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Influenza B is one of the infective agents that can cause rapid and fatal myocarditis in children. Here, we describe a fatal case of myocarditis in a previously healthy child, after infection with an influenza B/Victoria-lineage virus during the 2022–23 epidemic season in Italy. Influenza B virus was isolated also in a second case, a younger family member showing only a mild influenza-like illness. Genotypic and phenotypic analyses have been performed on both virus samples and results showed that HA1 sequences were identical and genetically and antigenically related to other B viruses circulating in 2022–23 season in Italy. However, a D129N substitution was found in the receptor binding domain of the HA of the two viruses, not detected in other circulating viruses in Italy but only in a proportion of those circulating in other European countries. Phenotypic analyses assessed the susceptibility towards either neuraminidase inhibitors and baloxavir. Annual influenza vaccination remains one of the best interventions to prevent complications such as myocarditis, particularly in children. [ABSTRACT FROM AUTHOR]

Unsolicited invitations to speak at medical meetings have proliferated as a type of spam email and phishing strategy to scam unsuspecting victims. We sought to determine the prevalence of such invitations to questionable meetings and determine the factors associated with receiving such solicitations. Data was collected for the number of speakers' invitations received over a 2-week period (April -May 2023) by radiologists of different subspecialties, academic ranks, and histories of publications and speaking engagements in the past 2-5 years. We analyzed the number of invitations received based on the variables. Thirty-three of 45 (73.3%) faculty members received 188 inappropriate invitation emails in the 2-week observation period. The mean number of invitation emails was 4.13 for each faculty (SD: 5.03, range 0-20). There was no correlation between the number of invitations and radiologists' subspecialty, academic rank (3.8 ± 5, 3.0 ± 4, and 5.5 ± 5.7 invitations for full, associate, and assistant professors respectively) and previous legitimate speaker invites. Only 6 (3.2%) out of 188 invitations to speak sent to radiologists were for radiology-related meetings. Having more than 10 publications since 2022 was associated with a 5.0 (1.2, 19.4) times higher odds of receiving more than 4 solicitations. A total of 73.3% of the faculty surveyed received unsolicited invitations to meetings in the 2-week study period and over 96% of the invitations were unrelated to their field of practice. Our results show that publications since 2022 was the most significant factor associated with receiving more solicitations. Invitations to questionable meetings targeting radiologists are frequent and often are unrelated to their specialties. The risk factors for receiving the invitations are unclear. Understanding these risk factors may enable educators especially junior investigators, to be better prepared to appropriately address such solicitations. [ABSTRACT FROM AUTHOR]

Symptomatic non-obstructive hypertrophic cardiomyopathy (HCM) presents significant diagnostic and therapeutic challenges. While myosin inhibition has shown benefits in obstructive HCM, its efficacy in non-obstructive HCM remains unclear. Both patient groups share a similar risk for HCM-related mortality, yet current therapeutic approaches for non-obstructive HCM are limited and primarily focus on symptom management rather than targeting underlying molecular mechanisms. The R92L mutation in cardiac troponin T, a common cause of HCM, leads to increased power of contraction that is energetically costly, resulting in an imbalance of myocardial energetics. It is well established that the phosphocreatine (PCr) to ATP ratio is decreased in HCM, and analysis of human myectomy samples shows associated severe structural mitochondrial damage. This energetic impairment contributes to diastolic dysfunction, and limited data suggest that metabolic interventions may offer therapeutic benefits in non-obstructive HCM. CK-271, a specific cardiac myosin inhibitor related to aficamten, has demonstrated potential in modulating myocardial contractility and improving cardiac function. This study investigates the efficacy of CK-271 in enhancing myocardial energetics, reducing hypertrophy, and improving diastolic function and exercise tolerance in a mouse model of non-obstructive HCM with the R92L troponin T mutation. We hypothesize that CK-271, a small molecule myosin inhibitor, will improve myocardial energetics, reduce cardiac hypertrophy, and enhance diastolic function, thereby improving exercise tolerance in a mouse model of non-obstructive hypertrophic cardiomyopathy (HCM) with the R92L troponin T mutation. Adult mice with fully developed hypertrophy due to the troponin R92L mutation were treated with the myosin inhibitor CK-271 in the diet for 16 weeks. Using 31P NMR spectroscopy, cardiac energetics were assessed by measuring the phosphocreatine (PCr) to ATP ratio. In R92L mice, treatment with CK-271 improved cardiac energetics, as evidenced by increased PCr/ATP ratios, which was associated with reduced left ventricular hypertrophy (decreased total wall thickness), decreased contractility, and improved diastolic function (increased E/A ratio and Em). Strikingly, CK-271 treatment also improved exercise tolerance in R92L mice. Our novel study suggests that the structural and functional benefits of myosin inhibition in HCM are, at least in part, due to improved cardiac energetics. This provides evidence supporting the conduct of clinical trials with myosin inhibition and/or metabolic modulation in non-obstructive HCM. [ABSTRACT FROM AUTHOR]

Total hip arthroplasty is an effective treatment for severe degenerative arthritis and is increasingly being used. Radiography is the primary modality for the initial diagnosis of osteoarthritis and preoperative planning. Additional radiographic views may include the spine and lower extremities in order to optimize implant positioning for the individual patient. Computed tomography is sometimes used for preoperative planning and intraoperative robotic assistance. Magnetic resonance imaging and diagnostic ultrasound is generally reserved for patients without obvious arthritis. Ultrasound-guided injections may provide diagnostic and/or therapeutic benefits. [ABSTRACT FROM AUTHOR]

Traditional approaches towards teaching magnetic resonance imaging (MRI) scanning and physics have limitations that a hands-on course may help overcome. A dedicated week of MRI instruction may help improve radiology resident confidence and competence. Additional benefits may include improved physician-technologist communication and accelerated mastery of MRI safety. Surveys and tests were approved by our Program Evaluation Committee and administered at the beginning and at the end of this one-week course. The course consisted of protected reading time as well as practice scanning with a research magnet and assisting with clinical scanning under the close supervision of a licensed MRI technologist. Eighteen senior residents (nine third-year and nine fourth-year) participated in this course during its first year. Few residents had previous experience with MRI physics, scanning, or research prior to residency. After this course, mean resident confidence increased by 0.47 points (3.33 vs 2.86; p =0.01) on a five-point Likert scale. Understanding of MRI physics, as measured by pre- and post-tests, increased by 22% (0.72 vs 0.50; p <0.01), corresponding to a large effect size of 1.29 (p <0.001). Resident feedback reported that this course was efficacious (5/5), engaging (4.9/5), and had optimal faculty oversight. The most highly rated component of the course was the opportunity to experiment with the research MR scanner (5/5). A dedicated week of MRI education was highly rated by residents and associated with improvements in confidence and understanding, suggesting a positive correlation between confidence and competence. Additional metrics, such as trends in scores on the American Board of Radiology's Core Examination over the next several years, may further support the apparent benefits of this hands-on MR course. [ABSTRACT FROM AUTHOR]

Colonoscopy for colorectal cancer screening is endoscopist dependent, and colonoscopy quality improvement programs aim to improve efficacy. This study evaluated the clinical benefit and safety of using a computer-aided detection (CADe) device in colonoscopy procedures. This randomized study prospectively evaluated the use of a CADe device at 5 academic and community centers by US board-certified gastroenterologists (n = 22). Participants aged ≥40 scheduled for screening or surveillance (≥3 years) colonoscopy were included; exclusion criteria included incomplete procedure, diagnostic indication, inflammatory bowel disease, and familial adenomatous polyposis. Patients were randomized by endoscopist to the standard or CADe colonoscopy arm using computer-generated, random-block method. The 2 primary endpoints were adenomas per colonoscopy (APC), the total number of adenomas resected divided by the total number of colonoscopies; and true histology rate (THR), the proportion of resections with clinically significant histology divided by the total number of polyp resections. The primary analysis used a modified intention-to-treat approach. Between January and September 2021, 1440 participants were enrolled to be randomized. After exclusion of participants who did not meet the eligibility criteria, 677 in the standard arm and 682 in the CADe arm were included in a modified intention-to-treat analysis. APC increased significantly with use of the CADe device (standard vs CADe: 0.83 vs 1.05, P =.002; total number of adenomas, 562 vs 719). There was no decrease in THR with use of the CADe device (standard vs CADe: 71.7% vs 67.4%, P for noninferiority <.001; total number of non-neoplastic lesions, 284 vs 375). Adenoma detection rate was 43.9% and 47.8% in the standard and CADe arms, respectively (P =.065). For experienced endoscopists performing screening and surveillance colonoscopies in the United States, the CADe device statistically improved overall adenoma detection (APC) without a concomitant increase in resection of non-neoplastic lesions (THR). ClinicalTrials.gov registration: NCT04754347. [Display omitted] Colonoscopies are widely performed in the United States to screen for colorectal cancer and detect it before it becomes an issue for patients. By using artificial intelligence during the procedure, detection rates and procedure quality are improved. [ABSTRACT FROM AUTHOR]

Optimizing chemotherapy to achieve disease and symptoms control is a noteworthy purpose in advanced breast cancer (ABC). We reported the activity and quality of life of a phase II study, comparing metronomic regimen with standard schedule as first line chemotherapy for ABC. Patients with HER2 negative ABC were randomized to non-pegylated liposomal doxorubicin (NPLD, 60 mg/m2 every 3 weeks) and cyclophosphamide (CTX, 600 mg/m2 every 3 weeks) (Arm A) or NPLD (20 mg/m2 day, on day 1, 8 and 15 every 4 weeks) and metronomic daily oral CTX 50 mg (ARM B). Primary end-points were overall response rate (ORR) and quality of life, secondary progression-free survival (PFS), overall survival (OS) and toxicity. From August 2012 to December 2017, 121 patients were enrolled, 105 evaluable. Median follow-up was 21.3 months. Most patients had hormone receptor positive. ORR was 43 % in arm A and 50 % in arm B. Median PFS was 8.9 months in arm A and 6,4 months in arm B. There was no difference in OS. Total score was not clinically different between the two arms. Grade 4 neutropenia was observed in 12 patients and 16 patients respectively; alopecia G2 in 41 % (77 %) vs 14 (27 %) in arm A and in arm B respectively. One cardiac toxicity was observed (arm A). First line metronomic chemotherapy for HER2 negative ABC had similar clinical activity and quite better tolerability than standard schedule and could be considered a further treatment option when chemotherapy is indicated. • Despite the role of biological and targeted drugs, chemotherapy remains a fundamental component of the therapeutic algorithm of ABC. • The purpose of treatment for ABC is relief of symptoms related tas well the maintenance of a good quality of life. • Treatment with low doses of anticancer drugs given on a continuous or frequent regular schedule over a long time is called metronomic chemotherapy. Metronomic chemotherapy causes less severe side effects than standard chemotherapy. • In our study, a metronomic schedule with liposomal anthracyclines is able to achieve similar ORR when compared to standard anthracycline schedule, while maintaining quality of life. • Toxicity was quite similar in the two arms, however dose delay was less frequent in metronomic arm. [ABSTRACT FROM AUTHOR]

Background. The combination of chemotherapy plus anti HER-2 agents is the mainstay of HER-2 positive advanced breast cancer (ABC) therapy. We conducted a phase II trial testing activity and safety of trastuzumab and metronomic capecitabine/cyclophosphamide (HEX) as first-line therapy in HER-2 positive ABC. Methods. Patients at first relapse or with synchronous metastasis were treated with trastuzumab (4 mg/kg, biweekly) plus oral capecitabine (1500 mg/daily) and cyclophosphamide (50 mg/daily). Primary endpoint was objective response rate (ORR), secondary endpoints progression-free survival (PFS), clinical benefit rate (CBR; PR + CR + SD for ≥ 24 weeks) and tolerability. Optimal two-stage design was applied. Results. Sixty patients with measurable ABC, tumors scored as +3 for HER-2 or FISH +, untreated for advanced disease were enrolled. Median age was 62.5 years, visceral metastases were present in most patients (57.9%). Median number of cycles was 16 (range 1–98). ORR was 56.7% (95% CI, 44.1–68.4%), with 5 CR (8.3%) and 29 PR (48.3%). Fifteen patients had SD (25%). The CBR was 78.2%. Nine progressions were observed (15%). Median PFS was 11 months. One year PFS was 47.7%. Median OS was 45.9 months. Worst toxicities were grade 3 hand-foot syndrome in 2 pts (3.3%), grade 3 anaemia in 2 pts (3.3%), grade 2 nausea in 2 pts (3.3%) and grade 3–4 diarrhea in 2 pts (3.3%). Cardiac toxicity grade 1 was reported in 1 pt. Conclusions. Combination of trastuzumab and metronomic oral chemotherapy has clinical activity. The tolerability was excellent and allowed the prolonged delivery of treatment. • Combination of chemotherapy plus anti HER-2 agents is the standard treatment of HER-2 positive breast cancer. • Combination of trastuzumab and metronomic chemotherapy is an alternative therapeutic approach. • Metronomic therapy allows long-term administration of drugs. • Mild toxicity in advanced breast cancer is desirable. [ABSTRACT FROM AUTHOR]

Low-grade chronic inflammation is a key process of angiogenesis in tumour progression. We investigated whether a synthetic analogue of apigenin, the 2-(3,4-dimethoxyphenyl)-3-phenyl-4H-pyrido[1,2-a] pyrimidin-4-one (called DB103), interfered with the mechanisms involved in the angiogenic process induced by the inflammatory cytokine tumour necrosis factor (TNFα). In endothelial cells, DB103 but not apigenin reduced the TNFα-induced oxidative stress. DB103 inhibited the activation of ERK1/2 but not JNK, p38 and Akt kinases, while apigenin was not so selective because it inhibited essentially all examined kinases. Similarly, apigenin inhibited the TNFα-induced transcription factors CREB, STAT3, STAT5 and NF-κB, while DB103 acted only on NF-κB. DB103 inhibited the induced-release of angiogenic factors such as monocyte chemotactic protein-1, interleukin-6 (IL-6) and angiopoietin-2 but not IL-8, while apigenin reduced the IL-6 and IL-8 release. DB103 revealed a better ability than apigenin to modulate proangiogenic responses induced by an inflammatory microenvironment. [ABSTRACT FROM AUTHOR]

As radiology is inherently a data-driven specialty, it is especially conducive to utilizing data processing techniques. One such technique, deep learning (DL), has become a remarkably powerful tool for image processing in recent years. In this work, the Association of University Radiologists Radiology Research Alliance Task Force on Deep Learning provides an overview of DL for the radiologist. This article aims to present an overview of DL in a manner that is understandable to radiologists; to examine past, present, and future applications; as well as to evaluate how radiologists may benefit from this remarkable new tool. We describe several areas within radiology in which DL techniques are having the most significant impact: lesion or disease detection, classification, quantification, and segmentation. The legal and ethical hurdles to implementation are also discussed. By taking advantage of this powerful tool, radiologists can become increasingly more accurate in their interpretations with fewer errors and spend more time to focus on patient care. [ABSTRACT FROM AUTHOR]

In an urban micro-climate environment, the convective heat transfer coefficient (CHTC) on the façades influences simulated building's energy demand and exterior wall surfaces temperatures. In this paper, it is analyzed how the CHTC values on the façades of a building located in an urban canyon influence the façades temperatures and how important is the choice of an accurate CHTC correlation on the space cooling and heating energy demand. CHTC correlations found in literature are based on some specific micro-climate parameters such as local wind speed, district construction density, temperature differences between façades and canyon air and wind direction. An accurate choice of the right correlation for the simulated urban environment is important to better represent the exterior walls heat removal due to outside wind climate. The effects of the use of different CHTC correlations have been evaluated by means of TRNSYS 17.0 simulation program. The study is performed for a building sited an urban street canyon with the aspect ratio H/W=1 and located in a Mediterranean climate, in Rome. The comparison performed between the results of the numerical simulations shows that some correlations lead to an underestimation of the space heating demand around 9.7% and to an overestimation of the space cooling demand around 17.5%. [ABSTRACT FROM AUTHOR]

The research concerns the assessment of the possibility to design a CCS pilot project in a deep saline aquifer of Northern Italy (Lombardia Region), one of the most populated and industrialized area of the Country. Lombardia Region emits about 70 Mt CO 2 per year, ranking the Region as the largest Italian producer. The study area covers an area of about 1500 km 2 , and the potential caprock-reservoir system has been identified in a clay and conglomerate formation, respectively. A 3D static geological model and a 3D fluid-dynamic model have been implemented in order to analyze the CO 2 storage process. After the evaluation of the storage capacity of the geological system identified in the study area, six different injection scenarios have been simulated, by considering 30 years of fluid injection at a rate of 0.3 Mt of CO 2 per year. For a preliminary assessment of safety conditions, CO 2 plume size, volume and displacement, together with overpressures distribution at the caprock-reservoir boundary have been simulated and analyzed. This study represent a first step for the evaluation of the storage capacity of the study area, and the results of the numerical simulations seems to confirm the possibility to develop a CCS pilot project in the future. The numerical simulations confirm, amongst the other, that the geological system is compatible with the storage of a mass of CO 2 consistent with the design of a pilot project. However, further analyses are necessary (such as detailed site-investigations to confirm some geological assumptions and exhaustive geomechanical studies) before considering this area fully suitable for CCS. [ABSTRACT FROM AUTHOR]

Since an important part of the world's energy is used for space cooling and heating of buildings, its minimization has great energy saving potential. Heat exchange between buildings and surrounding environment is due to convective and radiative heat flows. In this study a detailed building energy simulation (BES) has been carried out in order to analyze the effect of neighbouring buildings on these heat flows and in order to quantify mutual influence on the space cooling and heating demand of buildings. BESs were conducted for a stand-alone building and for a building situated in a typical street canyon. This study demonstrates the importance of considering the urban microclimate conditions for the prediction of the energy demand of buildings. With the implemented model most of the thermal effects of the urban microclimate can be modeled and quantified on a street canyon scale. Due to multiple reflections higher values of solar and thermal radiation are absorbed at the façades of buildings in street canyons than those that occur at stand-alone buildings façades. These effects cause higher surface temperatures in street canyons which means higher space cooling and lower space heating demands. Other reasons that cause this phenomenon are the lower convective heat transfer coefficients in street canyons that results in a reduction of the heat removal from street canyons and contribute to plump the urban heat island effect. [ABSTRACT FROM AUTHOR]

Several application scenarios in the Web of Data share the need to identify the commonalities between a pair of RDF resources. Motivated by such needs, we propose the definition and the computation of Least Common Subsumers (LCSs) in RDF . To this aim, we provide some original and fundamental reformulations, to deal with the peculiarities of RDF . First, we adapt a few definitions from Graph Theory to paths and connectedness in RDF -graphs. Second, we define rooted RDF -graphs ( r -graphs), in order to focus on a particular resource inside an RDF -graph. Third, we change the definitions of LCSs originally set up for Description Logics to r -graphs. According to the above reformulations, we investigate the computational properties of LCS in RDF , and find a polynomial-time characterization using a form of graph composition. This result remarkably distinguishes LCSs from Entailment in RDF , which is an NP-complete graph matching problem. We then devise algorithms for computing an LCS. A prototypical implementation works as a proof-of-concept for the whole approach in three application scenarios, and shows usefulness and feasibility of our proposal. Most of our examples are taken directly from real datasets, and are fully replicable thanks to the fact that the choice about which triples are selected for the computation is made explicit and flexible. [ABSTRACT FROM AUTHOR]

Several studies have reported the beneficial effects of mesenchymal stem cells (MSCs) in tissue repair and regeneration. New sources of stem cells in adult organisms are continuously emerging; dental tissues have been identified as a source of postnatal MSCs. Dental bud is the immature precursor of the tooth, is easy to access and we show in this study that it can yield a high number of cells with ≥ 95% expression of mesenchymal stemness makers and osteogenic capacity. Thus, these cells can be defined as Dental Bud Stem Cells (DBSCs) representing a promising source for bone regeneration of stomatognathic as well as other systems. Cell interactions with the extracellular matrix (ECM) and neighboring cells are critical for tissue morphogenesis and architecture; such interactions are mediated by integrins and cadherins respectively. We characterized DBSCs for the expression of these adhesion receptors and examined their pattern during osteogenic differentiation. Our data indicate that N-cadherin and cadherin-11 were expressed in undifferentiated DBSCs and their expression underwent changes during the osteogenic process (decreasing and increasing respectively), while expression of E-cadherin and P-cadherin was very low in DBSCs and did not change during the differentiation steps. Such expression pattern reflected the mesenchymal origin of DBSCs and confirmed their osteoblast-like features. On the other hand, osteogenic stimulation induced the upregulation of single subunits, αV, β3, α5, and the formation of integrin receptors α5β1 and αVβ3. DBSCs differentiation toward osteoblastic lineage was enhanced when cells were grown on fibronectin (FN), vitronectin (VTN), and osteopontin (OPN), ECM glycoproteins which contain an integrin-binding sequence, the RGD motif. In addition we established that integrin αVβ3 plays a crucial role during the commitment of MSCs to osteoblast lineage, whereas integrin α5β1 seems to be dispensable. These data suggest that functionalization of biomaterials with such ECM proteins would improve bone reconstruction therapies starting from dental stem cells. [ABSTRACT FROM AUTHOR]

Rationale and Objectives: The primary role of radiology in the preclinical setting is the use of imaging to improve students' understanding of anatomy. Many currently available Web-based anatomy programs include either suboptimal or overwhelming levels of detail for medical students.Our objective was to develop a user-friendly software program that anatomy instructors can completely tailor to match the desired level of detail for their curriculum, meets the unique needs of the first- and the second-year medical students, and is compatible with most Internet browsers and tablets.Materials and Methods: RadStax is a Web-based application developed using free, open-source, ubiquitous software. RadStax was first introduced as an interactive resource for independent study and later incorporated into lectures. First- and second-year medical students were surveyed for quantitative feedback regarding their experience.Results: RadStax was successfully introduced into our medical school curriculum. It allows the creation of learning modules with labeled multiplanar (MPR) image sets, basic anatomic information, and a self-assessment feature. The program received overwhelmingly positive feedback from students. Of 115 students surveyed, 87.0% found it highly effective as a study tool and 85.2% reported high user satisfaction with the program.Conclusions: RadStax is a novel application for instructors wishing to create an atlas of labeled MPR radiologic studies tailored to meet the specific needs their curriculum. Simple and focused, it provides an interactive experience for students similar to the practice of radiologists.This program is a robust anatomy teaching tool that effectively aids in educating the preclinical medical student. [ABSTRACT FROM AUTHOR]

Rationale and Objectives With rapid scientific and technological advancements in radiological research, there is renewed emphasis on promoting early research training to develop researchers who are capable of tackling the hypothesis-driven research that is typically funded in contemporary academic research enterprises. This review article aims to introduce radiology residents to the abundant radiology research opportunities available to them and to encourage early research engagement among trainees. Materials and Methods To encourage early resident participation in radiology research, we review the various research opportunities available to trainees spanning basic, clinical, and translational science opportunities to ongoing research in information technology, informatics, and quality improvement research. Conclusions There is an incredible breadth and depth of ongoing research at academic radiology departments across the country, and the material presented herein aspires to highlight both subject matter and opportunities available to radiology residents eager to engage in radiologic research. The opportunities for interested radiology residents are as numerous as they are broad, spanning the basic sciences to clinical research to informatics, with abundant opportunities to shape our future practice of radiology. [ABSTRACT FROM AUTHOR]

Online social networking services have changed the way we interact as a society and offer many opportunities to improve the way we practice radiology and medicine in general. This article begins with an introduction to social networking. Next, the latest advances in online social networking are reviewed, and areas where radiologists and clinicians may benefit from these new tools are discussed. This article concludes with several steps that the interested reader can take to become more involved in online social networking. [ABSTRACT FROM AUTHOR]

Fostering radiology research among medical students can enhance a student's interest and understanding of radiology and research. It increases the academic productivity of the mentor and the department. Radiology faculty and departments should actively seek to recruit and engage students in research. Once involved, students benefit greatly from being given clear responsibility, close supervision, timely feedback, and a degree of autonomy. At the heart of the student research process is the crucial mentor-mentee relationship, and mentors should be cognizant of their vital role and methods of encouraging and enhancing this relationship. Ultimately, the advancement of the field of radiology depends on constant innovation and improvement. Radiology research by medical students fuels both innovation and the development of future academic radiologists and physician-scientists, helping to secure future growth for our field. [Copyright &y& Elsevier]

The rapid advances in mobile computing technology have the potential to change the way radiology and medicine as a whole are practiced. Several mobile computing advances have not yet found application to the practice of radiology, while others have already been applied to radiology but are not in widespread clinical use. This review addresses several areas where radiology and medicine in general may benefit from adoption of the latest mobile computing technologies and speculates on potential future applications. [Copyright &y& Elsevier]

Abstract: The paper proposes a method for analysing, modelling and foresighting the business ecosystems as network structures interacting one with each other. The methodology''s name is “methodology of business ecosystem network analysis” (MOBENA). The paper shows how it is possible to systematically study the structure and fluxes of a business ecosystem. The main problems of other modelling languages for firm interactions that MOBENA tries to overcome are that (1) the methodologies tailored for BEs are very few, the others neglect interdependences or focus only on tangible or intangible aspects, and (2) they limit potential for strategic analysis and they do not take in a future-perspective. The paper includes an analysis of literature on Strategic Management (in particular, strategic models on relationships), Network Analysis and Foresight, from whence the theoretical proposal of the MOBENA is born. Then, the authors illustrate its application via a case study conducted inside the Telecom Italia Future Centre, and in particular taking as example the digital imaging ecosystem. The original aspects are the mapping of tangible and intangible relationships, the dynamic and foresight analysis, the possibility to set strategic guidance thanks to specific indicators. [Copyright &y& Elsevier]

Abstract: As highly dense urban areas are also the top energy consumers, the question as to how we can design our cities to be “solar ready”, i.e. suitable for successful integration of active and passive solar strategies in buildings, arises. Through a series of insolation simulations of typical urban morphologies found in the city of Toronto, this study will attempt to (i) identify if Toronto is “solar ready”, (ii) suggest strategies to overcome obstacles, and (iii) develop new urban formations that maximize insolation levels to promote the integration of solar strategies in our built environments. [Copyright &y& Elsevier]

Abstract: Objective: Apart from its role in bone metabolism, vitamin D may also influence cardiovascular disease. The objective of this study was: (1) to determine the effect of a single, oral, high-dose vitamin D supplementation on endothelial function and arterial stiffness in patients with peripheral arterial disease (PAD) and (2) to investigate the impact of this supplementation on coagulation and inflammation parameters. Methods: In this double-blind, placebo-controlled, interventional pilot study, we screened 76 Caucasian patients with PAD for vitamin D deficiency. Sixty-two were randomised to receive a single, oral supplementation of 100 000 IU vitamin D3 or placebo. At baseline and after 1 month, we measured serum vitamin D and parathormone levels, and surrogate parameters for cardiovascular disease. Results: Sixty-five of 76 patients (86%) had low 25-hydroxyvitamin D levels (<30 ng ml−1); of those, 62 agreed to participate in the study. At baseline, only parathormone was related to vitamin D. In supplemented patients, vitamin D levels increased from 16.3 ± 6.7 to 24.3 ± 6.2 ng ml−1 (P < 0.001), with wide variations between single patients; in the placebo group vitamin levels did not change. Seasonal factors accounted for a decrease of vitamin D levels by 8 ng ml−1 between summer and winter. After 1 month, none of the measured parameters was influenced by vitamin substitution. Conclusion: In this pilot study, most patients with PAD were vitamin D deficient. Vitamin D supplementation increased serum 25-hydroxyvitamin D without influencing endothelial function, arterial stiffness, coagulation and inflammation parameters, although the study was underpowered for definite conclusions. [Copyright &y& Elsevier]

Abstract: A stream is a time-ordered sequence of data values. It is possible to define a semantic stream as a time-ordered sequence of metadata, i.e., a concept stream. It may derive from a collection of semantic annotations referred to objects/subjects whose status evolves during a process as in case of product flow in supply chains. Although a concrete added value comes from the annotation of products and processes, several issues are inherited. Particularly, concept streams typically assume a not compact form, hence a fully comprehensive concise representation is needed. Leveraging capabilities allowed by EPCglobal RFID protocol standard, the paper proposes a general framework able to provide a compact representation of large concept streams also finding informative commonalities in them so allowing automated pattern analysis and trend discovery. A case study is presented to clarify the approach. [Copyright &y& Elsevier]

Abstract: Background: Patients with heart failure (HF) develop metabolic derangements including increased adipokine levels, insulin resistance, inflammation and progressive catabolism. It is not known whether metabolic dysfunction and adipocyte activation worsen in the setting of acute clinical decompensation, or conversely, improve with clinical recovery. Methods and Results: We assessed insulin resistance using homeostasis model assessment of insulin resistance (HOMA-IR), and measured plasma levels of N-terminal pro–B-type natriuretic peptide (NT-proBNP), adiponectin, visfatin, resistin, leptin, and tumor necrosis factor (TNF) α in 44 patients with acute decompensated HF (ADHF) due to left ventricular (LV) systolic dysfunction and again early (<1 wk) and late (> 6 mo) after clinical recovery, in 26 patients with chronic stable HF, and in 21 patients without HF. NT-proBNP was not increased in control subjects, mildly elevated in patients with stable HF, markedly elevated in patients with ADHF, and decreased progressively early and late after treatment. Compared to control subjects, plasma adiponectin, visfatin, leptin, resistin, and TNF-α were elevated in patients with chronic stable HF and increased further in patients with ADHF. Likewise, HOMA-IR was increased in chronic stable HF and increased further during ADHF. Adiponectin, visfatin, and HOMA-IR remained elevated at the time of discharge from the hospital, but returned to chronic stable HF levels. Adipokine levels were not related to body mass index in HF patients. HOMA-IR correlated positively with adipokines and TNF-α in HF patients. Conclusions: ADHF is associated with worsening of insulin resistance and elevations of adipokines and TNF-α, indicative of adipocyte activation. These metabolic abnormalities are reversible, but they temporally lag behind the clinical resolution of decompensated HF. [Copyright &y& Elsevier]

Abstract: Formation of the placenta is a crucial step in mammalian pregnancy. Apart from its function in ensuring an optimal supply of nutrients and oxygen to the fetus, the placenta is also the interface at which allo-recognition of invading trophoblast cells by the maternal immune system can potentially occur. We summarise here the “state of the art” on how variability of immune system genes that code for major histocompatibility complex (MHC) molecules and natural killer receptors (NKR) may impact on human placentation. MHC and NKR are the most polymorphic human genes. Our recent reports point out that specific combinations of fetal MHC and maternal NKR genes in humans correlate with the risk of pre-eclampsia, recurrent miscarriage (RM) and fetal growth restriction (FGR). Research in this field is still at an early stage and future studies in mouse and humans will be needed before the results can be translated to clinical applications. We discuss our recent work, as well as the opportunities offered by mouse genetics, to understand the cellular and molecular mechanisms underlying immune interactions at the maternal-fetal interface. [Copyright &y& Elsevier]

Abstract: To evaluate the cardiotoxicity, general toxicity, and activity of non-pegylated liposomal doxorubicin, in combination with docetaxel and trastuzumab, as first-line therapy in metastatic breast cancer. Thirty-one patients with metastatic human epidermal growth factor receptor 2-overexpressing breast cancer, who had not previously received chemotherapy for metastatic disease, received non-pegylated liposomal doxorubicin (50mg/m2), docetaxel (75mg/m2) and trastuzumab (2mg/kg/week) for up to eight cycles, followed by trastuzumab alone for up to 52 weeks. Cardiotoxicity was defined as a decrease in left ventricular ejection fraction (LVEF) to below 45%, or a decrease in LVEF of at least 20% from baseline. Mean LVEF was maintained at baseline level also in the subset of patients who had received anthracycline previously. Cardiotoxicity developed in three patients during the treatment cycles, and in two further patients after the end of the study. The most common adverse events were haematological toxicity, alopecia, asthenia and fever. The best overall response rate was 65.5%. Median time to progression was 13.0 months. The combination of non-pegylated liposomal doxorubicin, docetaxel and trastuzumab combines acceptable cardiac and general toxicity and promising activity as first-line therapy in metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Abstract: Vinorelbine (i.v.) plus capecitabine (oral) combination therapy is active in anthracycline/taxane pretreated patients with metastatic breast cancer. Availability of oral vinorelbine provides this combination in an all-oral formulation. Two consecutive phase II trials differing only in vinorelbine administration routes evaluated their respective activities and tolerabilities in this population. In the i.v. group (n = 38) disease control was 61% (37% PR, 24% SD), median TTP 6.8 months and median survival 11.3 months. In the oral group (n = 38) disease control was 77% (5.4% CR, 34% PR, 38% SD), median TTP 7 months and median survival 10 months. G3–G4 neutropenia was more common in the oral group (p < 0.05); G2–G3 anaemia and G3 thrombocytopenia were observed only in the oral group. Although the comparison between the two regimens was not randomized, the results observed in these two consecutive phase II studies may suggest that oral and iv vinorelbine, in combination with capecitabine, can achieve similar responses in patients with metastatic breast cancer refractory to anthra–taxane combinations. [Copyright &y& Elsevier]

Background: To date, no study has tested the effect of different heparin dosages on the hemostatic changes during off-pump coronary artery bypass graft (OPCABG) surgery, and a wide variety of empirical anticoagulation protocols are being applied. We tested the effect of two different heparin dosages on the activation of the hemostatic system in patients undergoing OPCABG procedures. Methods: Forty-two patients eligible for OPCABG procedures were assigned in a randomized fashion to low-dose heparin (150 IU/kg) or high-dose heparin (300 IU/kg). Prothrombin fragment 1+2, plasmin/alpha 2 -plasmin inhibitor complex, D-dimer, soluble tissue factor, tissue factor pathway inhibitor, total thrombin activatable fibrinolysis inhibitor (TAFI), and activated TAFIa were assayed by specific enzyme-linked immunosorbent assays at six different timepoints, before, during, and after surgery. Platelet function was evaluated by means of an in vitro bleeding time test, platelet function analyzer-100. Results: The OPCABG surgery was accompanied by significant changes of all plasma biomarkers, indicative of systemic activation of coagulation and fibrinolysis. A significant increase in circulating TAFIa was detected perioperatively and postoperatively, and multiple regression analysis indicated that prothrombin F1+2 but not plasmin/alpha 2 -antiplasmin complex was independently associated with TAFIa level. Platelet function analyzer-100 values did not change significantly after OPCABG. All hemostatic changes were similar in the two heparin groups, even perioperatively, when the difference in anticoagulation was maximal. Conclusions: Both early and late hemostatic changes, including TAFI activation, are similarly affected in the low-dose and high-dose heparin groups, suggesting that the increase in heparin dosage is not accompanied by a better control of clotting activation during OPCABG surgery. [Copyright &y& Elsevier]

Abstract: Background: The efficacy of proton pump inhibitors in patients at high risk of gastrointestinal injury receiving non-steroidal anti-inflammatory drugs is currently debated. Aims: To evaluate the effects of esomeprazole on the impairment of gastric ulcer healing associated with non-steroidal anti-inflammatory drug treatment. Methods: Gastric ulcers were induced in rats by acetic acid. Four days later, animals were treated daily with equivalent acid-inhibiting doses of esomeprazole or famotidine, alone or in combination with indomethacin. At day 3 or 7 of treatment, ulcerated tissues were processed to assess: ulcer area; malondialdehyde; prostaglandin E2; nuclear factor-kB; proliferating cell nuclear antigen and caspase-3 (Western blot). Results: In indomethacin-treated animals, esomeprazole was more effective than famotidine or the antioxidant melatonin in promoting ulcer healing. Malondialdehyde levels were increased by indomethacin, and this effect was counteracted by esomeprazole, but not famotidine. Esomeprazole and famotidine, given alone or in combination with indomethacin, increased proliferating cell nuclear antigen expression. Increased levels of prostaglandin E2 were detected in ulcerated tissues. Ulcer prostaglandin E2 production was reduced by indomethacin, alone or in combination with esomeprazole or famotidine, while it was enhanced when esomeprazole or famotidine were tested alone. The activation of caspase-3 was induced by indomethacin, and this effect was prevented by esomeprazole, but not famotidine. In the presence of indomethacin, esomeprazole, but not famotidine, enhanced nuclear factor-kB activation in gastric ulcers. Conclusions: Esomeprazole counteracts the detrimental action of indomethacin on ulcer repair through both acid-dependent and acid-independent effects. The acid-independent actions are related to decrease in tissue oxidation and apoptosis and to enhancement of nuclear factor-kB activation. [Copyright &y& Elsevier]

Nonalcoholic fatty liver disease (NAFLD) may be a risk factor for hepatocellular carcinoma (HCC), but the extent of this association still needs to be addressed. Pooled incidence rates of HCC across the disease spectrum of NAFLD have never been estimated by meta-analysis. In this systematic review, we searched Web of Science, Embase, PubMed, and the Cochrane Library from January 1, 1950 through July 30, 2020. We included studies reporting on HCC incidence in patients with NAFLD. The main outcomes were pooled HCC incidences in patients with NAFLD at distinct severity stages. Summary estimates were calculated with random-effects models. Sensitivity analyses and meta-regression analyses were carried out to address heterogeneity. We included 18 studies involving 470,404 patients. In patients with NAFLD at a stage earlier than cirrhosis, the incidence rate of HCC was 0.03 per 100 person-years (95% confidence interval [CI], 0.01–0.07; I2 = 98%). In patients with cirrhosis, the incidence rate was 3.78 per 100 person-years (95% CI, 2.47–5.78; I2 = 93%). Patients with cirrhosis undergoing regular screening for HCC had an incidence rate of 4.62 per 100 person-years (95% CI, 2.77–7.72; I2 = 77%). Patients with NAFLD-related cirrhosis have a risk of developing HCC similar to that reported for patients with cirrhosis from other etiologies. Evidence documenting the risk in patients with nonalcoholic steatohepatitis or simple steatosis is limited, but the incidence of HCC in these populations may lie below thresholds used to recommend a screening. Well-designed prospective studies in these subpopulations are needed. The protocol for this systematic review is registered in the Prospero database (registration number CRD42018092861). [ABSTRACT FROM AUTHOR]

Introduction: Despite the large number of drugs active in AGC, no combination can be considered as the gold standard treatment. Modest increase have been obtained in overall survival with the most widely employed regimens such as CF or ECF, often obtained at expense of increased toxicity. So there is a strong need to develop new active drugs to improve the clinical outcome. Taxotere showed to be effective in preclinical studies and some phase II trials confirmed its clinical efficacy. Recently, the addition of TXT to CDDP + FU (TCF regimen), obtained, in a large randomised phase III trial, better survival than CF alone. However the toxicity of this combination was relevant and mainly due to the association with CDDP. Considering these data the GOIM started a phase II study aiming to evaluate efficacy and safety of a three drugs combination, employing EPI instead of CDDP.Materials and methods: Forty-one histologically proven untreated gastric cancer patients, with advanced measurable disease, age between 18 and 75 years, performance status greater-or-equal, slanted 70 (Kfsky scale) and available to sign written informed consent, were enrolled. They received the following treatment: Epirubicin at 60 mg/m2 on day 1, Taxotere at 50 mg/m2 on day 1, Folinic Acid at 100 mg/m2 on days 1-2, Fluorouracil bolus at 400 mg/m2 on days 1-2 and Fluorouracil 22 h continuous infusion on days 1-2 every three weeks.Results: Amongst the 38 evaluable patients we observed 5 CR (13%), 9 PR (24%), 9 SD (24%) and 15 PD (39%) for an ORR of 37% (95% CI: 22-52) and a tumor growth control rate of 61%. The median time to progression was 4 months and the median survival was 9 months.The treatment was well tolerated. The main grade III-IV haematologic toxicities were leucopenia 7%, neutropenia 5% and anemia 5% while non-haematologics were diarrhoea 2%, alopecia 2% and cardiac 2%.Conclusion: The three drugs combination of Taxotere, Epirubicin and Fluorouracil is active and well tolerated first-line treatment in advanced gastric cancer patients. [ABSTRACT FROM AUTHOR]

Introduction: Folfox-4 is the standard adjuvant treatment in stage III colon cancer and is also recommended in high-risk stage II colon cancer. Oxaliplatin-based regimens are considered moderately emetogenic therapies. Palonosetron, a new selective inhibitor of 5-HT3 receptors, in combination with dexhametasone showed a high antiemetic activity in pivotal trials enrolling patients treated with moderately or high emetogenic regimens. Considering these data, the GOIM started a multicentre phase II trial aiming to evaluate the activity and safety of palonosetron plus dexhametasone in patients affected by radically resected colorectal cancer and treated with adjuvant folfox-4.Materials and methods: Patients with stage III or high-risk stage II colorectal cancer and receiving folfox-4 as adjuvant treatment entered into the trial. Informed written consent was required. A single pretreatment dose of palonosetron 0.25 mg (intravenous) i.v. followed by dexamethasone 8 mg i.v. was administered. Nausea and vomiting were evaluated on day 1 and over the following 4 d, with a patient diary including vomiting episodes, daily nausea and use of rescue medications. The main end-point of the study was the absence of vomiting in the entire period (5 d) at the first cycle. The absence of moderately or severe nausea and vomiting on days 1-5 was the secondary end-point. Adverse events were evaluated according to the NCI-CTC criteria.Results: Eighty-five patients entered into the study and were all evaluable for activity and safety. The absence of vomiting on the study period (days 1-5) was observed in 82 (96.5%) patients: one patient on the 1st and two on the 2nd day experienced mild vomiting. With respect to the secondary end-point, the complete control during the acute phase was 96.5% while during the late phase was 92%. The complete responses during the acute and delayed phases were 99% and 89.5%, respectively. The main side-effects (G1 grade) were: constipation 13%, headache 10%, vertigo and insomnia 2%.Conclusions: Palonosetron is a very active antiemetic drug for the prevention of nausea and vomiting induced by folfox-4 regimen. [ABSTRACT FROM AUTHOR]

Background: This study was carried out to evaluate total basal bilirubin levels as a predictive factor for survival and toxicity in patients with advanced colorectal carcinoma treated with CTP-11-based regimens.Patients and methods: The analysis was carried out on a data base including 287 patients affected by advanced colorectal carcinoma all treated with CPT-11 plus bolus and continuous venous infusion intravenous folinic acid and 5-fluorouracil on a biweekly schedule (FOLFIRI regimen). Patients were divided into four groups according to basal bilirubin levels as follows: <0.49 mg/dl; >0.50 and <0.99 mg/dl; >1.00 and <1.49 mg/dl; >1.50 mg/dl. Analysis of overall median survival and time-to-progression were correlated to performance status at entry, volume of liver metastases, and carcinoembrionary antigen.Results: Global statistical analysis showed that bilirubin levels were strongly correlated with time-to-progression and overall survival in a statistically significant fashion (p < 0.0001). The size of liver metastases represents the only study parameter which is correlated to basal bilirubin levels in a statistically significant fashion. Neutropaenia and diarrhoea were also correlated to baseline bilirubin levels in a statistically significant manner (p = 0.001).Conclusions: Data reported in this study support the observation that basal bilirubin levels are a biomarker able to predict, at least in part, the clinical efficacy and toxicity of CPT-11-based chemotherapy in patients with advanced colorectal carcinoma. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Despite the large number of drugs active in AGC, no combination can be considered as the gold standard treatment. Modest increase have been obtained in overall survival with the most widely employed regimens such as CF or ECF, often obtained at expense of increased toxicity. So there is a strong need to develop new active drugs to improve the clinical outcome. Taxotere showed to be effective in preclinical studies and some phase II trials confirmed its clinical efficacy. Recently, the addition of TXT to CDDP + FU (TCF regimen), obtained, in a large randomised phase III trial, better survival than CF alone. However the toxicity of this combination was relevant and mainly due to the association with CDDP. Considering these data the GOIM started a phase II study aiming to evaluate efficacy and safety of a three drugs combination, employing EPI instead of CDDP. Materials and methods: Forty-one histologically proven untreated gastric cancer patients, with advanced measurable disease, age between 18 and 75 years, performance status ⩾70 (Kfsky scale) and available to sign written informed consent, were enrolled. They received the following treatment: Epirubicin at 60mg/m2 on day 1, Taxotere at 50mg/m2 on day 1, Folinic Acid at 100mg/m2 on days 1–2, Fluorouracil bolus at 400mg/m2 on days 1–2 and Fluorouracil 22h continuous infusion on days 1–2 every three weeks. Results: Amongst the 38 evaluable patients we observed 5 CR (13%), 9 PR (24%), 9 SD (24%) and 15 PD (39%) for an ORR of 37% (95% CI: 22–52) and a tumor growth control rate of 61%. The median time to progression was 4 months and the median survival was 9 months. The treatment was well tolerated. The main grade III–IV haematologic toxicities were leucopenia 7%, neutropenia 5% and anemia 5% while non-haematologics were diarrhoea 2%, alopecia 2% and cardiac 2%. Conclusion: The three drugs combination of Taxotere, Epirubicin and Fluorouracil is active and well tolerated first-line treatment in advanced gastric cancer patients. [Copyright &y& Elsevier]

Abstract: Introduction Folfox-4 is the standard adjuvant treatment in stage III colon cancer and is also recommended in high-risk stage II colon cancer. Oxaliplatin-based regimens are considered moderately emetogenic therapies. Palonosetron, a new selective inhibitor of 5-HT3 receptors, in combination with dexhametasone showed a high antiemetic activity in pivotal trials enrolling patients treated with moderately or high emetogenic regimens. Considering these data, the GOIM started a multicentre phase II trial aiming to evaluate the activity and safety of palonosetron plus dexhametasone in patients affected by radically resected colorectal cancer and treated with adjuvant folfox-4. Materials and methods Patients with stage III or high-risk stage II colorectal cancer and receiving folfox-4 as adjuvant treatment entered into the trial. Informed written consent was required. A single pretreatment dose of palonosetron 0.25mg (intravenous) i.v. followed by dexamethasone 8mg i.v. was administered. Nausea and vomiting were evaluated on day 1 and over the following 4d, with a patient diary including vomiting episodes, daily nausea and use of rescue medications. The main end-point of the study was the absence of vomiting in the entire period (5d) at the first cycle. The absence of moderately or severe nausea and vomiting on days 1–5 was the secondary end-point. Adverse events were evaluated according to the NCI-CTC criteria. Results Eighty-five patients entered into the study and were all evaluable for activity and safety. The absence of vomiting on the study period (days 1–5) was observed in 82 (96.5%) patients: one patient on the 1st and two on the 2nd day experienced mild vomiting. With respect to the secondary end-point, the complete control during the acute phase was 96.5% while during the late phase was 92%. The complete responses during the acute and delayed phases were 99% and 89.5%, respectively. The main side-effects (G1 grade) were: constipation 13%, headache 10%, vertigo and insomnia 2%. Conclusions Palonosetron is a very active antiemetic drug for the prevention of nausea and vomiting induced by folfox-4 regimen. [Copyright &y& Elsevier]

Abstract: Background: This study was carried out to evaluate total basal bilirubin levels as a predictive factor for survival and toxicity in patients with advanced colorectal carcinoma treated with CTP-11-based regimens. Patients and methods: The analysis was carried out on a data base including 287 patients affected by advanced colorectal carcinoma all treated with CPT-11 plus bolus and continuous venous infusion intravenous folinic acid and 5-fluorouracil on a biweekly schedule (FOLFIRI regimen). Patients were divided into four groups according to basal bilirubin levels as follows: <0.49mg/dl; >0.50 and <0.99mg/dl; >1.00 and <1.49mg/dl; >1.50mg/dl. Analysis of overall median survival and time-to-progression were correlated to performance status at entry, volume of liver metastases, and carcinoembrionary antigen. Results: Global statistical analysis showed that bilirubin levels were strongly correlated with time-to-progression and overall survival in a statistically significant fashion (p <0.0001). The size of liver metastases represents the only study parameter which is correlated to basal bilirubin levels in a statistically significant fashion. Neutropaenia and diarrhoea were also correlated to baseline bilirubin levels in a statistically significant manner (p =0.001). Conclusions: Data reported in this study support the observation that basal bilirubin levels are a biomarker able to predict, at least in part, the clinical efficacy and toxicity of CPT-11-based chemotherapy in patients with advanced colorectal carcinoma. [Copyright &y& Elsevier]

Abstract: This paper is an updated review of the pre-clinical rationale and clinical results of new EGFR-targeted agents – cetuximab and panitumumab – employed in the management of advanced/ metastatic colorectal cancer. The addition of either biologic agent or last generation standard chemotherapy regimens – FOLFIRI and FOLFOX – has yielded better results as compared to those reported for chemotherapy alone. These results have been obtained without a significant increase in severe toxicity with the exception of skin side-effects. [Copyright &y& Elsevier]

Background: In the CAPRICORN trial, carvedilol reduced all-cause mortality by 23% over a mean follow-up of 1.3 years in clinically stabilized post–myocardial infarction (MI) patients with left ventricular dysfunction (LVD) with or without signs of heart failure. This analysis sought to assess the impact of carvedilol within the first 30 days of randomization. Methods: The effect of carvedilol initiated after acute MI with LVD (n = 975) was compared with the effect of placebo (n = 984) added to other standard-of-care therapies on mortality, fatal or nonfatal infarction, cardiac arrest, and their composite as well as withdrawals for adverse events during the first 30 days of therapy. Results: The carvedilol group experienced a reduction in mortality in the first 30 days (19 vs 33, hazard ratio [HR] 0.58, 95% CI 0.33-1.02); fatal or nonfatal MI (13 vs 23, HR 0.57, 95% CI 0.29-1.12); the composite end point of death, nonfatal MI, or cardiac arrest (31 vs 53, HR 0.58, 95% CI 0.38-0.91); and the composite of all-cause mortality or nonfatal MI (29 vs 51, HR 0.57, 95% CI 0.36-0.90). These effects were similar in direction and magnitude to those observed during the entire trial. The rates of adverse events leading to withdrawal were similar in the carvedilol and placebo groups, except for hypotension. Conclusions: In clinically stabilized post-MI patients with LVD, there is an early benefit with carvedilol treatment that is similar to that seen during long-term therapy. [Copyright &y& Elsevier]

Background: Left ventricular remodeling is characterized by increased collagen deposition in the extracellular matrix. Levels of plasma procollagen type III amino-terminal peptide (PIIINP), a marker of collagen turnover, are elevated in the setting of recent myocardial infarction, heart failure, and cardiomyopathy. Whether plasma PIIINP levels are a useful indicator of subclinical left ventricular abnormalities in ambulatory individuals has not been studied.Methods: We examined 967 Framingham Heart Study participants (mean age, 56 years; 60% women) who underwent routine echocardiography and measurement of plasma PIIINP levels. All participants were free of prior myocardial infarction or heart failure. Multivariable regression analyses were performed to examine the clinical and echocardiographic correlates of PIIINP levels.Results: Plasma PIIINP levels increased with age and body mass index but did not significantly correlate with other cardiovascular risk factors including hypertension and diabetes. In multivariable models, there was no association between plasma PIIINP levels and left ventricular mass (P = .89), left ventricular fractional shortening (P = .15), left ventricular end-diastolic dimension (P = .51), or left atrial size (P = .68). Plasma PIIINP levels were positively correlated with tissue inhibitor of metalloproteinase-1 levels (multivariable-adjusted, P = .001).Conclusions: The use of biomarkers of extracellular matrix turnover has generated recent interest, with plasma PIIINP being the most commonly studied biomarker in acute settings. However, our findings in a large, community-based cohort suggest that plasma PIIINP has limited use for the detection of structural heart disease in ambulatory individuals. [ABSTRACT FROM AUTHOR]

Abstract: Background: Aldosterone antagonists reduce morbidity and mortality in patients with severe heart failure, but the mechanisms responsible are not fully understood. Observations in animal models suggest that elevated levels of aldosterone promote oxidative stress and inflammation in the myocardium. It is unknown if these findings are relevant to heart failure patients who may have much lower aldosterone levels. Methods and Results: We therefore examined the relationship of plasma aldosterone levels to markers of oxidative stress, inflammation and matrix turnover in 58 patients with chronic, stable heart failure from systolic dysfunction (LV ejection fraction <0.40) who were not receiving aldosterone antagonists. Chronic, stable heart failure patients had modestly elevated levels of aldosterone. Additionally, these patients had elevated levels of 8-isoprostaglandin F2α, C-reactive protein, soluble intercellular adhesion molecule-1, osteopontin, brain natriuretic peptide, procollagen type III aminoterminal peptide, and tissue inhibitor of metalloproteinase-1. Among these patients with heart failure, aldosterone levels correlated with 8-iso-PGF2α (P = .003), ICAM-1 (P = .008), and TIMP-1 (P = .006) after adjustment for age, gender, race, diabetes, smoking, heart rate, left ventricular mass, and body mass index. Conclusion: In chronic, stable heart failure patients on standard therapy, higher aldosterone levels are associated with systemic evidence of oxidative stress, inflammation, and matrix turnover. [Copyright &y& Elsevier]

Abstract: Background: The nature of oxidative stress and the activity of antioxidant enzyme systems are incompletely characterized in the failing human heart. Methods and Results: We obtained ventricular myocardium from failing, explanted human hearts in patients with nonischemic dilated cardiomyopathy at the time of heart transplant to examine whether reactive oxygen species (ROS) production and antioxidant enzyme activity or expression were altered in end-stage human heart failure. Nonfailing myocardium was obtained from organ donors who were not eligible for transplantation. Electroparamagnetic resonance (EPR) with the O2 − spin trap 5-diethoxyphosphoryl-5-methyl-1-pyrroline N-oxide demonstrated that formation of superoxide anion was increased more than 2-fold in the failing (P < .001 vs. nonfailing) myocardium. Manganese superoxide dismutase (MnSOD) mRNA and catalase mRNA expression were increased by 52% (P =.05) and 116% (P < .05), respectively, in failing vs. nonfailing hearts. Copper-zinc superoxide dismutase (CuZnSOD) mRNA and glutathione peroxidase-1 (GPx-1) mRNA were unchanged. The expression of MnSOD, CuZnSOD, and catalase mRNA showed moderate correlation, suggesting coordinate regulation of gene expression. Activity was no different with regard to catalase, GPx-1, and glucose-6-phosphate dehydrogenase. MnSOD activity accounted for approximately 90% of total SOD activity, and was markedly decreased in failing hearts (by 61%, P < .05). MnSOD protein expression by western blot analysis was decreased in the failing group (P < .05 vs. nonfailing). Conclusion: The decrease in MnSOD activity in failing myocardium, in the setting of increased mRNA expression, may reflect decreased translation or processing, or a posttranslational modification of MnSOD. The increase in MnSOD mRNA in failing hearts is consistent with the thesis that there is increased oxidative stress in failing myocardium that leads to increase transcription of antioxidant enzymes. The source of this direct measure of ROS is likely superoxide. These observations have implications for the pathophysiology and treatment of heart failure. [Copyright &y& Elsevier]

Testing kinship between pairs of individuals is central to a wide range of applications. We focus on cases where many tests are done jointly. Typical examples include cases where DNA profiles are available from a burial site, a plane crash or a database of convicted offenders. The task is to determine the relationships between DNA profiles or individuals. Our approach generalises previous methods and implementations in several respects. We model general, possibly inbred, pairwise relationships which is important for non-human applications and in archaeological studies of ancient inbred populations. Furthermore, we do not restrict attention to autosomal markers. Some cases, such as distinguishing between maternal and paternal half siblings, can be solved using X-chromosomal markers. When many tests are done, the risk of errors increases. We address this problem by building on the theory of multiple testing and show how optimal thresholds for tests can be determined. We point out that the likelihood ratios in a blind search may be dependent so multiple testing methods and interpretation need to account for this. In addition, we show how a Bayesian approach can be helpful. Our examples, using simulated and real data, demonstrate the practical importance of the methods and implementation is based on freely available software. • Search for general pairwise relationships. • Finding optimal thresholds for likelihood ratios. • Correcting for multiple testing in relationship searching. • Bayesian version of blind search. [ABSTRACT FROM AUTHOR]