of a plaque to provoke a thrombotic event remains incompletely understood. This review summarizes the current understanding and literature on CAC. It outlines the pathophysiology of CAC and reviews laboratory, histopathological, and genetic studies, as well as imaging findings, to characterize different types of calcification and to elucidate their implications. Some patterns of calcification such as microcalcification portend increased risk of rupture and cardiovascular events and may improve prognosis assessment noninvasively. However, contemporary computed tomography cannot assess early microcalcification. Limited spatial resolution and blooming artifacts may hinder estimation of degree of coronary artery stenosis. Technical advances such as photon counting detectors and combination with nuclear approaches (eg, NaF imaging) promise to improve the performance of cardiac computed tomography. These innovations may speed achieving the ultimate goal of providing noninvasively specific and clinically actionable information., Competing Interests: Disclosures Dr Libby is an unpaid consultant to, or involved in clinical trials for Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Moderna, Novo Nordisk, Novartis, Pfizer, and Sanofi-Regeneron. Dr Libby is a member of the scientific advisory board for Amgen, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Dewpoint Therapeutics, Eulicid Bioimaging, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, PlaqueTec, TenSixteen Bio, Soley Thereapeutics, and XBiotech, Inc. Dr Libby’s laboratory has received research funding in the last 2 years from Novartis, Novo Nordisk, and Genentech. Dr Libby is on the Board of Directors of XBiotech, Inc. Dr Libby has a financial interest in Xbiotech, a company developing therapeutic human antibodies, in TenSixteen Bio, a company targeting somatic mosaicism and clonal hematopoiesis of indeterminate potential (CHIP) to discover and develop novel therapeutics to treat age-related diseases, and in Soley Therapeutics, a biotechnology company that is combining artificial intelligence with molecular and cellular response detection for discovering and developing new drugs, currently focusing on cancer therapeutics. Dr Libby’s interests were reviewed and are managed by Brigham and Women’s Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. Dr Libby reports the following patents: Il-1beta binding antibodies for use in treating cancer (US20230220063A1 - Pending); and Treatment of brain ischemia-reperfusion injury (US20220041710A1 - Pending).

While coronary artery disease remains a major cause of death, it is preventable. Therefore, the focus needs to shift to the early detection and prevention of atherosclerosis. Asymptomatic atherosclerosis is widely termed subclinical atherosclerosis, which is an early indicator of atherosclerotic burden, and understanding this disease is important because timely intervention could prevent future cardiovascular morbidity and mortality. We histologically recognize the earliest lesion of atherosclerosis as pathological intimal thickening, which is characterized by the presence of lipid pools. The difference between clinical atherosclerosis and subclinical atherosclerosis is whether the presence of atherosclerosis results in the clinical symptoms of ischemia, such as stroke, myocardial infarction, or chronic limb-threatening ischemia. In the absence of thrombosis, there are various types of histological plaque that encompass subclinical atherosclerosis: pathological intimal thickening, fibroatheroma, thin-cap fibroatheroma, plaque rupture, healed plaque ruptures, and fibrocalcific plaque. Plaque morphology that is most frequently responsible for acute coronary thrombosis is plaque rupture. Calcification of coronary arteries is the hallmark of atherosclerosis and is a predictor of future coronary events. Atherosclerosis occurs in other vascular beds and is most frequent in arteries of the lower extremity, followed by carotid, aorta, and coronary arteries, and the mechanisms leading to clinical symptoms are unique for each location., Competing Interests: Disclosures A.V. Finn has received consultant fees/honoraria from Abbott Vascular, Amgen, Biosensors, Boston Scientific, Celonova, Cook Medical, CSI, Lutonix Bard, Sinomed, and Terumo Corporation. R. Virmani is a consultant of Abbott Vascular, Boston Scientific, Celonova, OrbusNeich Medical, Terumo Corporation, W. C Gore, Edwards Lifesciences, Cook Medical, CSI, Recor Medical, SinoMedical Sciences Technology, Surmodics, and Bard BD. K Kawai, R Virmani, and A.V. Finn are employees of the CVPath Institute which has received GranuResearch/Clinical Trial support from NIH-HL141425, Leducq Foundation Grant, 4C Medical, 4Tech, Abbott Vascular, Ablative Solutions. Absorption Systems, Advanced NanoTherapies, Aerwave Medical, Alivas, Amgen. Asahi Medical, Aurios Medical, Avantec Vascular, BD, Biosensors, Biotronik, Biotyx Medical, Bolt Medical, Boston Scientific, Canon USA, Cardiac Implants, Cardiawave, CardioMech, Celonova, Cerus EndoVascuIar, Chansu Vascular Technologies, Childrens National Medical Center, Concept Medical, Cook Medical, Cooper Health, Cormaze Technologies GmbH, CRL/AcceILab, Croivalue, CSI, Dexcom, Edwards Lifesciences, Elucid Bioimaging, eLum Technologies, Emboline, Endotronix, Envision, Filterlex, Imperative Care, Innovalve, Innovative Cardiovascular Solutions, Intact Vascular, Interface Biolgics, Intershunt Technologies, Invatin Technologies, Lahav CRO, Limflow, L&J Biosciences, Lutonix, Lyra Therapeutics, Mayo Clinic, Maywell, MD Start, MedAIIiance, Medanex, Medtronic, Mercator, Microport, Microvention, Neovasc, Nephronyx, Nova Vascular, Nyra Medical, Occultech, Olympus, Ohio Health, OrbusNeich, Ossio, Phenox, Pi-Cardia, Polares Medical, Polyvascular, Profusa, ProKidney LLC, Protembis, Pulse Biosciences, Qool Therapeutics, Recombinetics, Recor Medical, Regencor, Renata Medical, Restore Medical, Ripple Therapeutics, Rush University, Sanofi, Shockwave, Sahajanand Medical Technologies, SoundPipe, Spartan Micro, Spectrawave, Surmodics, Terumo Corporation, The Jacobs Institute, Transmural Systems, Transverse Medical, TruLeaf Medical, UCSF, UPMC, Vesper, Vetex Medical, Whiteswell, WL Gore, and Xeltis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the article apart from those disclosed.

Background: Polygenic risk scores (PRSs) for coronary artery disease (CAD) potentially improve cardiovascular risk prediction. However, their relationship with histopathologic features of CAD has never been examined systematically., Methods: From 4327 subjects referred to CVPath by the State of Maryland Office Chief Medical Examiner for sudden death between 1994 and 2015, 2455 cases were randomly selected for genotyping. We generated PRS from 291 known CAD risk loci. Detailed histopathologic examination of the coronary arteries was performed in all subjects. The primary study outcome measurements were histopathologic plaque features determining severity of atherosclerosis, including %stenosis, calcification, thin-cap fibroatheromas, and thrombotic CAD., Results: After exclusion of cases with insufficient DNA sample quality or with missing data, 954 cases (mean age, 48.8±14.7 years; 75.7% men) remained in the final study cohort. Subjects in the highest PRS quintile exhibited more severe atherosclerosis compared with subjects in the lowest quintile, with greater %stenosis (80.3%±27.0% versus 50.4%±38.7%; adjusted P <0.001) and a higher frequency of calcification (69.6% versus 35.8%; adjusted P =0.004) and thin-cap fibroatheroma (26.7% versus 9.5%; adjusted P =0.007). Even after adjustment for traditional CAD risk factors, subjects within the highest PRS quintile had higher odds of severe atherosclerosis (ie, ≥75% stenosis; adjusted odds ratio, 3.77 [95% CI, 2.10-6.78]; P <0.001) and plaque rupture (adjusted odds ratio, 4.05 [95% CI, 2.26-7.24]; P <0.001). Moreover, subjects within the highest quintile had higher odds of CAD-associated cause of death, especially among those aged ≤50 years (adjusted odds ratio, 4.08 [95% CI, 2.01-8.30]; P <0.001). No statistically significant associations were observed with plaque erosion after adjusting for covariates., Conclusions: This is the first autopsy study investigating associations between PRS and atherosclerosis severity at the histopathologic level in subjects with sudden death. Our pathological analysis suggests PRS correlates with plaque burden and features of advanced atherosclerosis and may be useful as a method for CAD risk stratification, especially in younger subjects., Competing Interests: Disclosures R. Virmani and A.V. Finn have received institutional research support from R01 HL141425 Leducq Foundation Grant; 480 Biomedical; 4C Medical; 4Tech; Abbott; Accumedical; Amgen; Biosensors; Boston Scientific; Cardiac Implants; Celonova; Claret Medical; Concept Medical; Cook; CSI; DuNing, Inc; Edwards LifeSciences; Emboline; Endotronix; Envision Scientific; Lutonix/Bard; Gateway; Lifetech; Limflo; MedAlliance; Medtronic; Mercator; Merill; Microport Medical; Microvention; Mitraalign; Mitra Assist; NAMSA; Nanova; Neovasc; NIPRO; Novogate; Occlutech; OrbusNeich Medical; Phenox; Profusa; Protembis; Qool; Recor; Senseonics, Shockwave; Sinomed; Spectranetics; Surmodics; Symic; Vesper; W.L. Gore; and Xeltis. A.V. Finn has received honoraria from Abbott Vascular; Biosensors; Boston Scientific; Celonova; Cook Medical; CSI; Lutonix Bard; Sinomed; and Terumo Corporation and is a consultant to Amgen; Abbott Vascular; Boston Scientific; Celonova; Cook Medical; Lutonix Bard; and Sinomed. R. Virmani has received honoraria from Abbott Vascular; Biosensors; Boston Scientific; Celonova; Cook Medical; Cordis; CSI; Lutonix Bard; Medtronic; OrbusNeich Medical; CeloNova; SINO Medical Technology; ReCore; Terumo Corporation; W. L. Gore; and Spectranetics and is a consultant to Abbott Vascular; Boston Scientific; Celonova; Cook Medical; Cordis; CSI; Edwards Lifescience; Lutonix Bard; Medtronic; OrbusNeich Medical; ReCore; Sinomededical Technology; Spectranetics; Surmodics; Terumo Corporation; W.L. Gore; and Xeltis. N. Sotoodehnia is supported by the Laughlin family endowment and the following NIH and foundation awards: R01HL141989 and AHA19SFRN348300063. The other authors report no conflicts.

Background: Studies in humans and mice using the expression of an X-linked gene or lineage tracing, respectively, have suggested that clones of smooth muscle cells (SMCs) exist in human atherosclerotic lesions but are limited by either spatial resolution or translatability of the model., Methods: Phenotypic clonality can be detected by X-chromosome inactivation patterns. We investigated whether clones of SMCs exist in unstable human atheroma using RNA in situ hybridization (BaseScope) to identify a naturally occurring 24-nucleotide deletion in the 3'UTR of the X-linked BGN (biglycan) gene, a proteoglycan highly expressed by SMCs. BGN -specific BaseScope probes were designed to target the wild-type or deletion mRNA. Three different coronary artery plaque types (erosion, rupture, and adaptive intimal thickening) were selected from heterozygous females for the deletion BGN . Hybridization of target RNA-specific probes was used to visualize the spatial distribution of mutants. A clonality index was calculated from the percentage of each probe in each region of interest. Spatial transcriptomics were used to identify differentially expressed transcripts within clonal and nonclonal regions., Results: Less than one-half of regions of interest in the intimal plaque were considered clonal with the mean percent regions of interest with clonality higher in the intimal plaque than in the media. This was consistent for all plaque types. The relationship of the dominant clone in the intimal plaque and media showed significant concordance. In comparison with the nonclonal lesions, the regions with SMC clonality had lower expression of genes encoding cell growth suppressors such as CD74 , SERF-2 (small EDRK-rich factor 2), CTSB (cathepsin B), and HLA-DPA1 (major histocompatibility complex, class II, DP alpha 1), among others., Conclusions: Our novel approach to examine clonality suggests atherosclerosis is primarily a disease of polyclonally and to a lesser extent clonally expanded SMCs and may have implications for the development of antiatherosclerotic therapies., Competing Interests: Disclosures R. Virmani and A.V. Finn have received institutional research support from the National Institutes of Health (HL141425), Leducq Foundation Grant, 480 Biomedical, 4C Medical, 4Tech, Abbott, Accumedical, Amgen, Biosensors, Boston Scientific, Cardiac Implants, Celonova, Claret Medical, Concept Medical, Cook, CSI, DuNing, Inc, Edwards LifeSciences, Emboline, Endotronix, Envision Scientific, Lutonix/Bard, Gateway, Lifetech, Limflo, MedAlliance, Medtronic, Mercator, Merill, Microport Medical, Microvention, Mitraalign, Mitra Assist, NAMSA, Nanova, Neovasc, NIPRO, Novogate, Occulotech, OrbusNeich Medical, Phenox, Profusa, Protembis, Qool, Recor, Senseonics, Shockwave, Sinomed, Spectranetics, Surmodics, Symic, Vesper, W.L. Gore, and Xeltis. A.V. Finn has received honoraria from Abbott Vascular, Biosensors, Boston Scientific, Celonova, Cook Medical, CSI, Lutonix Bard, Sinomed, and Terumo Corporation and is a consultant at Amgen, Abbott Vascular, Boston Scientific, Celonova, Cook Medical, Lutonix Bard, and Sinomed. R. Virmani has received honoraria from Abbott Vascular, Biosensors, Boston Scientific, Celonova, Cook Medical, Cordis, CSI, Lutonix Bard, Medtronic, OrbusNeich Medical, Celonova, SINO Medical Technology, ReCor, Terumo Corporation, W.L. Gore, and Spectranetics and is a consultant at Abbott Vascular, Boston Scientific, Celonova, Cook Medical, Cordis, CSI, Edwards Lifesciences, Lutonix Bard, Medtronic, OrbusNeich Medical, ReCor, Sinomededical Technology, Spectranetics, Surmodics, Terumo Corporation, W.L. Gore, and Xeltis. The other authors report no conflicts.

Background: The benefit of clopidogrel monotherapy after 1-month dual antiplatelet therapy (DAPT) compared with 12-month DAPT with aspirin and clopidogrel was demonstrated in the STOPDAPT-2 (Short and Optimal Duration of Dual Antiplatelet Therapy After Everolimus-Eluting Cobalt-Chromium Stent-2), but not in the STOPDAPT-2 acute coronary syndrome (ACS); however, both trials were underpowered based on the actual event rates., Methods: We obtained the prespecified pooled population of 5997 patients as the STOPDAPT-2 total cohort (STOPDAPT-2: N=3009/STOPDAPT-2 ACS: N=2988; ACS: N=4136/chronic coronary syndrome [CCS]: N=1861), comprising 2993 patients assigned to 1-month DAPT followed by clopidogrel monotherapy, and 3004 patients assigned to 12-month DAPT with aspirin and clopidogrel after percutaneous coronary intervention. The primary end point was the composite of cardiovascular (cardiovascular death, myocardial infarction, definite stent thrombosis, or any stroke) or bleeding (Thrombolysis in Myocardial Infarction major/minor) end points at 1 year., Results: One-month DAPT was noninferior to 12-month DAPT for the primary end point (2.84% versus 3.04%; hazard ratio [HR], 0.94 [95% CI, 0.70-1.27]; P noninferiority =0.001; P superiority =0.68). There was no significant risk-difference for the cardiovascular end point between the 1- and 12-month DAPT groups (2.40% versus 1.97%; HR, 1.24 [95% CI, 0.88-1.75]; P noninferiority =0.14; P superiority =0.23). There was a lower risk of the bleeding end point with 1-month DAPT relative to 12-month DAPT (0.50% versus 1.31%; HR, 0.38 [95% CI, 0.21-0.70]; P superiority =0.002). One-month DAPT relative to 12-month DAPT was associated with a lower risk for major bleeding regardless of ACS or CCS (ACS: HR, 0.46 [95% CI, 0.23-0.94]; P =0.03, and CCS: HR, 0.26 [95% CI, 0.09-0.79]; P =0.02; P interaction =0.40), while it was associated with a numerical increase in cardiovascular events in ACS patients, but not in CCS patients, although not statistically significant and without interaction (ACS: HR, 1.50 [95% CI, 0.99-2.27]; P =0.053, and CCS: HR, 0.74 [95% CI, 0.38-1.45]; P =0.39; P interaction =0.08)., Conclusions: Clopidogrel monotherapy after 1-month DAPT compared with 12-month DAPT with aspirin and clopidogrel had a benefit in reducing major bleeding events without being associated with increase in cardiovascular events., Registration: URL: https://www., Clinicaltrials: gov; Unique identifiers: NCT02619760, NCT03462498.

Abstract: Poor adherence to medication in patients with heart failure (HF) is associated with poor clinical outcomes. Although social support has been reported to improve medication adherence in patients with HF, the detailed underlying mechanism of this association is unclear. This study investigated appropriate social support types to ensure medication adherence, as well as patient characteristics that benefit from such social support in patients with HF. This was a retrospective observational study investigating the association of social support with medication adherence in 824 patients with HF who were registered in a prospective multicenter database. First, we analyzed the association between social support types and poor medication adherence leading to hospitalization. An interaction analysis was performed to detect patients' characteristics that benefited most from social support in terms of medical adherence. Fifty patients (6.1%) were hospitalized for poor adherence to medications. Multivariable analysis revealed that not receiving assisted living, which was defined as having supporting individuals at least once a week, was independently associated with poor medication adherence-related hospitalization. An interaction analysis revealed that patients with dementia benefited from assisted living significantly, whereas male patients or current smokers did not. Summarily, assisted living at least once a week was appropriate for improving medication adherence in patients with HF and was particularly effective in patients with dementia. Performed in a super-aging region in Japan, this study may also suggest the relevance of social support in preventing HF exacerbation in other developed countries that will experience an aging society in the near future., Competing Interests: H. Kitaoka reports the receipt of personal fees from Takeda Pharmaceutical Company, Ltd; Daiichi-Sankyo Company; Mitsubishi Tanabe Pharma Corporation, Ltd; and grants from Takeda Pharmaceutical Company, Ltd; Daiichi-Sankyo Company; Bayer Yakuhin, Ltd; Otsuka Pharmaceutical, Ltd; and Actelion Pharmaceuticals Japan, Ltd. The remaining authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Persistent postural-perceptual dizziness (PPPD) is a recently defined diagnostic syndrome characterized by chronic symptoms of dizziness, unsteadiness, and/or non-spinning vertigo. Although PPPD has been studied in adults, reports in the pediatric population are few. The goal of this study was to describe the presentation and treatment of PPPD in a group of pediatric patients., Study Design: Retrospective chart review., Setting: Tertiary referral center., Patients: ≤21 years old, who met Bárány Society consensus criteria for a diagnosis of PPPD and were followed for ≥6 months or until symptom resolution., Main Outcome Measuress: Patient demographics, comorbidities, symptom chronicity, and response to treatment(s)., Results: Of the 53 patients identified, 44 (83.0%) were women. Mean age at the time of initial evaluation was 14.6 years old. Common diagnoses in addition to PPPD included benign paroxysmal positional vertigo (64.2%), vestibular migraine (56.6%), and anxiety (28.3%). A high proportion of patients (43.4%) reported initially missing school or work due to their symptoms. Eighteen patients (34.0%) reported symptom resolution ranging from 2 to 48 months after diagnosis (median 9 mo). Of these patients, 15 of 18 attended physical therapy (PT), 11 of 18 attended cognitive behavioral therapy (CBT) and/or biofeedback therapy, and 10 of 18 took selective serotonin reuptake inhibitor (SSRI) medications, and 7 of 18 (40%) did a combination of all three therapies., Conclusion: PPPD can impact patients at a young age, and prolonged symptoms present a significant burden to children and adolescents, many of whom are unable to attend school. Treatments such as PT, CBT, and SSRI medication may be effective., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2021, Otology & Neurotology, Inc.)

Purpose: To investigate the effect of denoise processing by artificial intelligence (AI) on the optical coherence tomography angiography (OCTA) images in eyes with retinal lesions., Methods: Prospective, observational, cross-sectional study. Optical coherence tomography angiography imaging of a 3 × 3-mm area involving the lesions (neovascularization, intraretinal microvascular abnormality, and nonperfusion area) was performed five times using OCT-HS100 (Canon, Tokyo, Japan). We acquired AI-denoised OCTA images and averaging OCTA images generated from five cube scan data through built-in software. Main outcomes were image acquisition time and the subjective assessment by graders and quantitative measurements of original OCTA images, averaging OCTA images, and AI-denoised OCTA images. The parameters of quantitative measurements were contrast-to-noise ratio, vessel density, vessel length density, and fractal dimension., Results: We studied 56 eyes from 43 patients. The image acquisition times for the original, averaging, and AI-denoised images were 31.87 ± 12.02, 165.34 ± 41.91, and 34.37 ± 12.02 seconds, respectively. We found significant differences in vessel density, vessel length density, fractal dimension, and contrast-to-noise ratio (P < 0.001) between original, averaging, and AI-denoised images. Both subjective and quantitative evaluations showed that AI-denoised OCTA images had less background noise and depicted vessels clearly. In AI-denoised images, the presence of fictional vessels was suspected in 2 of the 35 cases of nonperfusion area., Conclusion: Denoise processing by AI improved the image quality of OCTA in a shorter time and allowed more accurate quantitative evaluation.

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Background: Although methods to overcome difficulties associated with mirror-image conditions have been investigated, the ideal spatial relationship among the operator line of sight, monitor location, and camera location remains unclear. Moreover, the best training method for improving laparoscopic surgical skills under varying operator line of sight, camera, and monitor positions is unknown. We aimed to investigate the role of laparoscopic training under mirror-image conditions in improving surgical efficiency and whether prior surgical experience affects such training., Methods: This prospective study was conducted at the Department of Surgical Oncology, Tokyo University, Japan. Twenty-five surgeons participated. Novice (n=14), trained (n=7), and expert (n=4) participants performed the simulated task in a box trainer while varying the positional relationships among the surgeons, camera, and monitor. Five patterns were repeatedly performed 5 times per day for 4 days over 2 weeks., Results: The most significant differences in terms of the time required to complete the task under mirror-image conditions among the 3 groups were on day 1 (novices: 185.8 s, trained: 79.7 s, and experts: 46.5 s, P=0.009). However, after 4 days of training, the corresponding times did not differ among the 3 groups (26.0, 30.7, and 23.1 s, respectively; P=0.415). Laparoscopic training was sufficiently effective under mirror-image conditions., Conclusions: Mirror-image surgical conditions provided the most difficult setting, because surgeons and assistants often became disoriented, and task performance was most degraded. However, just 4 days of training was found to be sufficient to overcome the difficulties encountered while performing laparoscopic procedures under mirror-image conditions., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: To precisely quantify retinal nonperfusion areas (NPAs) in branch retinal vein occlusion using widefield optical coherence tomography angiography (OCTA) and examine their association with neovascular complications., Methods: We enrolled 26 patients with treatment-naïve branch retinal vein occlusion and prospectively examined them for 12 months. After 3 monthly ranibizumab injections to treat macular edema, each patient underwent ultra-widefield (UWF) fluorescein angiography (FA) and OCTA. Ultra-widefield FA was additionally performed at Month 12. For UWF FA, the retinal NPA was measured using the equipment's built-in software. For OCTA, we used panoramic image montaged from 5 single 12 × 12 mm2 images and quantified the retinal NPA using a Gullstrand eye with a grid scale at each patient. Measurements were expressed in terms of actual values and disc area units., Results: The retinal NPAs as measured using single OCTA and panoramic OCTA were significantly associated with that measured using UWF FA (P < 0.001 for both). Retinal neovascularization lesions were observed in 4 (15.4%) of 26 eyes. For patients with accompanying neovascularization, the retinal NPA measured using UWF FA, single OCTA, and panoramic OCTA were 187.9 ± 39.5 mm2 (109.9 ± 21.4 disc area), 34.3 ± 13.7 mm2 (19.9 ± 7.7 disc area), and 106.6 ± 24.5 mm2 (62.4 ± 13.6 disc area), respectively, which were larger than for those without neovascularization (P < 0.001, 0.014, and <0.001, respectively)., Conclusion: Using widefield OCTA, we could quantify the retinal NPA of eyes with branch retinal vein occlusion. These could serve as valid references to assess the risk of neovascular complications.

Background: Safety and efficacy of clopidogrel monotherapy after very short dual antiplatelet therapy (DAPT) is uncertain in patients undergoing complex percutaneous coronary intervention (PCI)., Methods: We conducted a post hoc subgroup analysis based on the complexity of PCI in the STOPDAPT-2 trial (Short and Optimal Duration of Dual Antiplatelet Therapy-2), which randomly compared 1-month DAPT followed by clopidogrel monotherapy with 12-month DAPT after cobalt-chromium everolimus-eluting stent implantation. Complex PCI was defined as any of the following: 3 vessels treated, ≥3 stents implanted, ≥3 lesions treated, bifurcation with 2 stents, >60 mm total stent lengths, and target of chronic total occlusion. The primary end point was the composite of cardiovascular (cardiovascular death/myocardial infarction/definite stent thrombosis/stroke) and bleeding (TIMI [Thrombolysis in Myocardial Infarction] major/minor) end points. The major secondary end points were the cardiovascular and bleeding end points., Results: Among the 3009 study patients, there were 509 patients (16.9%) with complex PCI (1-month DAPT: N=245, and 12-month DAPT: N=264) and 2500 patients (83.1%) without complex PCI (1-month DAPT: N=1255, and 12-month DAPT: N=1245). There were no significant interactions between the complexity of PCI and the effects of 1-month DAPT versus 12-month DAPT on the primary end point (complex PCI: 1.67% versus 5.32%, hazard ratio, 0.30 [95% CI, 0.10–0.92], P=0.04, and noncomplex PCI: 2.50% versus 3.35%, hazard ratio, 0.75 [95% CI, 0.47–1.20], P=0.23; Pinteraction=0.14), and on the major secondary cardiovascular end point (complex PCI: 1.67% versus 3.04%, hazard ratio, 0.54 [95% CI, 0.16–1.79], P=0.31, and noncomplex PCI: 2.02% versus 2.39%, hazard ratio, 0.86 [95% CI, 0.50–1.47], P=0.58; Pinteraction=0.49). The cumulative 1-year incidence of the major secondary bleeding end point was significantly lower in the 1-month DAPT group than in the 12-month DAPT group regardless of the complexity of PCI (complex PCI: 0% versus 2.29%, log-rank P=0.02, and noncomplex PCI: 0.48% versus 1.38%, log-rank P=0.02)., Conclusions: The effects of clopidogrel monotherapy after 1-month DAPT relative to 12-month DAPT for the primary and major secondary end points were comparable in complex PCI and noncomplex PCI without significant interactions., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02619760.

Objective: Determine the safety and efficacy of balloon dilation of the Eustachian tube (ET) in pediatric patients., Study Design: Retrospective matched cohort study., Setting: Tertiary medical center., Patients: Pediatric patients (<18 yr) with persistent (>1.5 yr) chronic Eustachian tube dysfunction (ETD) with previous tympanostomy tube (TT) insertion versus matched controls., Interventions: Balloon dilation of the cartilaginous ET (BDET) was performed using concomitant myringotomy with/without tube placement and adjunctive procedures if indicated versus controls (TT)., Main Outcome Measures: Otitis media with effusion (OME)/retraction with need for additional tube, tympanogram, audiogram, otomicroscopy, ET mucosal inflammation/opening score, and Valsalva maneuver., Results: Forty six ETs (26 patients), ages 7 to 17 years (mean 12.5) underwent BDET. Mean follow-up was 2.3 years (standard deviation [SD], 1.1; range, 6 mo-5 yr). Significant improvements were observed for all measures. Tympanic membranes were healthy in 9% preoperatively, 38% at 6 months, 55% at 12 months, and 93% at 36 months postoperatively. Tympanograms improved to type A in 50% at 6 months, 59% at 12 months, and 85% at 36 months. Mean scores of mucosal inflammation declined from 3.2 (±0.6) preoperatively to 2.5 (±0.7) at 6 months and 1.7 (±0.6) at 36 months postoperatively. BDET had lower risk of failure versus TT insertion (adjusted hazard ratio [HR] 0.26; 95% confidence interval [CI]: 0.10, 0.70; p = 0.007). Probability of being failure free at 2 years was 87% (95% CI: 70, 94%) after BDET and 56% (95% CI: 40, 70%) after TT insertions., Conclusions: BDET is a safe and possibly effective procedure in selected pediatric patients with chronic ETD., Competing Interests: Conflicts of Interest: Author D.P. is a consultant for Acclarent. For the remaining authors none were declared., (Copyright © 2020, Otology & Neurotology, Inc.)

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Abstract: One-stage resections of primary colorectal cancer and liver metastases have been reported to be feasible and safe. Minimally invasive approaches have become more common for both colorectal and hepatic surgeries. This study aimed to investigate outcomes of these combined surgical procedures among different approaches.We retrospectively analyzed patients diagnosed as having primary colorectal cancer with synchronous liver metastases and who underwent 1-stage primary resection and hepatectomy with curative intent in our hospital. According to the surgical approach for the primary tumor and hepatic lesions, namely open laparotomy (Op) or laparoscopic approach (Lap), patients were classified into Op-Op, Lap-Op (laparoscopic colorectal resection plus open hepatectomy), and Lap-Lap groups, respectively. Clinicopathological factors were reviewed, and short- and long-term outcomes were compared among the groups.The Op-Op, Lap-Op, and Lap-Lap groups comprised 36, 18, and 17 patients, respectively. The superior/posterior hepatic segments were more frequently resected via an open approach. There was no laparoscopic major hepatectomy. The median volume of intraoperative blood loss was smaller in the Lap-Lap and Lap-Op groups (290 and 270 mL) than in the Op-Op group (575 mL, P = .008). The hospital stay after surgery was shorter in the Lap-Lap and Lap-Op groups (median: 17 days and 15 days, vs 19 days for the Op-Op group, P = .033). The postoperative complication rates and survivals were similar among the groups.Application of laparoscopy to 1-stage resections of primary colorectal cancer and liver metastases may offer advantages of enhanced recovery from surgical treatment, given appropriate patient selection., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Cardiac injury is common in patients who are hospitalized with coronavirus disease 2019 (COVID-19) and portends poorer prognosis. However, the mechanism and the type of myocardial damage associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain uncertain., Methods: We conducted a systematic pathological analysis of 40 hearts from hospitalized patients dying of COVID-19 in Bergamo, Italy, to determine the pathological mechanisms of cardiac injury. We divided the hearts according to presence or absence of acute myocyte necrosis and then determined the underlying mechanisms of cardiac injury., Results: Of the 40 hearts examined, 14 (35%) had evidence of myocyte necrosis, predominantly of the left ventricle. Compared with subjects without necrosis, subjects with necrosis tended to be female, have chronic kidney disease, and have shorter symptom onset to admission. The incidence of severe coronary artery disease (ie, >75% cross-sectional narrowing) was not significantly different between those with and without necrosis. Three of 14 (21.4%) subjects with myocyte necrosis showed evidence of acute myocardial infarction, defined as ≥1 cm 2 area of necrosis, whereas 11 of 14 (78.6%) showed evidence of focal (>20 necrotic myocytes with an area of ≥0.05 mm 2 but <1 cm 2 ) myocyte necrosis. Cardiac thrombi were present in 11 of 14 (78.6%) cases with necrosis, with 2 of 14 (14.2%) having epicardial coronary artery thrombi, whereas 9 of 14 (64.3%) had microthrombi in myocardial capillaries, arterioles, and small muscular arteries. We compared cardiac microthrombi from COVID-19-positive autopsy cases to intramyocardial thromboemboli from COVID-19 cases as well as to aspirated thrombi obtained during primary percutaneous coronary intervention from uninfected and COVID-19-infected patients presenting with ST-segment-elevation myocardial infarction. Microthrombi had significantly greater fibrin and terminal complement C5b-9 immunostaining compared with intramyocardial thromboemboli from COVID-19-negative subjects and with aspirated thrombi. There were no significant differences between the constituents of thrombi aspirated from COVID-19-positive and -negative patients with ST-segment-elevation myocardial infarction., Conclusions: The most common pathological cause of myocyte necrosis was microthrombi. Microthrombi were different in composition from intramyocardial thromboemboli from COVID-19-negative subjects and from coronary thrombi retrieved from COVID-19-positive and -negative patients with ST-segment-elevation myocardial infarction. Tailored antithrombotic strategies may be useful to counteract the cardiac effects of COVID-19 infection.

Global autobiographical amnesia is a rare disorder that is characterized by a sudden loss of autobiographical memories covering many years of an individual's life. Generally, routine neuroimaging studies such as CT and MRI yield negative findings in individuals with global autobiographical amnesia. However, in recent case reports, functional analyses such as SPECT and fMRI have revealed changes in activity in various areas of the brain when compared with controls. Studies using iomazenil (IMZ) SPECT with individuals with global autobiographical amnesia have not been reported. We report the case of a 62-year-old Japanese woman with global autobiographical amnesia who had disappeared for ∼4 weeks. [123I]-IMZ SPECT showed reduced IMZ uptake in her left medial temporal lobe and no significant reduction on N-isopropyl-[123I] p-iodoamphetamine (IMP) SPECT in the identical region. Because IMZ binds to the central benzodiazepine receptor, this dissociation between IMZ and IMP SPECT was thought to reflect the breakdown of inhibitory neurotransmission in the left medial temporal lobe. Moreover, when the woman recovered most of her memory 32 months after fugue onset, the IMZ SPECT-positive lesion had decreased in size. Because the woman had long suffered verbal abuse from her former husband's sister and brother, which can also cause global autobiographical amnesia, it is difficult to conclude whether the IMZ SPECT-positive lesion in the left medial temporal lobe was the cause or the result of her global autobiographical amnesia. Although only one case, these observations suggest that IMZ SPECT may be useful in uncovering the mechanisms underlying global autobiographical amnesia., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Perineural invasion (PNI) is a prognostic factor in patients with colorectal cancer. Neurotrophic factors, molecular determinants of PNI, are altered in their expression levels in patients with ulcerative colitis. In this study, we evaluated the frequency of PNI in colitis-associated cancer (CAC) and sporadic cancer.We retrospectively reviewed 778 colorectal cancers with pathological T3-T4 in 761 patients all of whom were surgically resected without preoperative treatment. The lesions were classified into either CAC or sporadic cancer based on the clinical information. Clinicopathological findings including PNI were compared between CACs and sporadic cancers. Moreover, we analyzed the risk factors for positive PNI by multivariate analysis using a logistic regression model.Ten of the cancers (1.3%) were diagnosed as CACs, and the remaining 768 as sporadic cancers. CACs were characterized by being nonobstructive and predominantly located in the rectum. The CACs had a larger size and more frequent undifferentiated histology than sporadic cancers. PNI was observed more frequently in CACs (90%) than in sporadic cancers without obstruction (45%, P = .007). On multivariate analysis, CAC was one of the significant factors associated with PNI (odds ratio: 9.05, P = .040).Our results suggest that CAC was more likely to exhibit PNI than sporadic colorectal cancer.

Inflammatory pain hypersensitivity is associated with activation of primary afferent neurons. This study investigated the existence of the inflammasome in dorsal root ganglion (DRG) and the functional significance in the development of inflammatory pain hypersensitivity. Tissue inflammation was induced in male C57BL/6 mice with complete Freund's adjuvant (CFA) or ceramide injection into the hind paw. Behavioral testing was performed to investigate inflammation-induced pain hypersensitivity. Ipsilateral L5 DRGs were obtained for analysis. Expression of nucleotide oligomerization domain-like receptors (NLRs) was analyzed with real-time PCR. Cleaved interleukin (IL)-1β and NLRP2 expression was investigated with immunohistochemistry and western blotting. Caspase 1 activity was also measured. A caspase 1 inhibitor and NLRP2 siRNA were intrathecally administered to inhibit NLRP2 inflammasome signaling in DRG. Cleaved IL-1β expression was significantly increased after CFA injection in small-sized DRG neurons. The amount of cleaved IL-1β and caspase 1 activity were also increased. Among several NLRs, NLRP2 mRNA was significantly increased in DRG after CFA injection. NLRP2 was expressed in small-sized DRG neurons. Intrathecal injection of a caspase 1 inhibitor or NLRP2 siRNA reduced CFA-induced pain hypersensitivity and cleaved IL-1β expression in DRG. Induction of cleaved IL-1β and NLRP2 in DRG neurons was similarly observed after ceramide injection. NLRP2 siRNA inhibited ceramide-induced pain hypersensitivity. These results confirmed the existence of NLRP2 inflammasome in DRG neurons. Activation of the NLRP2 inflammasome leads to activation of DRG neurons and subsequent development of pain hypersensitivity in various types of tissue inflammation.

Background: The optimal cutoff value of fractional flow reserve (FFR) derived from coronary computed tomography angiography (FFR CT ) remains unclear., Methods: The current study population consisted of 93 patients with 139 vessels, who had suspected coronary artery disease by computed tomography angiography and underwent invasive FFR. We evaluated diagnostic performance of FFR CT according to different FFR CT cutoff values and FFR CT ranges with invasive FFR ≤0.80 as the reference standard., Results: In per-vessel analysis, median invasive FFR was 0.85 (interquartile range, 0.75-0.90), and 57 out of 139 vessels (41%) showed hemodynamically significant stenosis (≤0.80). Median FFR CT was 0.77 (interquartile range, 0.66-0.84; mean difference [invasive FFR-FFR CT ], 0.06±0.11). Per-vessel accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 73%, 95%, 59%, 61%, and 94% for the cutoff value of FFR CT ≤0.80, 81%, 86%, 78%, 73%, and 89% for FFR CT ≤0.75, and 83%, 74%, 89%, 82%, and 83% for FFR CT ≤0.70, respectively. Per-vessel accuracy across the different ranges of FFR CT ≤0.60, 0.61 to 0.70, 0.71 to 0.80, 0.81 to 0.90, and >0.90 with the cutoff value of FFR CT ≤0.80 were 95%, 74%, 32%, 93%, and 100%, respectively. Setting a gray zone of FFR CT 0.71 to 0.80 provided high positive predictive value (82%; n=42/51) in the range of FFR CT ≤0.70 and high negative predictive value (94%; n=48/51) in FFR CT >0.80., Conclusions: This study suggested that referral to invasive coronary angiography should be considered individually in the range of FFR CT 0.71 to 0.80, whereas dichotomous decision could be made in FFR CT ≤0.70 and >0.80. Future prospective studies evaluating clinical outcomes are needed to establish optimal FFR CT -based diagnostic algorithm.

Objective: To investigate whether arginine methylation is altered in patients with amyotrophic lateral sclerosis (ALS) and how it affects disease severity, progression, and prognosis., Methods: We compared the immunoreactivity of protein arginine methyltransferase 1 (PRMT1) and its products, asymmetric dimethylated proteins (ASYM), in postmortem spinal cord. We also measured the concentrations of total l-arginine and methylated arginine residues, including asymmetric dimethyl l-arginine (ADMA), symmetric dimethyl arginine, and monomethyl arginine, in CSF samples from 52 patients with ALS using liquid chromatography-tandem mass spectrometry, and we examined their relationship with the progression and prognosis of ALS., Results: The immunoreactivity of both PRMT1 ( p < 0.0001) and ASYM ( p = 0.005) was increased in patients with ALS. The concentration of ADMA in CSF was substantially higher in patients with ALS than in disease controls. The ADMA/l-arginine ratio was correlated with the change of decline in the ALS Functional Rating Scale at 12 months after the time of measurement ( r = 0.406, p = 0.010). A Cox proportional hazards model showed that the ADMA/l-arginine ratio was an independent predictor for overall survival. Moreover, a high ADMA/l-arginine ratio predicted poor prognosis, even in a group with normal percentage forced vital capacity., Conclusion: There was an enhancement of arginine dimethylation in patients with ALS, and the ADMA/l-arginine ratio predicted disease progression and prognosis in such patients., (© 2019 American Academy of Neurology.)

Rationale: The prevalence of anastomotic recurrence (AR) in colorectal cancer (CRC) after resection of the primary tumor (PT) is 5% to 14%. However, no association has been observed between specific somatic genetic alterations and AR. Such associations may shed light on the mechanism of AR., Patient Concerns: We experienced 2 patients with AR of CRC. The first patient was a 42-year-old woman who underwent resection of an AR of rectal cancer 2 times within 19 months after resection of the PT. The second patient was a 77-year-old woman who underwent resection of an AR of ascending colon cancer twice within 38 months after resection of the PT., Diagnosis: Both cases were diagnosed as repetitive AR., Interventions: Loss of heterozygosity analysis, microsatellite instability (MSI) study of 9 microsatellite loci, and mutational analysis of KRAS, BRAF, APC, TP53, and SMAD4 were performed., Outcomes: All the lesions, except 1, harbored mutations in APC, KRAS, and TP53, without MSI, after neoadjuvant chemoradiotherapy. The APC, KRAS, and TP53 mutations were pathogenic or likely pathogenic in the PTs and ARs. Both women harbored the same KRAS G13D mutation, which accounts for 8% of all KRAS mutations in sporadic CRC s. The probability of the incidental occurrence of KRAS G13D mutations in both cases is 0.64%, provided that the mutations were independent of AR., Lessons: Our findings may shed light on the mechanism of AR in CRC, namely, that the PT harbored the same mutations as the AR and the lesions in both cases harbored the KRAS G13D mutation.

Background: Despite recommendations in the guidelines and consensus documents, there has been no randomized controlled trial evaluating oral anticoagulation (OAC) alone without antiplatelet therapy (APT) in patients with atrial fibrillation and stable coronary artery disease beyond 1 year after coronary stenting., Methods: This study was a prospective, multicenter, open-label, noninferiority trial comparing OAC alone to combined OAC and single APT among patients with atrial fibrillation beyond 1 year after stenting in a 1:1 randomization fashion. The primary end point was a composite of all-cause death, myocardial infarction, stroke, or systemic embolism. The major secondary end point was a composite of the primary end point or major bleeding according to the International Society on Thrombosis and Haemostasis classification. Although the trial was designed to enroll 2000 patients during 12 months, enrollment was prematurely terminated after enrolling 696 patients in 38 months., Results: Mean age was 75.0±7.6 years, and 85.2% of patients were men. OAC was warfarin in 75.2% and direct oral anticoagulants in 24.8% of patients. The mean CHADS 2 score was 2.5±1.2. During a median follow-up interval of 2.5 years, the primary end point occurred in 54 patients (15.7%) in the OAC-alone group and in 47 patients (13.6%) in the combined OAC and APT group (hazard ratio, 1.16; 95% CI, 0.79-1.72; P=0.20 for noninferiority, P=0.45 for superiority). The major secondary end point occurred in 67 patients (19.5%) in the OAC-alone group and in 67 patients (19.4%) in the combined OAC and APT group (hazard ratio, 0.99; 95% CI, 0.71-1.39; P=0.016 for noninferiority, P=0.96 for superiority). Myocardial infarction occurred in 8 (2.3%) and 4 (1.2%) patients, whereas stroke or systemic embolism occurred in 13 (3.8%) and 19 (5.5%) patients, respectively. Major bleeding occurred in 27 (7.8%) and 36 (10.4%) patients, respectively., Conclusions: This randomized trial did not establish noninferiority of OAC alone to combined OAC and APT in patients with atrial fibrillation and stable coronary artery disease beyond 1 year after stenting. Because patient enrollment was prematurely terminated, the study was underpowered and inconclusive. Future larger studies are required to establish the optimal antithrombotic regimen in this population., Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01962545.

Background: We recently reported anti-CD40 monoclonal antibody and rapamycin (aCD40/rapa) to be a reliable, nontoxic, immunosuppressive regimen for combined islet and kidney transplantation (CIKTx) in nonhuman primates. In the current study, we attempted to induce allograft tolerance through the mixed chimerism approach using a conditioning regimen with aCD40 and belatacept (Bela)., Methods: Five CIKTx or kidney transplant alone recipients were treated with aCD40/rapa for 4 months. All recipients then received a conditioning regimen including horse antithymocyte globulin and aCD40/Bela. The results were compared with previous reports of recipients treated with Bela-based regimens., Results: All 3 CIKTx recipients developed mixed chimerism, which was significantly superior to that observed in the previous Bela-based studies. Nevertheless, all CIKTx recipients in this study lost their islet and renal allografts as a result of cellular and humoral rejection on days 140, 89, and 84. The 2 kidney transplant-alone recipients were treated with the same conditioning regimen and suffered rejection on days 127 and 116, despite the development of excellent chimerism. B lymphocyte reconstitution dominated by memory phenotypes was associated with early development of donor-specific antibodies in 4 of 5 recipients. In vitro assays showed no donor-specific regulatory T cell expansion, which has been consistently observed in tolerant recipients with our mixed chimerism approach., Conclusions: Despite displaying excellent immunosuppressive efficacy, costimulatory blockade with anti-CD40 monoclonal antibody (2C10R4) may inhibit the induction of renal or islet allograft tolerance via a mixed chimerism approach.

Background: Cephalometric analysis has long been, and still is one of the most important tools in evaluating craniomaxillofacial skeletal profile. To perform this, manual tracing of x-ray film and plotting landmarks have been required. This procedure is time-consuming and demands expertise. In these days, computerized cephalometric systems have been introduced; however, tracing and plotting still have to be done on the monitor display. Artificial intelligence is developing rapidly. Deep learning is one of the most evolving areas in artificial intelligence. The authors made an automated landmark predicting system, based on a deep learning neural network., Methods: On a personal desktop computer, a convolutional network was built for regression analysis of cephalometric landmarks' coordinate values. Lateral cephalogram images were gathered through the internet and 219 images were obtained. Ten skeletal cephalometric landmarks were manually plotted and coordinate values of them were listed. The images were randomly divided into 153 training images and 66 testing images. Training images were expanded 51 folds. The network was trained with the expanded training images. With the testing images, landmarks were predicted by the network. Prediction errors from manually plotted points were evaluated., Results: Average and median prediction errors were 17.02 and 16.22 pixels. Angles and lengths in cephalometric analysis, predicted by the neural network, were not statistically different from those calculated from manually plotted points., Conclusion: Despite the variety of image quality, using cephalogram images on the internet is a feasible approach for landmark prediction.

Background: Allogeneic adipose-derived mesenchymal stem cells (ADSC) are promising cell sources for cell therapy to treat ischemic cardiomyopathy (ICM). We hypothesized that ADSC transplantation via the new cell spray method may be a feasible, safe, and effective treatment for ICM., Methods: Human ADSCs were acquired from white adipose tissue. Porcine ICM models were established by constriction of the left anterior descending coronary artery. Adipose-derived mesenchymal stem cells were spread over the surface of the heart via cell spray in fibrinogen and thrombin solutions. The cardiac function was compared with that of the control group., Results: Adipose-derived mesenchymal stem cells were successfully transplanted forming a graft-like gel film covering the infarct myocardium. Premature ventricular contractions were rarely detected in the first 3 days after transplantation. Echocardiography and magnetic resonance imaging revealed improved cardiac performance of the ADSC group at 4 and 8 weeks after transplantation. Systolic and diastolic parameters were significantly greater in the ADSC group at 8 weeks after transplantation. Histological examination showed significantly attenuated left ventricular remodeling and a greater vascular density in the infarct border area in the ADSC group. Moreover, the coronary flow reserve was maintained, and expression levels of angiogenesis-related factors in the infarct border and remote areas were significantly increased., Conclusions: Spray method implantation of allogenic ADSCs can improve recovery of cardiac function in a porcine infarction model. This new allogenic cell delivery system may help to resolve current limitations of invasiveness and cost in stem cell therapy.

Objectives: Drugs are mainly metabolized by hepatic enzymes, the activity of which can differ between individuals. Although it is ideal to measure the hepatic clearance of liver-targeted drugs in individualized medicine, blood enzyme tests typically measure metabolic drug clearance in the entire body, and not just in the liver. We investigated whether I-iomazenil imaging can directly assess and quantify the activity of hepatic drug-metabolizing enzymes., Materials and Methods: Hepatic enzymes that metabolize I-iomazenil were identified by thin-layer chromatography in mouse liver homogenates with bis(4-nitrophenyl) phosphate (BNPP) inhibitor for carboxylesterase enzymes and nicotinamide adenine dinucleotide phosphate (NADPH) generator for cytochrome P450 enzymes. Whole-body images of mice were acquired using I-iomazenil with and without BNPP, and the distribution was also obtained. The metabolism of I-iomazenil in the blood, liver, gall bladder, and bladder was investigated by thin-layer chromatography., Results: From the in-vitro metabolism of I-iomazenil using BNPP, the enzyme converting I-iomazenil to I-R-COOH was identified as carboxylesterase, and that converting I-iomazenil to M2 was identified as cytochrome P450 in experiments with and without an NADPH generator. The biological distribution and whole-body imaging showed increased accumulation in the liver of mice administered BNPP compared with normal mice, but decreased levels in the gall bladder and small intestine. The main fraction in bile and urine was I-R-COOH, with two unknown metabolites (M1 and M2), I, and I-iomazenil also being present., Conclusion: I-iomazenil whole-body imaging has good possibility of direct measurement of hepatic carboxylesterase activity as accumulation of I-R-COOH in the gall bladder through bile and in the bladder through urine.

Identification of secondary colonic neoplasia proximal to obstructing colorectal cancer is essential for determining the range of colorectal resection.We examined the accuracy of 18-fluoro deoxy glucose-positron emission tomography (FDG-PET) for detection of colonic neoplasia.We recruited patients with obstructing colorectal cancer from our registry. Preoperative FDG-PET was performed, and the detection rate for colonic neoplasia was estimated. Preoperative colonoscopy or postoperative colonoscopy within a year after operation was employed as the indexed standard.Ninety-three patients were included in this study. Colonic neoplasia proximal to obstruction was confirmed in 83 cases. The sensitivity and positive predictive value of FDG-PET were 25.3% and 77.8%, respectively. The sensitivity was higher in larger lesions (3.2% for <5 mm, 29.4% for 6-10 mm, 45.5% for 11-20 mm, and 71.4% for >21 mm) and in higher pathological grade lesions (14.6% for low-grade adenoma, 38.5% for high-grade adenoma, 66.7% for carcinoma in situ, and 100% for invasive carcinoma). The round shape in PET images was a predictor for neoplasia, with an area under the curve of 0.75293 at an aspect ratio of 1.70.FDG-PET should be used as a screening modality for invasive colorectal cancer (CRC) proximal to obstructing colorectal cancer.

Objective: We aimed to clarify the prognostic impact of primary tumor location on recurrence after curative surgery and subsequent survival in patients with nonmetastatic colon cancer., Summary of Background Data: Right and left colon cancers are suggested to be oncologically different; however, their prognostic differences have been conflictingly reported., Methods: A total of 5664 patients with curatively resected stage II-III colon cancer were reviewed, retrospectively. Relapse-free survival (RFS) after primary surgery and cancer-specific survival (CSS) after recurrence were compared between patients with right and left colon cancer. Patients' backgrounds were matched using propensity scores., Results: Although patients with right colon cancer had more advanced disease, their 5-year RFS rate was significantly superior compared with that in those with left colon cancer (83.9% vs 81.1%, P = 0.019). However, the 5-year CSS after recurrence rate was significantly inferior in patients with right colon cancer compared with that in those with left colon cancer (30.6% vs 43.6%, P = 0.016)., Conclusions: The primary tumor location of nonmetastatic colon cancer might have different prognostic implications for the rates of recurrence after curative resection and cancer-specific mortality after recurrence.

Background: Acute wound healing is a dynamic process that results in the formation of scar tissue. The mechanisms of this process are not well understood; numerous signaling pathways are thought to play a major role. Here, the authors have identified β-catenin-dependent Wnt signaling as an early acute-phase reactant in acute wound healing and scar formation., Methods: The authors created 6-mm full-thickness excisional cutaneous wounds on adult β-catenin-dependent Wnt signal (BAT-gal) reporter mice. The expression of canonical Wnt after wounding was analyzed using X-gal staining and quantitative real-time polymerase chain reaction. Next, recombinant mouse Wnt3a (rmWnt3a) was injected subcutaneously to the wound edge, daily. The mice were killed at stratified time points, up to 15 days after injury. Histologic analysis, quantitative real-time polymerase chain reaction, and Western blot were performed., Results: Numerous individual Wnt ligands increased in expression after wounding, including Wnt3a, Wnt4, Wnt10a, and Wnt11. A specific pattern of Wnt activity was observed, localized to the hair follicle and epidermis. Mice injected with rmWnt3a exhibited faster wound closure, increased scar size, and greater expression of fibroblast growth factor receptor-2 and type I collagen., Conclusions: The authors' data suggest that β-catenin-dependent Wnt signaling expression increases shortly after cutaneous wounding, and exogenous rmWnt3a accelerates reepithelialization, wound matrix maturation, and scar formation. Future experiments will focus on the intersection of Wnt signaling and other known profibrotic cytokines.

Objective: To determine if discussing cochlear implantation (CI) with patients with enlarged vestibular aqueducts (EVA) and their families before reaching audiological criteria for CI candidacy effects the length of time between reaching audiological candidacy and CI surgery, and to describe the universal newborn hearing screening (UNHS) results and communication modality in this sample., Patients: Forty-two patients (25 females) with confirmed EVA and cochlear implants., Intervention(s): Diagnostic CI visit., Main Outcome Measures: The primary outcome measure is the difference in length of time between reaching audiological candidacy for CI and surgical implantation between those who had preliminary discussions regarding CI with their medical and healthcare providers before reaching audiological candidacy versus who had discussions after reaching candidacy. The secondary outcome measure is the result of the UNHS and primary mode of communication used by each patient., Results: Discussing CI before reaching audiological candidacy was associated with a significantly shorter duration between reaching audiological candidacy and receiving CI (median = 3.1 mo; interquartile range [IQR] = 1.7-5.4) as compared with discussing CI after reaching candidacy (median = 5.8 mo; IQR = 3.2-11.2; p = 0.012). Participants born after the implementation of the UNHS, 16 of 24 patients referred on one or both ears. Communication modalities were evenly divided between utilizing sign-support English and oral/aural communicators only., Conclusions: Discussion of CI in patients with EVA before reaching audiological candidacy reduces the amount of time the child is without adequate auditory access and contributes to a constructive and interactive preparatory experience.

Objective: Psychosocial stress may influence the risk of disease through its association with oxidative DNA damage. We examined whether perceived stress and depressive symptoms were associated with urinary excretion of 8-hydroxydeoxyguanosine (8-OHdG), with mutual interaction on 8-OHdG., Methods: This cross-sectional study included 6517 individuals aged 45 to 74 years who participated, between 2010 and 2012, in a follow-up survey of an ongoing cohort study. Perceived stress during the past year was measured using a self-report questionnaire. Depressive symptoms were evaluated using the Zung Self-Rating Depression Scale. Urinary 8-OHdG concentrations were measured using a column switching high-pressure liquid chromatography system coupled to an electrochemical detector., Results: Higher perceived stress was significantly associated with higher 8-OHdG (2.1% increase per one-category increase of stress; ptrend = .025), even after adjusting for sex, age, supplement use, psychosocial factors, psychotropic medication use, smoking, and body mass index. This association was modestly attenuated after further adjustment for physical activity, suggesting possible mediation or confounding by this factor. Depressive symptoms were not significantly associated with 8-OHdG. No significant interaction was detected between perceived stress and depressive symptoms on 8-OHdG., Conclusions: In a general Japanese population, we found a weak positive association between perceived stress and urinary excretion of 8-OHdG, whereas no association was observed between depressive symptoms and 8-OHdG. Further studies are needed to examine whether the association between perceived stress and 8-OHdG is modified by depressive symptoms.

Background: Retinal and optic disc perfusion in nonarteritic anterior ischemic optic neuropathy (NAION) is incompletely understood. Our aim was to investigate the characteristics of the microvascular structures at the peripapillary area and optic disc, and their associations with retinal structure and function in patients with NAION., Methods: We conducted a prospective, observational case series study. Thirty-four eyes, consisting of 15 NAION eyes and 19 normal eyes, were included. Optical coherence tomography (OCT) angiography was used to measure the vessel densities in the peripapillary superficial retina and whole-depth mode inside the optic disc. Measurement of circumpapillary retinal nerve fiber layer (cpRNFL) thickness was performed using OCT. Sectorial division analysis of cpRNFL was performed by eliminating the influences of the difference in disc rotation between OCT images and OCT angiography images., Results: The vessel densities of peripapillary retina and inside the optic disc were significantly reduced in the NAION compared to the normal (both P < 0.001). Both the severity of visual field defect and cpRNFL thinning were significantly associated with the peripapillary vessel density (P = 0.006, P = 0.046), but not with the optic disc vessel density (P = 0.981, P = 0.856). cpRNFL and peripapillary vessel density showed reduction predominantly in the superior sectors, corresponding to the visual field defect. However, the correlations showed discrepancy of the sectors., Conclusions: The microvascular structures in the peripapillary retina and optic disc were reduced, but the cpRNFL thinning was associated with vessel density only in the peripapillary retina, indicating that the vessel densities in the peripapillary retina and optic disc may be differently affected in the pathological process of NAION.

Little is known about the relationships between patient factors and the antihyperglycemic agents that have been prescribed as initial therapy by diabetes specialists for patients with type 2 diabetes. Moreover, there has been little clarification of the subsequent usage patterns and related factors that influenced the continuation or discontinuation of the drug or the addition of another drug. To provide information on these issues, we evaluated the clinical characteristics of Japanese patients with type 2 diabetes for whom different types of oral hypoglycemic agents (i.e., either sulfonylureas, biguanides, or DPP-4 inhibitors (DPP-4Is)) were chosen as initial monotherapy by diabetes specialists and evaluated subsequent usage patterns.Prescription data on 3 different antidiabetic agents from December 2009 to March 2015 from diabetes specialists' patient registries were used to identify variables at baseline related to initial prescriptions; also, the addition of another hypoglycemic drug or discontinuation of the initial therapy was evaluated 1 year after the initial prescription. Analyzed were data on 2666 patients who received initial monotherapy with either a sulfonylurea (305 patients), biguanide (951 patients), or DPP-4I (1410 patients). Patients administered sulfonylureas were older, had a lower body mass index (BMI), longer duration of diabetes, and worse glycemic control than recipients of biguanides. Use of biguanides was related to younger age, short duration of diabetes, and obesity but was negatively associated with poor glycemic control. Older age but neither obesity nor poor glycemic control was associated with DPP-4Is. In all 3 groups a high HbA1c value was related to adding another hypoglycemic agent to the initial therapy. Moreover, adding another drug to a DPP-4I was related to a younger age and higher BMI.Patients' age, duration of diabetes, obesity, and glycemic control at baseline influenced the choice of hypoglycemic agents. Selection of a biguanide differs greatly from that of a sulfonylurea or DPP-4I with regard to age and obesity.

Objective: To construct a predictive model of postoperative colorectal neoplasm development using a nomogram., Background: Although patients with colorectal cancer (CRC) are known to be at high risk of developing metachronous adenoma or CRC, no statistical model for predicting the incidence of postoperative colorectal lesions has been reported., Methods: A total of 309 CRC patients who underwent surgical resection received regular endoscopic follow-up to detect the development of metachronous adenoma or adenocarcinoma. The patients were divided into the derivation set (n = 209) and the validation set (n = 100). The nomogram to predict the 3- and 5-year adenoma-free survival rates was constructed using the derivation set, and a calibration plot and concordance index (c-index) were calculated. The predictive utility of the nomogram was validated in the validation set., Results: Sex, age, and number of synchronous lesions at the time of surgery for primary CRC were adopted as variables for the nomogram. The nomogram showed moderate calibration, with a c-index of 0.709 in the derivation set and 0.712 in the validation set., Conclusions: A nomogram based on sex, age, and number of synchronous lesions at the time of surgery has the ability to predict postoperative adenoma-free survival.

The aim of this study was to clarify patient factors contributing to complications after laparoscopic surgery for colorectal cancers. A total of 333 colorectal cancer patients who underwent laparoscopic colorectal resection between January 2007 and December 2012 were enrolled. The association between patient factors and the incidence of complications were analyzed. Postoperative complications were divided into 2 categories: infectious complications and noninfectious complications. The overall complication rate was 13% and mortality rate 0%. Multivariate analysis showed that body mass index >25 kg/m [odds ratio (OR)=3.02, P=0.0254] and tumor location (right colon cancer/rectal cancer: OR=0.11, P=0.0083) were risk factors for infectious complications; in addition, male sex (OR=3.91, P=0.0102) and cancer stage (stage 2/stage 4: OR=0.17, P=0.0247) were risk factors for noninfectious complications. This study shows that different patient factors are associated with the risk of different types of complications.

This article evaluates the suitability of cadavers embalmed by the saturated salt solution (SSS) method for surgical skills training (SST). SST courses using cadavers have been performed to advance a surgeon's techniques without any risk to patients. One important factor for improving SST is the suitability of specimens, which depends on the embalming method. In addition, the infectious risk and cost involved in using cadavers are problems that need to be solved. Six cadavers were embalmed by 3 methods: formalin solution, Thiel solution (TS), and SSS methods. Bacterial and fungal culture tests and measurement of ranges of motion were conducted for each cadaver. Fourteen surgeons evaluated the 3 embalming methods and 9 SST instructors (7 trauma surgeons and 2 orthopedists) operated the cadavers by 21 procedures. In addition, ultrasonography, central venous catheterization, and incision with cauterization followed by autosuture stapling were performed in some cadavers. The SSS method had a sufficient antibiotic effect and produced cadavers with flexible joints and a high tissue quality suitable for SST. The surgeons evaluated the cadavers embalmed by the SSS method to be highly equal to those embalmed by the TS method. Ultrasound images were clear in the cadavers embalmed by both the methods. Central venous catheterization could be performed in a cadaver embalmed by the SSS method and then be affirmed by x-ray. Lungs and intestines could be incised with cauterization and autosuture stapling in the cadavers embalmed by TS and SSS methods. Cadavers embalmed by the SSS method are sufficiently useful for SST. This method is simple, carries a low infectious risk, and is relatively of low cost, enabling a wider use of cadavers for SST.

Synthetic artificial dura mater materials, such as expanded polytetrafluoroethylene sheets, are widely used in dura mater reconstruction in cases involving brain tumors or trauma surgery. In patients with postoperative infection related to the use of artificial dura mater, surgical debridement of the infected wound and removal of the artificial dura mater materials are necessary to control infection. In cases involving cerebrospinal fluid leakage, dura mater reconstruction must be performed immediately. Many useful techniques for performing dura mater reconstruction to treat postoperative infection have been reported; however, some have drawbacks with respect to the need for microvascular anastomosis or difficulties in obtaining watertight closure. We successfully treated 6 patients with postoperative artificial dura mater infection using free thigh fascia lata. Some surgeons believe that the use of free fascia in infected wounds is dangerous because free fascia is a non-vascularized tissue. However, performing complete debridement and covering such free fascia with well-vascularized tissue allow the fascia to become vascularized and tolerant of infection. Therefore, if the blood flow in the scalp is acceptable after a sufficient debridement, free fascia lata can be used for reconstruction in patients with postoperative infection of artificial dura mater. Furthermore, skull reconstruction can be performed safely and easily with solid-type artificial bone, sometimes combined with tissue expansion, thus resulting in good aesthetic outcomes.

Temporomandibular joint dislocation is not frequently encountered, but it is often difficult to reduce the dislocation with conventional methods described in textbooks. The key points to success of reduction depend on the patient's position, route of approach, and timing of reducing each side. We apply a manipulation technique for disk displacement to the reduction that corresponds to these key points. Using our method, temporomandibular joint dislocation can be easily reduced, without using sedative or analgesics. This method is simple, convenient, and worth trying in place of the conventional method.

Objective: Depression and sleep apnea (SA) are common among patients with a recent acute myocardial infarction (AMI), and both are associated with increased risk for adverse outcomes. We tested the hypothesis that there is an interaction between them in relation to post-AMI prognosis., Methods: Participants were patients with a recent AMI, 337 of them were depressed and 379 were nondepressed, who participated in a substudy of the Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial. SA was identified from Holter electrocardiogram by an algorithm that detects cyclic variation of heart rate., Results: During a median follow-up of 25 months, 83 (11.6%) patients either died or experienced a recurrent AMI and 43 (6.0%) patients died. Among 94 patients with both depression and SA, these end points occurred in 25 (26.6%) and 20 (21.3%) at 3.9- and 6.9-times higher prevalence than predicted probabilities by ENRICHD clinical risk scores (p <.001 for both). In the patients with depression alone, SA alone, or neither, the prevalence was similar to the predicted probability. Depression and SA showed significant interactions in prediction of these end points (p = .02 and p = .03). SA independently predicted these end points in patients with depression (p = .001 and p <.001) but not in those without depression (p = .84 and p = .73). Similarly, depression independently predicted these end points in patients with SA (p <.001 for both) but not in those without SA (p = .12 and p = .61)., Conclusions: Depression and SA are interactively associated with adverse clinical outcomes after AMI., Trial Registration: clinicaltrials.gov Identifier: NCT00313573.

Background: Several recent randomized trials comparing everolimus-eluting stent (EES) and sirolimus-eluting stent (SES) reported similar outcomes. However, only 1 trial was powered for a clinical end point, and no trial was powered for evaluating target-lesion revascularization., Methods and Results: Randomized Evaluation of Sirolimus-eluting versus Everolimus-eluting stent Trial is a prospective multicenter randomized open-label trial comparing EES with SES in Japan. The trial was powered for evaluating noninferiority of EES relative to SES in terms of target-lesion revascularization. From February and July 2010, 3197 patients were randomly assigned to receive either EES (1597 patients) or SES (1600 patients). At 1 year, the primary efficacy end point of target-lesion revascularization occurred in 65 patients (4.3%) in the EES group and in 76 patients (5.0%) in the SES group, demonstrating noninferiority of EES to SES (P(noninferiority)<0.0001, and P(superiority)=0.34). Cumulative incidence of definite stent thrombosis was low and similar between the 2 groups (0.32% versus 0.38%, P=0.77). An angiographic substudy enrolling 571 patients (EES, 285 patients and SES, 286 patients) demonstrated noninferiority of EES relative to SES regarding the primary angiographic end point of in-segment late loss (0.06±0.37 mm versus 0.02±0.46 mm, P(noninferiority)<0.0001, and P(superiority)=0.24) at 278±63 days after index stent implantation., Conclusions: One-year clinical and angiographic outcome after EES implantation was noninferior to and not different from that after SES implantation in a stable coronary artery disease population with relatively less complex coronary anatomy. One-year clinical outcome after both EES and SES use was excellent with a low rate of target-lesion revascularization and a very low rate of stent thrombosis., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035450.