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Secondary, or functional, mitral regurgitation (FMR) was recently recognized as a separate clinical entity, complicating heart failure with reduced ejection fraction (HFrEF) and entailing particularly poor outcome. Currently, there is a lack of targeted therapies for FMR due to the fact that pathomechanisms leading to FMR progression are incompletely understood. In this study, we sought to perform metabolomic profiling of HFrEF patients with severe FMR, comparing results to patients with no or mild FMR.Targeted plasma metabolomics and untargeted eicosanoid analyses were performed in samples drawn from HFrEF patients (n = 80) on optimal guideline-directed medical therapy. Specifically, 17 eicosanoids and 188 metabolites were analysed. Forty-seven patients (58.8%) had severe FMR, and 33 patients (41.2%) had no or non-severe FMR. Comparison of eicosanoid levels between groups, accounting for age, body mass index, and sex, revealed significant up-regulation of six eicosanoids (11,12-EET, 13(R)-HODE, 12(S)-HETE, 8,9-DiHETrE, metPGJ2, and 20-HDoHE) in severe FMR patients. Metabolites did not differ significantly. In patients with severe FMR, but not in those without severe FMR, levels of 8,9-DiHETrE above a cut-off specified by receiver-operating characteristic analysis independently predicted all-cause mortality after a median follow-up of 43 [interquartile range 38, 48] months [hazard ratio 12.488 (95% confidence interval 3.835-40.666), P 0.0001].We report the up-regulation of various eicosanoids in patients with severe FMR, with 8,9-DiHETrE appearing to predict mortality. Our observations may serve as a nucleus for further investigations into the causes and consequences of metabolic derangements in this important valvular abnormality.

AIMS: To develop a suite of quality indicators (QIs) for the evaluation of the care and outcomes for adults with pulmonary arterial hypertension (PAH). METHODS AND RESULTS: We followed the European Society of Cardiology (ESC) methodology for the development of QIs. This included (i) the identification of key domains of care for the management of PAH, (ii) the proposal of candidate QIs following systematic review of the literature, and (iii) the selection of a set of QIs using a modified Delphi method. The process was undertaken in parallel with the writing of the 2022 ESC/European Respiratory Society (ERS) guidelines for the diagnosis and treatment of pulmonary hypertension and involved the Task Force chairs, experts in PAH, Heart Failure Association (HFA) members and patient representatives. We identified five domains of care for patients with PAH: structural framework, diagnosis and risk stratification, initial treatment, follow-up, and outcomes. In total, 23 main and one secondary QIs for PAH were selected. CONCLUSION: This document presents the ESC QIs for PAH, describes their development process and offers scientific rationale for their selection. The indicators may be used to quantify and improve adherence to guideline-recommended clinical practice and improve patient outcomes. ispartof: EUROPEAN JOURNAL OF HEART FAILURE vol:25 issue:4 pages:469-477 ispartof: location:England status: published

The petrosal lobules (in whole or part homologous with the paraflocculi) of the cerebellum regulate functions associated with vision including smooth pursuit and velocity control of eye movements, suggesting a possible relationship between the petrosal lobules and behavioral adaptation. Previous studies have produced diverging conclusions regarding the lobules' ecological signal. The current study examines lobule scaling within an ecologically diverse but phylogenetically constrained sample of extant mammals to determine whether ecology influences relative petrosal lobule size. Using the endocasts of 140 Euarchontoglires (Primates, Scandentia, Dermoptera, Lagomorpha, Rodentia), petrosal lobule size was evaluated relative to endocranium and body size, accounting for phylogenetic relationships and ecology (locomotor behavior, diet, activity pattern). Results show a strong positive relationship between lobule size and both endocranial volume and body mass. Phylogeny is a major factor in the scaling of the petrosal lobules, with significant differences in relative size identified between orders and suborders. Concerning ecology, fossorial taxa were found to have significantly smaller petrosal lobules relative to body mass compared to other locomotor groups across Euarchontoglires. The small lobules possessed by this group may reflect an adaptation related to reduced visual reliance. In contrast to previous research, no relationship was identified between relative lobule size and any other ecological variables. While variation in relative lobule size may be adaptively significant in some groups (i.e., fossorial species), it is critical to study the evolution of petrosal lobule size within a narrow phylogenetic scope, with inclusion of fossil material to inform our understanding of evolutionary trajectories.

Although therapeutic options for patients with advanced renal cell carcinoma (RCC) have increased in the past decade, no biomarkers are yet available for patient stratification or evaluation of therapy resistance. Given the dynamic and heterogeneous nature of clear cell RCC (ccRCC), tumor biopsies provide limited clinical utility, but liquid biopsies could overcome these limitations. Prior liquid biopsy approaches have lacked clinically relevant detection rates for patients with ccRCC. This study employed ccRCC‐specific markers, CAIX and CAXII, to identify circulating tumor cells (CTC) from patients with metastatic ccRCC. Distinct subtypes of ccRCC CTCs were evaluated for PD‐L1 and HLA‐I expression and correlated with patient response to therapy. CTC enumeration and expression of PD‐L1 and HLA‐I correlated with disease progression and treatment response, respectively. Longitudinal evaluation of a subset of patients demonstrated potential for CTC enumeration to serve as a pharmacodynamic biomarker. Further evaluation of phenotypic heterogeneity among CTCs is needed to better understand the clinical utility of this new biomarker., Circulating tumor cells (CTCs) were evaluated for their expression of programmed death ligand‐1 (PD‐L1) and human leukocyte antigen class I (HLA‐I), so that biomarkers of therapeutic resistance of clear cell renal cell carcinoma can be developed. CTCs were captured with antibody‐conjugated magnetic beads against EpCAM and CAIX then probed for CAXII and CK expression using microfluidic technology.

Hintergrund: Bisher fehlen robuste epidemiologische Kennzahlen sowie Daten zur Komorbidität bei Kindern mit Urtikaria. Sie bilden die Grundlage zur Gestaltung einer effizienten Gesundheitsversorgung. Methodik: Retrospektive Studie zur Analyse von epidemiologischen Kennzahlen bei Kindern mit Urtikaria. Grundlage der Analyse sind Routinedaten einer deutschlandweit tätigen Krankenkasse (DAK-Gesundheit). Versicherte unter 18 Jahren, die in den Jahren 2010-2015 mindestens eine ambulant oder stationär gestellte Urtikaria-Diagnose gemäß der ICD-10-Klassifikation erhielten, wurden in die Analysen aufgenommen und mit Kindern ohne entsprechende Diagnose verglichen. Ergebnisse: Von 2,3 Millionen Versicherten waren 313 581 (13,5 %) unter 18 Jahre (153 214 weiblich). Bei 1,7 % der 313 581 Patienten wurde Urtikaria diagnostiziert. Die administrative Prävalenz der Urtikaria nahm mit zunehmendem Alter von 3,0 % in der Altersgruppe der 0-3-Jährigen auf 1,0 % bei den 14-18-Jährigen ab. Jungen und Mädchen waren in allen Altersgruppen fast gleich häufig betroffen. Atopische Erkrankungen als Komorbidität traten bei Kindern mit Urtikaria häufiger auf als in der Kontrollgruppe (16,0 % vs. 8,0 %). Auch Autoimmunerkrankungen, psychische Probleme und Adipositas traten bei Kindern mit Urtikaria häufiger auf als in der Kontrollgruppe. Schlussfolgerungen: Die erhöhte administrative Prävalenz spezifischer Komorbidität bei Kindern mit Urtikaria deutet auf einen erhöhten Screening-Bedarf hin. Es gilt, multimodale Behandlungsstrategien zu entwickeln und interdisziplinäre Zusammenarbeit zu fördern.

Background To date, robust epidemiological metrics as well as data on comorbidity in pediatric urticaria are lacking. They form the basis for the design of efficient healthcare. Methods Retrospective study to analyze epidemiological data in pediatric urticaria. The analysis is based on routine data of a health insurance company operating throughout Germany (DAK-Gesundheit). Insured people under 18 years of age who received at least one confirmed outpatient or inpatient urticaria diagnosis according to the ICD-10 classification in the years 2010 to 2015 were included in the analysis and compared to children without a corresponding diagnosis. Results Of 2.3 million insured individuals, 313,581 (13.5 %) were under 18 years of age (153,214 female). Urticaria was diagnosed in 1.7 % of the 313,581 patients. The prevalence of urticaria decreased with age from 3.0 % in the 0-3-year age group to 1.0 % in the 14-18-year age group. Boys and girls were almost equally affected in all age groups. Atopic diseases as comorbidity occurred more frequently in children with urticaria than in the control group (16.0 % vs. 8.0 %). Autoimmune diseases, mental health problems, and obesity also occurred more frequently in children with urticaria than in the control group. Conclusions The increased prevalence of specific comorbidities in children with urticaria suggests an increased need for screening. Multimodal treatment strategies need to be developed and interdisciplinary collaboration promoted.

BACKGROUND Late gadolinium enhancement (LGE) imaging in patients with implantable cardioverter-defibrillators (ICD) is limited by device-related artifacts (DRA). The use of wideband (WB) LGE protocols improves LGE images, but their efficacy with different ICD types is not well known. PURPOSE To assess the effects of WB LGE imaging on DRA in different non-MR conditional ICD subtypes. STUDY TYPE Retrospective. POPULATION A total of 113 patients undergoing cardiac magnetic resonance imaging with three ICD subtypes: transvenous (TV-ICD, N = 48), cardiac-resynchronization therapy device (CRT-D, N = 48), and subcutaneous (S-ICD, N = 17). FIELD STRENGTH/SEQUENCE 5 T scanner, standard LGE, and WB LGE imaging with a phase-sensitive inversion recovery segmented gradient echo sequence. ASSESSMENT DRA burden was defined as the number of artifact-positive short-axis LGE slices as percentage of the total number of short-axis slices covering the left ventricle from based to apex, and was determined for WB and standard LGE studies for each patient. Additionally, artifact area on each slice was quantified. STATISTICAL TESTS Shapiro-Wilks, Kruskal-Wallis analysis of variance, Dunn tests with Bonferroni correction, and Mann-Whitney U-test. RESULTS In patients with TV-ICD, DRA burden was significantly reduced and nearly eliminated with WB LGE compared to standard LGE imaging (median [interquartile range]: 0 [0-7]% vs. 18 [0-50]%, P

AIM To assess in a cross-sectional clinical study the effect of antibiotics on the diversity, structure and metabolic pathways of bacterial communities in various oral environments in patients with acute primary infections. METHODOLOGY Samples of saliva (SA), supragingival biofilm (SB) and from the pulp cavity (PC) were collected from teeth with acute primary infections and then grouped according to previous use of antibiotics (NoAtb = no antibiotics [n = 6]; Atb = antibiotics [n = 6]). DNA sequencing was conducted using MiSeq (Illumina, San Diego, CA, USA). The V1-V3 hyper-variable region of the 16S rRNA gene was amplified. A custom Mothur pipeline was used for 16S rRNA processing. Subsequent analyses of the sequence dataset were performed in R (using vegan, phyloseq and ggplot2 packages) or QIIME. RESULTS Twelve patients aged from 22 to 56 years were recruited. Participants in the Atb group had taken the beta-lactamics amoxicillin (5/6) or cephalexin (1/6) for 2-3 days. A total of 332 bacterial taxa (OTUs) were identified, belonging to 120 genera, 60 families and nine phyla. Firmicutes (41%) and Bacteroidetes (38%) were the most abundant phyla in all samples. Taxa clustered significantly by oral site (PCoA analysis; P

Centrosome amplification (CA) is a common phenomenon in cancer, promotes genomic stability and cancer evolution, and has been reported to promote metastasis. CA promotes a stochastic gain/loss of chromosomes during cell division, known as chromosomal instability (CIN). However, it is unclear whether CA is present in circulating tumor cells (CTCs), the seeds for metastasis. Here, we surveyed CA in CTCs from human subjects with metastatic breast cancer. CTCs were captured by CD45 exclusion and selection of EpCAM‐positive cells using an exclusion‐based sample preparation technology platform known as VERSA (versatile exclusion‐based rare sample analysis). Centriole amplification (centrin foci> 4) is the definitive assay for CA. However, determination of centrin foci is technically challenging and incompatible with automated analysis. To test if the more technically accessible centrosome marker pericentrin could serve as a surrogate for centriole amplification in CTCs, cells were stained with pericentrin and centrin antibodies to evaluate CA. This assay was first validated using breast cancer cell lines and a nontransformed epithelial cell line model of inducible CA, then translated to CTCs. Pericentrin area and pericentrin area x intensity correlate well with centrin foci, validating pericentrin as a surrogate marker of CA. CA is found in CTCs from 75% of subjects, with variability in the percentage and extent of CA in individual circulating cells in a given subject, similar to the variability previously seen in primary tumors and cell lines. In summary, we created, validated, and implemented a novel method to assess CA in CTCs from subjects with metastatic breast cancer. Such an assay will be useful for longitudinal monitoring of CA in cancer patients and in prospective clinical trials for assessing the impact of CA on response to therapy., Circulating tumor cells (CTCs) are a rare population of cancer cells released into peripheral circulation from primary and metastatic cancer sites. Centrosome amplification (CA) has been reported in virtually all human cancers and has been shown to make cells more invasive. In this study, we develop an assay to detect CA in CTCs. We find that CA is prevalent in CTCs from subjects with metastatic breast cancer.

The International Classification of Diseases (ICD) provides a common language for use worldwide as a diagnostic and classification tool for epidemiology, clinical purposes and health management. Since its first edition, the ICD has maintained a framework distributing conditions according to topography, with the result that some complex conditions, such as allergies and hypersensitivity disorders (A/H) including anaphylaxis, have been poorly represented. The change in hierarchy in ICD-11 permitted the construction of the pioneer section addressed to A/H, which may result in more accurate mortality and morbidity statistics, including more accurate accounting for mortality due to anaphylaxis, strengthen classification, terminology and definitions. The ICD-11 was presented and adopted by the 72nd World Health Assembly in May 2019 and the implementation is ongoing worldwide. We here present the outcomes from an online survey undertaken to reach out the allergy community worldwide in order to peer review the terminology, classification and definitions of A/H introduced into ICD-11 and to support their global implementation. Data are presented here for 406 respondents from 74 countries. All of the sub-sections of the new A/H section of the ICD-11 had been considered with good accuracy by the majority of respondents. We believe that, in addition to help during the implementation phase, all the comments provided will help to improve the A/H classification and to increase awareness by different disciplines of what actions are needed to ensure more accurate epidemiological data and better clinical management of A/H patients.

Background The pediatric Appropriate Use Criteria (AUC) for outpatient transthoracic echocardiography (TTE) aim to reduce practice variation. Little is known on variation in TTE use between physicians. Understanding this variation will help identify areas for improvement in standardization of TTE use. Methods and results This is a retrospective review of initial outpatient visits at 6 pediatric cardiology centers in the United States prior to AUC release. Variation in TTE use was examined using multilevel generalized mixed effects models. Forward selection identified combinations of variables that explained the most variance in TTE use between physicians. Due to collinearity, physician compensation model and center were analyzed separately. Of 2883 encounters, the most common indication was murmur (36%), followed by chest pain (15.2%). Overall TTE use was 41.9%, and varied widely between centers (22.9%-52.6%), and between physicians within centers. Center alone explained 29% of this physician variance. Adding physician characteristics increased the variance explained to 57%, which only minimally improved by adding patient characteristics. The variance explained was driven by subspecialty. The center-based multivariable model explained more variance over compensation model. Conclusions Center was the single largest determinant of physician variance in TTE use, followed by physician subspecialty. Efforts to reduce practice variation, such as the AUC, should be employed across centers and all pediatric cardiac providers. Center appears to have a stronger impact on variance than compensation model, though in this dataset the effect of center and compensation are hard to separate from each other and deserve further evaluation.

Catalytic CO methanation represents an important reaction to improve the feed gas quality for hydrogen fuel cells. Previously, the large potential of small bare and ligated ruthenium clusters as highly selective and active catalysts has been shown by employing gas phase clusters as model systems. Now, density functional theory (DFT) calculations are employed to demonstrate the possibility to translate the gas phase CO methanation reaction mediated by a ligated Ru-4(CO)(13)H-2(+) complex into the framework of a ZSM-5 zeolite. Such a translation, manifested by a reaction pathway which is mechanistically and energetically similar to the gas phase analogue, is possible since the zeolite framework does not influence the reactive center. Furthermore, we reveal the important role of the CO ligand environment in protecting the Ru-4(+) metal core from formation of bonds with the zeolite and in the creation of the reactive center by promoting the cooperatively enhanced adsorption and dissociation of H-2.

Species’ responses at the genetic level are key to understanding the long-term consequences of anthropogenic global change. Herbaria document such responses, and, with contemporary sampling, provide high-resolution time-series of plant evolutionary change. Characterizing genetic diversity is straightforward for model species with small genomes and a reference sequence. For nonmodel species—with small or large genomes—diversity is traditionally assessed using restriction-enzyme-based sequencing. However, age-related DNA damage and fragmentation preclude the use of this approach for ancient herbarium DNA. Here, we combine reduced-representation sequencing and hybridization-capture to overcome this challenge and efficiently compare contemporary and historical specimens. Specifically, we describe how homemade DNA baits can be produced from reduced-representation libraries of fresh samples, and used to efficiently enrich historical libraries for the same fraction of the genome to produce compatible sets of sequence data from both types of material. Applying this approach to both Arabidopsis thaliana and the nonmodel plant Cardamine bulbifera, we discovered polymorphisms de novo in an unbiased, reference-free manner. We show that the recovered genetic variation recapitulates known genetic diversity in A. thaliana, and recovers geographical origin in both species and over time, independent of bait diversity. Hence, our method enables fast, cost-efficient, large-scale integration of contemporary and historical specimens for assessment of genome-wide genetic trends over time, independent of genome size and presence of a reference genome.

The metabolic syndrome is a cluster of conditions that increase an individual's risk of developing diseases. Being physically active throughout life is known to reduce the prevalence and onset of some aspects of the metabolic syndrome. Furthermore, previous studies have demonstrated that an individual's gut microbiome composition has a large influence on several aspects of the metabolic syndrome. However, the mechanism(s) by which physical activity may improve metabolic health are not well understood. We sought to determine if endurance exercise is sufficient to prevent or ameliorate the development of the metabolic syndrome and its associated diseases. We also analyzed the impact of physical activity under metabolic syndrome progression upon the gut microbiome composition. Utilizing whole‐body low‐density lipoprotein receptor (LDLR) knockout mice on a “Western Diet,” we show that long‐term exercise acts favorably upon glucose tolerance, adiposity, and liver lipids. Exercise increased mitochondrial abundance in skeletal muscle but did not reduce liver fibrosis, aortic lesion area, or plasma lipids. Lastly, we observed several changes in gut bacteria and their novel associations with metabolic parameters of clinical importance. Altogether, our results indicate that exercise can ameliorate some aspects of the metabolic syndrome progression and alter the gut microbiome composition., In this study, we sought to determine if endurance exercise is sufficient to prevent or ameliorate the development of metabolic syndrome and its associated diseases and the impact of physical activity under metabolic syndrome progression upon the gut microbiome. Utilizing the whole‐body low‐density lipoprotein receptor (LDLR) knockout mice on a “Western Diet,” we show that long‐term exercise acts favorably upon glucose tolerance, adiposity, and liver lipids. Our results indicate that exercise can ameliorate some aspects of the metabolic syndrome progression and alter the gut microbiome.

Interest in trauma-informed approaches has grown substantially. These approaches are characterized by integrating understanding of trauma throughout a program, organization, or system to enhance the quality, effectiveness, and delivery of services provided to individuals and groups. However, variation in definitions of trauma-informed approaches, coupled with underdeveloped research on measurement, poses challenges for evaluating the effectiveness of models designed to support a trauma-informed approach. This systematic review of peer-reviewed and gray literature identified 49 systems-based measures that were created to assess the extent to which relational, organizational, and community/system practices were trauma-informed. Measures were included if they assessed at least one component of a trauma-informed approach, were not screening or diagnostic instruments, were standardized, were relevant to practices addressing the psychological impacts of trauma, were printed in English, and were published between 1988 and 2018. Most (77.6%) measures assessed organizational-level staff and climate characteristics. There remain several challenges to this emerging field, including inconsistently reported psychometric data, redundancy across measures, insufficient evidence of a link to stakeholder outcomes, and limited information about measurement development processes. We discuss these opportunities and challenges and their implications for future research and practice.

Background Despite the increasing use of potent P2Y12 inhibitors, further atherothrombotic events still impair the prognosis of many acute coronary syndrome (ACS) patients. This may in part be attributable to intact platelet aggregation via the human thrombin receptors protease-activated receptor (PAR)-1 and PAR-4. Objective We studied PAR mediated platelet aggregation in ACS patients following percutaneous coronary intervention (PCI) with stent implantation in a cross-sectional study. Methods Platelet aggregation to ADP as well as to the PAR-1 agonist SFLLRN and the PAR-4 agonist AYPGKF was assessed by multiple electrode aggregometry in 194 ACS patients on dual antiplatelet therapy with aspirin and either prasugrel (n = 114) or ticagrelor (n = 80) 3 days after PCI. Results Based on the consensus cutoff value, high on-treatment residual platelet reactivity to ADP (HRPR ADP) was observed in only 2 prasugrel-treated patients. Both patients with HRPR ADP had also a normal response to SFLLRN and AYPGKF. Among the 112 prasugrel-treated patients with adequate P2Y12 inhibition, 50 patients (45%) still had a normal response to SFLLRN, and 70 patients (63%) still had a normal response to AYPGKF. Among the 80 ticagrelor-treated patients with adequate P2Y12 inhibition, 25 patients (31%) still had a normal response to SFLLRN, and 50 (63%) still had a normal response to AYPGKF. Conclusion Normal platelet aggregation via PAR-1 and PAR-4 is preserved in many patients with adequate P2Y12 inhibition by prasugrel and ticagrelor. The present findings may at least in part explain adverse ischemic events despite potent P2Y12 inhibition.

Background:\ud Synovial sepsis of unknown origin is a rare cause of lameness in the adult horse, and a haematogenous pathogenesis has been proposed in previous cases.\ud \ud Objectives:\ud To describe the features and outcome of synovial sepsis of unknown origin in adult Thoroughbred racehorses.\ud \ud Study design:\ud Retrospective case series.\ud \ud Methods:\ud Hospital records for admissions between 2005 and 2015 were reviewed to identify adult horses diagnosed with synovial sepsis of unknown origin. Presentation, clinicopathological, microbiological and diagnostic imaging findings were recorded. Treatment methods, surgical findings, complications and long-term outcome were evaluated.\ud \ud Results:\ud Eleven cases were identified over the study period. Diagnosis was established from clinical examination and clinicopathologic findings, which were comparable to other aetiologies of synovial sepsis. Affected structures included synovial joints, tendon sheaths and bursae. Concurrent osteochondritis dissecans or articular cartilage lesions were evident during arthroscopic surgery in three cases. Significant intrasynovial haemorrhage was not identified. Microbial culture of synovial fluid or synovial biopsy was positive in 6/11 of cases, with all isolates being Gram-positive cocci. Of the 6 positive microbial cultures, all isolates demonstrated in vitro sensitivity to a cephalosporin antimicrobial agent. A concurrent remote wound was present in a single case. No other potential origins of bacteraemia were identified. Treatment methods included endoscopic surgery, standing multineedle lavage, intravenous regional limb perfusion, intrasynovial medication and/or systemic antimicrobial administration. All horses survived to hospital discharge. For the 6/11 cases that raced following synovial sepsis, the median period for return to racing was 221 days.\ud \ud Main limitations:\ud A small study population, which was retrospectively reviewed.\ud \ud Conclusions:\ud Synovial sepsis of unknown origin is rare in the adult Thoroughbred racehorse and can affect a range of synovial structures. A concurrent potential source of bacteraemia is rarely identified. With appropriate management, the prognosis to return to racing is fair.

One of the fundamental processes in nature, the oxidation of water, is catalyzed by a small CaMn3 O4 ⋅MnO cluster located in photosystem II (PS II). Now, the first successful preparation of a series of isolated ligand-free tetrameric Can Mn4-n O4+ (n=0-4) cluster ions is reported, which are employed as structural models for the catalytically active site of PS II. Gas-phase reactivity experiments with D2 O and H218 O in an ion trap reveal the facile deprotonation of multiple water molecules via hydroxylation of the cluster oxo bridges for all investigated clusters. However, only the mono-calcium cluster CaMn3 O4+ is observed to oxidize water via elimination of hydrogen peroxide. First-principles density functional theory (DFT) calculations elucidate mechanistic details of the deprotonation and oxidation reactions mediated by CaMn3 O4+ as well as the role of calcium.

Basal cell carcinoma (BCC) is the most common malignant tumor among fair-skinned individuals, and its incidence had been steadily rising in the past decades. In order to maintain the highest quality of patient care possible, the German S2k guidelines were updated following a systematic literature search and with the participation of all professional societies and associations involved in the management of the disease. Part 2 addresses issues such as proper risk stratification, the various therapeutic approaches, and prevention as well as follow-up of patients with basal cell carcinoma.

Basal cell carcinoma is the most common malignant tumor among fair-skinned individuals, and its incidence has been rising steadily in the past decades. In order to maintain the highest quality of patient care possible, the German S2k guidelines were updated following a systematic literature search and with the participation of all professional societies and associations involved in the management of the disease. Part 1 highlights new developments in genetics in particular as well as aspects regarding epidemiology, diagnosis, and histology.

BACKGROUND: Despite routine use of echocardiographic parameters to evaluate the severity of cardiac amyloidosis (CA), this methodology has not been well validated. We developed a histopathologic schema for quantifying CA burden and evaluated its relationship with clinical outcomes. Additionally, echocardiographic parameters were tested as potential noninvasive indices of CA burden. METHODS: We retrospectively studied 59 patients with CA (17 light chain, 42 transthyretin) who underwent endomyocardial biopsies. Light microscopy with staining was used to categorize CA burden as mild-to-moderate (

BACKGROUND Quantitative 3D assessment of the aortic root may improve planning and success of aortic valve (AV)-sparing operations. AIMS To use 3D transesophageal echocardiography (TEE) to assess the effect of chronic aortic dilatation on aortic root shape and aortic regurgitation (AR) severity and to examine the effects of AV-sparing operations. METHODS AND RESULTS To determine the changes with chronic aortic dilatation, we studied 48 patients, 23 with aortic dilatation (Group 1 ≤ mild AR, n = 13; Group 2 ≥ moderate AR, n = 10) and 25 Controls. To determine the changes in AV-sparing operations, a subgroup of 15 patients were examined pre- and post surgery. 3D-TEE images were analyzed using multiplanar reconstruction (QLAB, Philips, Philips Medical Systems, Andover, MA, USA) to obtain aortic root areas, diameters, and lengths. We also calculated a novel parameter called total coaptation surface area (TCoapSA), which sums the contact surface area of all the AV cusps. Compared to Controls, Groups 1 and 2 had significantly larger aortic root areas, inter-commissural distances, and cusp heights. Compared to Group 1 and Controls, Group 2 had significantly smaller TCoapSA when adjusted for aortic annular area (P = 0.001) with shorter coaptation height (P

Aim To investigate the long‐term clinical benefit of dual antiplatelet therapy with potent P2Y12 inhibitors compared to clopidogrel in patients with acute coronary syndrome (ACS). Methods In this prospective multicenter observational study, we enrolled 708 patients with ACS treated with clopidogrel (n = 137), ticagrelor (n = 260) or prasugrel (n = 311). Major adverse cardiac events (MACE; over 1 year) and long‐term mortality (median: 5.6 years; interquartile range [IQR] 4.9‐6.5 years) were assessed. Multiple electrode aggregometry (MEA) was used to measure adenosine diphosphate (ADP)‐ and arachidonic acid (AA)‐induced platelet aggregation. Results Type of P2Y12 inhibitor emerged as an independent predictor of long‐term mortality and MACE: patients treated with potent platelet inhibitors prasugrel or ticagrelor were at lower risk for long‐term mortality (adjusted hazard ratio [HR] = 0.44; 95% CI: 0.22‐0.92; P = .028) or MACE (adjusted HR = 0.38; 95% CI: 0.20‐0.73; P = .004) than those treated with clopidogrel independent from clinical risk factors. In contrast, the efficacy of clopidogrel decreased with increasing severity of ACS: platelet aggregation was 37% higher in patients with ST segment elevation myocardial infarction (STEMI) and 25% higher in patients with non‐ST elevation myocardial infarction (non‐STEMI) compared to patients with unstable angina (P = .039). Patients with diabetes achieved less potent ADP‐ and AA‐induced platelet inhibition under clopidogrel, compared to patients without diabetes (P = .045; P = .030, respectively). Conclusion In the setting of ACS, treatment with ticagrelor or prasugrel reduced long‐term mortality and 1‐year MACE as compared to clopidogrel.

Objective Gene therapy holds great promise for the treatment of osteoarthritis (OA) because a single intraarticular injection can lead to long-term expression of therapeutic proteins within the joint. This study was undertaken to investigate the use of a helper-dependent adenovirus (HDAd)-mediated intraarticular gene therapy approach for long-term expression of interleukin-1 receptor antagonist (IL-1Ra) as sustained symptomatic and disease-modifying therapy for OA. Methods In mouse models of OA, efficacy of HDAd-IL-1Ra was evaluated by histologic analysis, micro-computed tomography (micro-CT), and hot plate analysis. In a horse OA model, safety and efficacy of HDAd-IL-1Ra were evaluated by blood chemistry, analyses of synovial fluid, synovial membrane, and cartilage, and gross pathology and lameness assessments. Results In skeletally immature mice, HDAd-IL-1Ra prevented development of cartilage damage, osteophytes, and synovitis. In skeletally immature and mature mice, treatment with HDAd-interleukin-1 receptor antagonist post-OA induction resulted in improved-albeit not significantly-cartilage status assessed histologically and significantly increased cartilage volume, cartilage surface, and bone surface covered by cartilage as assessed by micro-CT. Fewer osteophytes were observed in HDAd-IL-1Ra-treated skeletally immature mice. Synovitis was not affected in skeletally immature or mature mice. HDAd-IL-1Ra protected against disease-induced thermal hyperalgesia in skeletally mature mice. In the horse OA model, HDAd-IL-1Ra therapy significantly improved lameness parameters, indicating efficient symptomatic treatment. Moreover, macroscopically and histologically assessed cartilage and synovial membrane parameters were significantly improved, suggesting disease-modifying efficacy. Conclusion These data from OA models in small and large animals demonstrated safe symptomatic and disease-modifying treatment with an HDAd-expressing IL-1Ra. Furthermore, this study establishes HDAd as a vector for joint gene therapy.

The majority of youth living in the United States experience a potentially traumatic event (PTE) by 18 years of age, with many experiencing multiple PTEs. Variation in the nature and range of PTE exposure differentially impacts youth functioning, although this association is poorly understood. We used latent class analysis (LCA) to identify patterns of PTE exposure from caregiver and youth report in a treatment-seeking sample of children and adolescents (N = 701) and examined how these patterns predict youths' behavioral health outcomes. We identified four classes based on both caregiver and youth reports of PTE exposure, with the best-fitting model representing a constrained measurement model across reporters; these included high polyvictimization, moderate polyvictimization (general), moderate polyvictimization (interpersonal), and low polyvictimization classes. Prevalence of classes varied across reporters, and agreement in classification based on caregiver and youth report was mixed. Despite these differences, we observed similar patterns of association between caregiver- and youth-reported classes and their respective ratings of posttraumatic stress disorder and depressive symptoms, as well as both caregiver and therapist ratings of problem behavior, with Cohen's d effect size estimates of significant differences ranging from d = 0.25 to d = 0.51. The PTE exposure classes did not differ with respect to ratings of child functioning. Findings highlight the importance of gathering information from multiple informants.

Background Extemporaneous formulations broaden the spectrum of therapeutic options for topical treatment in particular and thus improve patient care. The latest amendment to the Regulation on the Operation of Pharmacies issued in 2012 brought about changes in prescribing and manufacturing practices. The aim of the present study was to assess the relevance of extemporaneous formulations in everyday clinical practice. Methods We used data from the German Institute for Drug Use Evaluation (DAPI) to analyze the prescribing practice for compounded preparations in Germany between the fourth quarter of 2011 and the third quarter of 2014. In doing so, we determined the total cost associated with extemporaneous formulations covered by statutory health insurance funds in the outpatient setting. Results Approximately three out of ten prescriptions (30.54 %) by German dermatologists during the observation period were extemporaneous formulations. While dermatologists make up only 2.7 % of physicians working in the statutory health care system in Germany, they prescribe more than half of all compounded preparations (53.6 %). Each dermatologist prescribed an average of 270.4 formulations per quarter; that number was 13.5 (1.3 %) for all other medical specialties. On average, 1,983,687 extemporaneous formulations overall (1.3 % of all prescriptions) were prescribed per quarter, corresponding to a total cost of € 40,944,982 (0.55 %). Conclusions Apart from finished medicinal products, extemporaneous formulations play a key role in outpatient care. Based on the principles of evidence-based and patient-oriented medicine, the quality of compounded preparations and the prescribing practice of physicians (standardized vs. individual formulations) should be further investigated to optimize the quality of these preparations.

Good-quality chest compressions improve outcomes in cardiac arrest. While manual chest compressions are suboptimal in this regard, the LUCAS device has been shown to improve the effectiveness of chest compressions during cardiopulmonary resuscitation (CPR). The complication rate associated with mechanical CPR, however, has not been adequately studied. Limited evidence suggests no difference in internal injury between manual and mechanical CPR. We report the case of a patient on anticoagulation who developed a mediastinal hematoma post mechanical CPR and on whom subtle findings on initial echocardiography could have alerted the clinician to this complication early during the clinical course. This case further suggests that there may be special populations of patients in whom we may need to be more vigilant in the use of mechanical CPR.

Methane represents the major constituent of natural gas. It is primarily used only as a source of energy by means of combustion, but could also serve as an abundant hydrocarbon feedstock for high quality chemicals. One of the major challenges in catalysis research nowadays is therefore the development of materials that selectively cleave one of the four C-H-bonds of methane and make it thus amenable for further chemical conversion to more valuable compounds. Employing infrared spectroscopy and first-principles calculations it is uncovered herein that the interaction of methane with small gold cluster cations leads to selective C-H bond dissociation and the formation of hydrido-methyl complexes H-Aux+-CH3. The distinctive selectivity offered by these gold clusters originates from a fine interplay between the closed-shell nature of the gold d-bands and relativistic effects in gold. Such fine balance in fundamental interactions could prove a 'tunable' feature in rational catalyst design.

Objectives/Hypothesis Head and neck free flap patients require complex postoperative care. The quality of care for these patients often depends on their management from the time they leave the operating room. The purpose of this study was to investigate the impact of a postoperative inpatient coordinator (IC) for head and free flap patients on quality outcomes: length of stay (LOS), 30-day unplanned return to the emergency department (30dRED), 30-day unplanned readmissions (30dUR), and complication rates. Study Design Retrospective cohort study. Methods One hundred eighty-eight consecutive patients who underwent head and neck free flap surgery between January 2012 and January 2016 were reviewed using a prospective database. Patients had an IC for their entire hospitalization (group 1) or for less than their entire hospitalization (group 2). Logistic regression analysis was performed to identify risk factors for quality outcomes. Results Mean LOS was 13.8 days and 17.3 days in groups 1 and 2, respectively (P = .002). The 30dRED rate was 12% and 22%, respectively (P = .04). Group 2 had an increased LOS by 4.1 days (P = .001) and a 2.4 fold increased 30dRED (P = .03). 30dUR and complications were not influenced by the IC (P > .05). Conclusions An IC may help decrease LOS and 30dRED in head and neck free flap patients. Level of Evidence 4 Laryngoscope, 2017

Background With the increasing use of transcatheter aortic valve replacement (TAVR) in patients with aortic stenosis (AS), computed tomography (CT) remains the standard for annulus sizing. However, 3D transesophageal echocardiography (TEE) has been an alternative in patients with contraindications to CT. We sought to (1) test the feasibility, accuracy, and reproducibility of prototype 3DTEE analysis software (Philips) for aortic annular measurements and (2) compare the new approach to the existing echocardiographic techniques. Methods We prospectively studied 52 patients who underwent gated contrast CT, procedural 3DTEE, and TAVR. 3DTEE images were analyzed using novel semi-automated software designed for 3D measurements of the aortic root, which uses multiplanar reconstruction, similar to CT analysis. Aortic annulus measurements included area, perimeter, and diameter calculations from these measurements. The results were compared to CT-derived values. Additionally, 3D echocardiographic measurements (3D planimetry and mitral valve analysis software adapted for the aortic valve) were also compared to the CT reference values. Results 3DTEE image quality was sufficient in 90% of patients for aortic annulus measurements using the new software, which were in good agreement with CT (r-values: .89–.91) and small (

Objectives Mesenchymal stem cells (MSCs) are frequently delivered via needle injection for treatment of musculoskeletal injuries. The purpose of this study was to evaluate the effect of needle diameter on the viability of MSCs. Methods Equine bone marrow-derived MSCs from 5 horses were suspended in PBS, and held at room temperature for 7 hours to mimic shipping conditions. Two replicate samples for each needle size (20, 22, 23, or 25-gauge [ga]) were aspirated into a 3 mL syringe and re-injected into the holding vial 3 times, to reproduce the resuspension of cells prior to injection in clinical cases. Cells were stained with fluorescein diacetate and propidium iodide to measure viability. Flow cytometry (FC) was performed to compare cell debris and intact cells between groups. Results MSC viability was higher when cells were passed through a 20-ga rather than a 25-ga needle. Cell suspensions passed through a 20-ga needle contained a larger percentage of intact cells, compared to 25-ga samples. The percentage of debris present in cell suspensions tended to increase with decreasing needle diameter. Neither horse nor passage had a significant effect on viability. Conclusions Cell damage is more likely when MSCs are passed through 25-ga rather than 20-ga needles. Clinical relevance Use of needles larger than 25-ga is recommended to maintain the viability of MSCs injected in horses.

Background Although left ventricular (LV) ejection fraction (EF) and global longitudinal strain (GLS) are recommended by the current echocardiographic chamber quantification guidelines, these measurements are not performed routinely. Because EF measurements rely on manual tracing of LV boundaries, and are subject to inter-reader variability and experience dependence, we hypothesized that semiautomated GLS measurements using speckle tracking would be more reproducible and less experience-dependent. Methods Images from 30 patients were analyzed to obtain biplane EF using manual tracing. GLS was measured in three long-axis views using EchoInsight software (Epsilon Imaging) that automatically detects LV endocardial boundary, which is edited manually as necessary and is then automatically tracked throughout the cardiac cycle. All measurements were performed by an expert echocardiographer and three first-year cardiology fellows. Results Semiautomated GLS analysis showed excellent correlation (r=.98) and small bias (-1.0±13% of measured value) between the experienced and less experienced readers, superior to EF (r=.91, bias 7.3±16%). Also, in repeated measurements, GLS showed higher intra-class correlation (ICC=.98) than EF (ICC=.89). Additionally, GLS analysis required ~1 minute per patient, while biplane EF measurements took twice as long. Conclusions Semiautomated GLS measurements are fast, less experience-dependent, and more reproducible than conventional EF measurements. This is probably because, irrespective of experience, the readers' choice of boundary position varies less when asked to refine the automated detection than to draw borders without initial clues. This technique may facilitate the workflow of a busy laboratory and make a step forward toward incorporating quantitative analysis into everyday echocardiography practice.

The myelin-associated protein Nogo-A contributes to the failure of axon regeneration in the mammalian central nervous system (CNS). Inhibition of axon growth by Nogo-A is mediated by the Nogo-66 receptor (NgR). Nonmammalian vertebrates, however, are capable of spontaneous CNS axon regeneration, and we have shown that retinal ganglion cell (RGC) axons regenerate in the lizard Gallotia galloti. Using immunohistochemistry, we observed spatiotemporal regulation of Nogo-A and NgR in cell bodies and axons of RGCs during ontogeny. In the adult lizard, expression of Nogo-A was associated with myelinated axon tracts and upregulated in oligodendrocytes during RGC axon regeneration. NgR became upregulated in RGCs following optic nerve injury. In in vitro studies, Nogo-A-Fc failed to inhibit growth of lizard RGC axons. The inhibitor of protein kinase A (pkA) activity KT5720 blocked growth of lizard RGC axons on substrates of Nogo-A-Fc, but not laminin. On patterned substrates of Nogo-A-Fc, KT5720 caused restriction of axon growth to areas devoid of Nogo-A-Fc. Levels of cyclic adenosine monophosphate (cAMP) were elevated over sustained periods in lizard RGCs following optic nerve lesion. We conclude that Nogo-A and NgR are expressed in a mammalian-like pattern and are upregulated following optic nerve injury, but the presence of Nogo-A does not inhibit RGC axon regeneration in the lizard visual pathway. The results of outgrowth assays suggest that outgrowth-promoting substrates and activation of the cAMP/pkA signaling pathway play a key role in spontaneous lizard retinal axon regeneration in the presence of Nogo-A. Restriction of axon growth by patterned Nogo-A-Fc substrates suggests that Nogo-A may contribute to axon guidance in the lizard visual system. J. Comp. Neurol. 525:936-954, 2017. © 2016 Wiley Periodicals, Inc.

Objective The present study investigated whether the glycoprotein (GP)IIb/IIIa receptor blocker abciximab might be a successful bridging strategy to achieve adequate levels of platelet inhibition rapidly in cases where prasugrel is used in morphine-pretreated ST-elevation myocardial infarction (STEMI) patients. Methods In a prospective observational cohort study, 32 patients presenting with STEMI were given prasugrel at a loading dose of 60 mg. Patients were stratified into four groups, according to morphine and/or abciximab use. Adenosine diphosphate (ADP)-induced platelet aggregation was measured at four time points: at baseline, and at 2 h, 1 day and 2 days after prasugrel loading. Results Morphine use was associated with a three-fold higher level of ADP-induced platelet aggregation 2 h after prasugrel loading compared with no morphine/no abciximab (P = 0.019). However, when abciximab was infused in the catheterization laboratory, the effect of morphine on ADP-induced platelet aggregation disappeared (P = 0.884). This interaction was also seen in the presence of high on-treatment platelet reactivity (HTPR) at 2 h; while HTPR was seen in 88% of morphine users/no abciximab users, it was found in only 17–20% in the three other groups (P = 0.003). The effect of morphine disappeared by day 1 – 2. Conclusion The infusion of the GPIIb/IIIa receptor blocker abciximab allows immediate and efficient platelet inhibition in STEMI patients concomitantly receiving the oral ADP receptor blocker prasugrel and morphine.

PURPOSE To examine a novel non-convex star ordering/shutter for reducing the number of breath-holds in cardiac three-dimensional (3D) T1 Mapping MRI with multiple breath-holds. METHODS A novel ordering, Non-Convex Star (NCS) was designed to acquire 3D volumes in a modified look-locker inversion recovery (MOLLI) T1 mapping sequence to provide more spatial resolution and coverage in fewer breath-holds. The proposed 3D-MOLLI approach using NCS was first validated in two phantoms using artifact power (AP) measurement against the fully sampled phantom. This was followed by an in vivo study in seven swine, in which the T1 values of the left ventricular (LV) myocardium divided into the American Heart Association (AHA) 16-segment model was compared against the reference multislice two-dimensional (2D) clinical reference and 3D volume without NCS breath-hold reduction. RESULTS NCS breath-hold reduction yielded less AP compared with the matched SENSE accelerated phantom volume (P

Zusammenfassung Seit Jahrzehnten ist bekannt, dass Tumoren vom Immunsystem erkannt und zerstort werden konnen. Diese, vor allem in Tierversuchen gewonnene Erkenntnis konnte jedoch in der Vergangenheit nicht zum Nutzen unserer Patienten umgesetzt werden, da immunonkologische Therapieansatze in den letzten Jahrzehnten in der Anwendung beim Menschen stets versagt haben. Daher hat, mit Ausnahme der adjuvanten Interferontherapie, keines dieser Verfahren den Einzug in die klinische Versorgung gefunden. Langzeituberleben unter guter Lebensqualitat war dabei sehr wenigen Patienten vorbehalten. Mit den neuen immunologischen Therapieansatzen wird jedoch sowohl das Langzeituberleben als auch die Lebensqualitat onkologischer Patienten neu definiert. Auf die neuen „Immun-Checkpoint-Inhibitoren“ spricht erstmals ein relevanter Teil der behandelten Patienten an und diese zeigen in der Regel langandauernde Remissionen bis hin zur Heilung. Schon jetzt ist klar, dass die Immuntherapie in Zukunft eine der wesentlichen Therapiesaulen bei der Behandlung des metastasierten Melanoms und auch vieler anderer fortgeschrittener Tumoren bilden wird. In dieser Ubersicht werden die wichtigsten neuen Therapiemodalitaten besprochen und sowohl deren Wirkprinzip als auch klinische Daten zum Therapieansprechen und zu erwartenden Nebenwirkungen der Therapie referiert.