Knowledge Gaps in Cardiovascular Care of Older Adults: A Scientific Statement from the American Heart Association, American College of Cardiology, and American Geriatrics Society: Executive Summary.
The incidence and prevalence of most cardiovascular disorders increase with age, and cardiovascular disease (CVD) is the leading cause of death and major disability in adults aged 75 and older. Despite the effect of CVD on quality of life, morbidity, and mortality in older adults, individuals aged 75 and older have been markedly underrepresented in most major cardiovascular trials, and virtually all trials have excluded older adults with complex comorbidities, significant physical or cognitive disabilities, frailty, or residence in nursing homes and assisted living facilities. As a result, current guidelines are unable to provide evidence-based recommendations for diagnosis and treatment of older adults typical of those encountered in routine clinical practice. The objectives of this scientific statement are to summarize current guideline recommendations as they apply to older adults, identify critical gaps in knowledge that preclude informed evidence-based decision-making, and recommend future research to close existing knowledge gaps. To achieve these objectives, a detailed review was conducted of current American College of Cardiology/American Heart Association (ACC/AHA) and American Stroke Association (ASA) guidelines to identify content and recommendations that explicitly targeted older adults. A pervasive lack of evidence to guide clinical decision-making in older adults with CVD was found, as well as a paucity of data on the effect of diagnostic and therapeutic interventions on outcomes that are particularly important to older adults, such as quality of life, physical function, and maintenance of independence. Accordingly, there is a critical need for a multitude of large population-based studies and clinical trials that include a broad spectrum of older adults representative of those seen in clinical practice and that incorporate relevant outcomes important to older adults in the study design. The results of these studies will provide the foundation for future evidence-based guidelines applicable to older adults and enhance person-centered care of older individuals with CVD in the United States and around the world.


Diameter dependent electron transfer kinetics in semiconductor-enzyme complexes.
Excited state electron transfer (ET) is a fundamental step for the catalytic conversion of solar energy into chemical energy. To understand the properties controlling ET between photoexcited nanoparticles and catalysts, the ET kinetics were measured for solution-phase complexes of CdTe quantum dots and Clostridium acetobutylicum [FeFe]-hydrogenase I (CaI) using time-resolved photoluminescence spectroscopy. Over a 2.0-3.5 nm diameter range of CdTe nanoparticles, the observed ET rate (kET) was sensitive to CaI concentration. To account for diameter effects on CaI binding, a Langmuir isotherm and two geometric binding models were created to estimate maximal CaI affinities and coverages at saturating concentrations. Normalizing the ET kinetics to CaI surface coverage for each CdTe diameter led to k(ET) values that were insensitive to diameter, despite a decrease in the free energy for photoexcited ET (ΔGET) with increasing diameter. The turnover frequency (TOF) of CaI in CdTe-CaI complexes was measured at several molar ratios. Normalization for diameter-dependent changes in CaI coverage showed an increase in TOF with diameter. These results suggest that k(ET) and H2 production for CdTe-CaI complexes are not strictly controlled by ΔG(ET) and that other factors must be considered.


Etiologic spectrum and prognosis of longitudinally extensive transverse myelopathies.
Patients with a first episode of longitudinal extensive transverse myelopathy (LETM) were reviewed with two objectives: to evaluate the clinical spectrum of LETM and to analyze the related clinical and laboratory variables that can be used as functional prognostic markers. A retrospective review was conducted of clinical, radiologic and biochemical data of patients admitted for LETM between 1993 and 2011. Our cohort included 72 patients [median age 41 years, interquartile range (IQR) 29-61.5]. Median follow-up was 34 months (IQR 17.2-63). The modified Rankin Scale (mRS) score was ≥2 at the end of follow-up in 72.2%. The final diagnosis was idiopathic LETM in 22 patients, multiple sclerosis in 18, parainfectious disease in 11, systemic disease in 9, spinal cord infarction and neuromyelitis optica spectrum disorders in 3 patients each, and acute demyelinating encephalomyelitis, dural fistula, and tumor-related LETM in 2 patients each. Unfavorable outcome was associated with mRS ≥2 at admission [odds ratio (OR) 1.39, 95% confidence interval (CI) 1.16-1.66] and older age (OR 1.06, 95% CI 1.01-1.11). Idiopathic LETM was the most frequent diagnosis at the end of follow-up. Older age and clinically severe disease at onset were independent prognostic factors of poorer functional recovery.


A comparative pharmacodynamic study of the arrhythmogenicity of antidepressants, fluvoxamine and imipramine, in guinea pigs.
Among several classes of antidepressants, tricyclic antidepressants are known to prolong QTc intervals (QT interval corrected by heart rate) in electrocardiograms, while selective serotonin uptake inhibitors (SSRI) are considered to be devoid of arrhythmogenicity. In this study, we aimed to compare the arrhythmogenic potencies of imipramine (IMI), a typical tricyclic antidepressant, and fluvoxamine (FLV), an SSRI, at therapeutic and supratherapeutic concentrations using guinea pigs in vivo. Guinea pigs were anesthetized, and IMI (10 and 20 mg/kg/h) or FLV (20 mg/kg/h) was intravenously administered for 90 minutes to obtain the time-courses of drug concentrations in plasma and the changes in the QTc intervals during and after the drug administration. IMI induced distinct QTc prolongation in a dose-dependent manner, while FLV prolonged QTc intervals only slightly. A pharmacokinetic-pharmacodynamic analysis revealed that the potency for QTc prolongation of IMI was 1.7-fold higher than that of FLV. Taking the therapeutic concentration into account, the clinical risk of FLV for QTc prolongation was suggested to be 5-fold lower than that of IMI. Therefore, this SSRI agent was suggested to be safer than the tricyclic antidepressant for patients with cardiac risk factors, including arrhythmia, or for those taking other arrhythmogenic drugs concomitantly.


Important considerations for the validation of QSAR models for in vitro mutagenicity.
While high-level performance metrics generated from the validation of quantitative structure-activity relationship (QSAR) systems can provide valuable information on how well these models perform and where they need to be improved, they require appropriate interpretation. There is no universal performance metric which will answer all of the questions a user might ask relating to a model, and therefore, a combination of metrics should usually be considered. Furthermore, results may vary according to the chemical space being used to validate a model, and, in some cases, it may be the validation data which is lacking or ambiguous rather than the prediction being made. Finally, users also need to consider the interpretability of the predictions being made, alongside the accuracy of the predictions. In this paper, we will discuss these important considerations in more detail within the context of the results obtained at Lhasa Limited as part of the National Institute of Health Sciences (NIHS) QSAR challenge project.


The zinc finger protein A20 inhibits TNF-induced NF-kappaB-dependent gene expression by interfering with an RIP- or TRAF2-mediated transactivation signal and directly binds to a novel NF-kappaB-inhibiting protein ABIN.
The zinc finger protein A20 is a tumor necrosis factor (TNF)- and interleukin 1 (IL-1)-inducible protein that negatively regulates nuclear factor-kappa B (NF-kappaB)-dependent gene expression. However, the molecular mechanism by which A20 exerts this effect is still unclear. We show that A20 does not inhibit TNF- induced nuclear translocation and DNA binding of NF-kappaB, although it completely prevents the TNF- induced activation of an NF-kappaB-dependent reporter gene, as well as TNF-induced IL-6 and granulocyte macrophage-colony stimulating factor gene expression. Moreover, NF-kappaB activation induced by overexpression of the TNF receptor-associated proteins TNF receptor-associated death domain protein (TRADD), receptor interacting protein (RIP), and TNF recep- tor-associated factor 2 (TRAF2) was also inhibited by expression of A20, whereas NF-kappaB activation induced by overexpression of NF-kappaB-inducing kinase (NIK) or the human T cell leukemia virus type 1 (HTLV-1) Tax was unaffected. These results demonstrate that A20 inhibits NF-kappaB-dependent gene expression by interfering with a novel TNF-induced and RIP- or TRAF2-mediated pathway that is different from the NIK-IkappaB kinase pathway and that is specifically involved in the transactivation of NF-kappaB. Via yeast two-hybrid screening, we found that A20 binds to a novel protein, ABIN, which mimics the NF-kappaB inhibiting effects of A20 upon overexpression, suggesting that the effect of A20 is mediated by its interaction with this NF-kappaB inhibiting protein, ABIN.


Toward highly radiative white light emitting nanostructures: a new approach to dislocation-eliminated GaN/InGaN core-shell nanostructures with a negligible polarization field.
White light emitting InGaN nanostructures hold a key position in future solid-state lighting applications. Although many suggested approaches to form group III-nitride vertical structures have been reported, more practical and cost effective methods are still needed. Here, we present a new approach to GaN/InGaN core-shell nanostructures at a wafer level formed by chemical vapor-phase etching and metal-organic chemical vapor deposition. Without a patterning process, we successfully obtained high quality and polarization field minimized In-rich GaN/InGaN core-shell nanostructures. The various quantum well thicknesses and the multi-facets of the obelisk-shaped core-shell nanostructures provide a broad spectrum of the entire visible range without changing the InGaN growth temperature. Due to their high crystal quality and polarization field reduction, the core-shell InGaN quantum wells show an ultrafast radiative recombination time of less than 200 ps and uniformly high internal quantum efficiency in the broad spectral range. We also investigated the important role of polarization fields in the complex recombination dynamics in InGaN quantum wells.


Strategies for feeding the preterm infant.
According to many experts in neonatal nutrition, the goal for nutrition of the preterm infant should be to achieve a postnatal growth rate approximating that of the normal fetus of the same gestational age. Unfortunately, most preterm infants, especially those born very preterm with extremely low birth weight, are not fed sufficient amounts of nutrients to produce normal fetal rates of growth and, as a result, end up growth-restricted during their hospital period after birth. Growth restriction is a significant problem, as numerous studies have shown definitively that undernutrition, especially of protein, at critical stages of development produces long-term short stature, organ growth failure, and both neuronal deficits of number and dendritic connections as well as later behavioral and cognitive outcomes. Furthermore, clinical follow-up studies have shown that among infants fed formulas, the nutrient content of the formula is directly and positively related to mental and motor outcomes later in life. Nutritional requirements do not stop at birth. Thus, delaying nutrition after birth 'until the infant is stable' ignores the fundamental point that without nutrition starting immediately after birth, the infant enters a catabolic condition, and catabolism does not contribute to normal development and growth. Oxygen is necessary for all metabolic processes. Recent trends to limit oxygen supply to prevent oxygen toxicity have the potential, particularly when the blood hemoglobin concentration falls to less than 8 g/dl, to develop growth failure. Glucose should be provided at 6-8 mg/min/kg as soon after birth as possible and adjusted according to frequent measurements of plasma glucose to achieve and maintain concentrations >45 mg/dl but <120 mg/dl to avoid the frequent problems of hyperglycemia and hypoglycemia. Similarly, lipid is required to provide at least 0.5 g/kg/day to prevent essential fatty acid deficiency. However, the high rate of carbohydrate and lipid supply that preterm infants often get, based on the incomplete assumption that this is necessary to promote protein growth, tends to produce increased fat in organs like the liver and heart as well as adipose tissue. More and better essential fatty acid nutrition is valuable, but more organ and adipose fat has no known benefit and many problems. Amino acids and protein are essential not only for body growth but for metabolic signaling, protein synthesis, and protein accretion. 3.5-4.0 g/kg/day are necessary to produce normal protein balance and growth in very preterm infants. Attempts to promote protein growth with insulin has many problems - it is ineffective while contributing to even further organ and adipose tissue fat deposition. Enteral feeding always is indicated and to date nearly all studies have shown that minimal enteral feeding approaches (e.g., 'trophic feeds') promote the capacity to feed enterally. Milk has distinct advantages over formulas in avoiding necrotizing enterocolitis (NEC), and while feeding is associated with NEC, minimal enteral feeding regimens produce less NEC than those geared towards more aggressive introduction of enteral feeding. Finally, overfeeding has the definite potential to produce adipose tissue, or obesity, which then leads to insulin resistance, glucose intolerance, and diabetes. This scenario occurs more commonly as infants are fed more and gain weight more rapidly after birth, regardless of their birth weight. Infants with IUGR and postnatal growth failure may be uniquely 'set up' for this outcome, while infants with in utero obesity, such as infants of diabetic mothers, already are well along this adverse outcome pathway.


Molecular prediction of lytic vs lysogenic states for Microcystis phage: Metatranscriptomic evidence of lysogeny during large bloom events.
Microcystis aeruginosa is a freshwater bloom-forming cyanobacterium capable of producing the potent hepatotoxin, microcystin. Despite increased interest in this organism, little is known about the viruses that infect it and drive nutrient mobilization and transfer of genetic material between organisms. The genomic complement of sequenced phage suggests these viruses are capable of integrating into the host genome, though this activity has not been observed in the laboratory. While analyzing RNA-sequence data obtained from Microcystis blooms in Lake Tai (Taihu, China), we observed that a series of lysogeny-associated genes were highly expressed when genes involved in lytic infection were down-regulated. This pattern was consistent, though not always statistically significant, across multiple spatial and temporally distinct samples. For example, samples from Lake Tai (2014) showed a predominance of lytic virus activity from late July through October, while genes associated with lysogeny were strongly expressed in the early months (June-July) and toward the end of bloom season (October). Analyses of whole phage genome expression shows that transcription patterns are shared across sampling locations and that genes consistently clustered by co-expression into lytic and lysogenic groups. Expression of lytic-cycle associated genes was positively correlated to total dissolved nitrogen, ammonium concentration, and salinity. Lysogeny-associated gene expression was positively correlated with pH and total dissolved phosphorous. Our results suggest that lysogeny may be prevalent in Microcystis blooms and support the hypothesis that environmental conditions drive switching between temperate and lytic life cycles during bloom proliferation.


Synovial tissue macrophage as a source of the chemotactic cytokine IL-8.
Cells of the synovial microenvironment may recruit neutrophils (PMN) and lymphocytes into synovial fluid, as well as lymphocytes into the synovial tissues, of arthritic patients. We have investigated the production of the chemotactic cytokine IL-8 by using sera, synovial fluid, synovial tissue, and macrophages and fibroblasts isolated from synovial tissues from 75 arthritic patients. IL-8 levels were higher in synovial fluid from rheumatoid (RA) patients (mean +/- SE, 14.37 +/- 5.8 ng/ml), compared with synovial fluid from osteoarthritis patients (0.135 +/- 17 ng/ml) (p less than 0.05) or from patients with other arthritides (5.52 +/- 5.11 ng/ml). IL-8 from RA sera was 8.44 +/- 2.33 ng/ml, compared with nondetectable levels found in normal sera. IL-8 levels from RA sera and synovial fluid were strongly positively correlated (r = 0.96, p less than 0.05). Moreover, RA synovial fluid chemotactic activity for PMN in these fluids was inhibited 40 +/- 5% upon incubation with neutralizing polyclonal antibody to IL-8. Synovial tissue fibroblasts released only small amounts of constitutive IL-8 but could be induced to produce IL-8 by stimulation with either IL-1 beta, TNF-alpha, or LPS. In contrast, unlike normal PBMC or alveolar macrophages, macrophages isolated from RA synovial tissue constitutively expressed both IL-8 mRNA and antigenic IL-8. RA synovial macrophage IL-8 expression was not augmented by incubation with either LPS, TNF-alpha, or IL-1 beta. Immunohistochemical analysis of synovial tissue showed that a greater percentage of RA macrophages than osteoarthritis macrophages reacted with anti-IL-8. Whereas macrophages were the predominant cell for immunolocalization of IL-8, less than 5% of synovial tissue fibroblasts were positive for immunolocalized IL-8. These results suggest that macrophage-derived IL-8 may play an important role in the recruitment of PMN in synovial inflammation associated with RA.


Feeding problems in severely demented patients seen from task and relationship aspects.
This study aimed at increasing the understanding of feeding problems in severely demented patients cared for in a task assignment system. Twenty-three video-recordings made during the feeding of 15 severely demented patients and 55 focused interviews with 45 caregivers, who fed the 15 patients during that period were analysed regarding the feeding problems seen from a task aspect and from a relationship aspect. The result indicated that the problems were partly of a more constant nature and partly fluctuated from meal to meal. Feeding problems regarding the task aspect were mentioned first by the caregivers in the interviews in spite of the fact that the patients had severe communication problems which could be expected to cause great problems in the relationship between the patient and his caregiver. Reasons for these findings are suggested.


Update on the role of emerging stem cell technology in head and neck medicine.
Head and neck surgery is a broad discipline that involves the management of complex conditions such as burns, skin cancer, head and neck cancer, congenital abnormalities, and facial rejuvenation. For patients with cancer, surgery, radiotherapy, and chemotherapy are often the main modes of treatment. Many patients require follow-up reconstructive surgery, and the use of stem cells offers novel treatments that could aid recovery. Laryngeal, tracheal, and neuronal tissues are frequently damaged by surgery in the head and neck and these tissues have little intrinsic regenerative ability. Pluripotent embryonic stem cells retain the ability to differentiate into a wide variety of cells meaning that large tissue defects can be reduced by stimulating new cell growth. Research has demonstrated potential benefits of using stem cells in facial rejuvenation procedures and the management of burns sequelae. The advancements made in the use of adult progenitor stem cells as a possible source for pluripotent stem cells (induced pluripotent stem cells) mean that ethical considerations around the use of embryological tissue can be minimized, allowing for more research to take place. Currently, the evidence base for the use of stem cells in head and neck surgery is limited, but it has now been proven that stem cells can act as a source for lost or damaged tissue in the head and neck. With continuous advancements being made in the fields of tissue engineering, it is likely that stem cells will play a major role in head and neck surgery in the future.


Danger signals activating the immune response after trauma.
Sterile injury can cause a systemic inflammatory response syndrome (SIRS) that resembles the host response during sepsis. The inflammatory response following trauma comprises various systems of the human body which are cross-linked with each other within a highly complex network of inflammation. Endogenous danger signals (danger-associated molecular patterns; DAMPs; alarmins) as well as exogenous pathogen-associated molecular patterns (PAMPs) play a crucial role in the initiation of the immune response. With popularization of the "danger theory," numerous DAMPs and PAMPs and their corresponding pathogen-recognition receptors have been identified. In this paper, we highlight the role of the DAMPs high-mobility group box protein 1 (HMGB1), interleukin-1α (IL-1α), and interleukin-33 (IL-33) as unique dual-function mediators as well as mitochondrial danger signals released upon cellular trauma and necrosis.


Worldwide patterns of ancestry, divergence, and admixture in domesticated cattle.
The domestication and development of cattle has considerably impacted human societies, but the histories of cattle breeds and populations have been poorly understood especially for African, Asian, and American breeds. Using genotypes from 43,043 autosomal single nucleotide polymorphism markers scored in 1,543 animals, we evaluate the population structure of 134 domesticated bovid breeds. Regardless of the analytical method or sample subset, the three major groups of Asian indicine, Eurasian taurine, and African taurine were consistently observed. Patterns of geographic dispersal resulting from co-migration with humans and exportation are recognizable in phylogenetic networks. All analytical methods reveal patterns of hybridization which occurred after divergence. Using 19 breeds, we map the cline of indicine introgression into Africa. We infer that African taurine possess a large portion of wild African auroch ancestry, causing their divergence from Eurasian taurine. We detect exportation patterns in Asia and identify a cline of Eurasian taurine/indicine hybridization in Asia. We also identify the influence of species other than Bos taurus taurus and B. t. indicus in the formation of Asian breeds. We detect the pronounced influence of Shorthorn cattle in the formation of European breeds. Iberian and Italian cattle possess introgression from African taurine. American Criollo cattle originate from Iberia, and not directly from Africa with African ancestry inherited via Iberian ancestors. Indicine introgression into American cattle occurred in the Americas, and not Europe. We argue that cattle migration, movement and trading followed by admixture have been important forces in shaping modern bovine genomic variation.


Inelastic electron scattering from a helical potential: transverse polarization and the structure factor in the single scattering approximation.
We analyze single scattering of unpolarized photoelectrons through a monolayer of chiral molecules modeled by a continuous hardcore helix and spin-orbit coupling. The molecular helix is represented by an optical contact potential containing a non-hermitian component describing inelastic events. Transmitted photoelectrons are transversely polarized at optimal angles, and separated into up and down spin with up to 20% efficiency. Such a process involves the interference of both spin-orbit and inelastic strengths, that are parameterized quantitatively to recent experiments in chiral self-assembled monolayers (SAMs). The structure factor of the model chiral molecule shows the energy dependence of the differential cross section which decays strongly as energy increases. Larger incident momenta reduce axial deviations from the forward direction and the spin-orbit interaction becomes less effective. Transverse electron polarization is then restricted to a characteristic energy window.


Sensing starvation: a homoserine lactone--dependent signaling pathway in Escherichia coli.
When nutrients become limiting, many bacteria differentiate and become resistant to environmental stresses. For Escherichia coli, this process is mediated by the sigma s subunit of RNA polymerase. Expression of sigma s was induced by homoserine lactone, a metabolite synthesized from intermediates in threonine biosynthesis. Homoserine lactone-dependent synthesis of sigma s was prevented by overexpression of a newly identified protein, RspA. The function of homoserine lactone derivatives in many cell density-dependent phenomena and the similarity of RspA to a Streptomyces ambofaciens protein suggest that synthesis of homoserine lactone may be a general signal of starvation.


A new method for the preparation of monoporous hollow microspheres.
The feasibility of producing a hollow microsphere with a single hole in its shell by coaxial electrohydrodynamic atomization (CEHDA) is demonstrated. Polymethylsilsesquioxane (PMSQ) was used as a model shell material encapsulating a core of a volatile liquid, perfluorohexane (PFH), which was subsequently evaporated to produce the hollow microspheres. The diameters of the microspheres and of the single surface pore were controlled by varying the flow rate of the components, the concentration of the PMSQ solution, and the applied voltage in the CEHDA process. The particles were characterized by scanning electron microscopy, and the ranges obtained were 275-860 nm for the microsphere diameter and 35-135 nm for the pore size. The process overcomes several of the key problems associated with existing methods of monoporous microsphere formation including removing the need for elevated temperatures, multiple processing steps, and the use of surfactants and other additives.


Molecular determinants for the thermodynamic and functional divergence of uniporter GLUT1 and proton symporter XylE.
GLUT1 facilitates the down-gradient translocation of D-glucose across cell membrane in mammals. XylE, an Escherichia coli homolog of GLUT1, utilizes proton gradient as an energy source to drive uphill D-xylose transport. Previous studies of XylE and GLUT1 suggest that the variation between an acidic residue (Asp27 in XylE) and a neutral one (Asn29 in GLUT1) is a key element for their mechanistic divergence. In this work, we combined computational and biochemical approaches to investigate the mechanism of proton coupling by XylE and the functional divergence between GLUT1 and XylE. Using molecular dynamics simulations, we evaluated the free energy profiles of the transition between inward- and outward-facing conformations for the apo proteins. Our results revealed the correlation between the protonation state and conformational preference in XylE, which is supported by the crystal structures. In addition, our simulations suggested a thermodynamic difference between XylE and GLUT1 that cannot be explained by the single residue variation at the protonation site. To understand the molecular basis, we applied Bayesian network models to analyze the alteration in the architecture of the hydrogen bond networks during conformational transition. The models and subsequent experimental validation suggest that multiple residue substitutions are required to produce the thermodynamic and functional distinction between XylE and GLUT1. Despite the lack of simulation studies with substrates, these computational and biochemical characterizations provide unprecedented insight into the mechanistic difference between proton symporters and uniporters.


Generation of osteochondral tissue constructs with chondrogenically and osteogenically predifferentiated mesenchymal stem cells encapsulated in bilayered hydrogels.
This study investigated the ability of chondrogenic and osteogenic predifferentiation of mesenchymal stem cells (MSCs) to play a role in the development of osteochondral tissue constructs using injectable bilayered oligo(poly(ethylene glycol) fumarate) (OPF) hydrogel composites. We hypothesized that the combinatorial approach of encapsulating cell populations of both chondrogenic and osteogenic lineages in a spatially controlled manner within bilayered constructs would enable these cells to maintain their respective phenotypes via the exchange of biochemical factors even without the influence of external growth factors. During monolayer expansion prior to hydrogel encapsulation, it was found that 7 (CG7) and 14 (CG14) days of MSC exposure to TGF-β3 allowed for the generation of distinct cell populations with corresponding chondrogenic maturities as indicated by increasing aggrecan and type II collagen/type I collagen expression. Chondrogenic and osteogenic cells were then encapsulated within their respective (chondral/subchondral) layers in bilayered hydrogel composites to include four experimental groups. Encapsulated CG7 cells within the chondral layer exhibited enhanced chondrogenic phenotype when compared to other cell populations based on stronger type II collagen and aggrecan gene expression and higher glycosaminoglycan-to-hydroxyproline ratios. Osteogenic cells that were co-cultured with chondrogenic cells (in the chondral layer) showed higher cellularity over time, suggesting that chondrogenic cells stimulated the proliferation of osteogenic cells. Groups with osteogenic cells displayed mineralization in the subchondral layer, confirming the effect of osteogenic predifferentiation. In summary, it was found that MSCs that underwent 7 days, but not 14 days, of chondrogenic predifferentiation most closely resembled the phenotype of native hyaline cartilage when combined with osteogenic cells in a bilayered OPF hydrogel composite, indicating that the duration of chondrogenic preconditioning is an important factor to control. Furthermore, the respective chondrogenic and osteogenic phenotypes were maintained for 28 days in vitro without the need for external growth factors, demonstrating the exciting potential of this novel strategy for the generation of osteochondral tissue constructs for cartilage engineering applications.


Evaluating the importance of routine drainage following laparoscopic pelvic lymph node dissection for gynecological malignancies.
To determine the efficacy of drainage following pelvic lymph node (PLN) dissection, especially for cases involving laparoscopic surgery. In this retrospective study, 368 patients with malignant gynecological tumors who underwent systemic PLN dissection at Keio University Hospital between January 2012 and October 2018 were enrolled. Drainage tubes were placed in the retroperitoneal fossa in all patients. Medical records were used for data collection. Laparoscopy was performed on 81 patients, and laparotomy was performed on 287 patients. In the laparoscopy group, tubes were removed 1 day post surgery. In the laparotomy group, tubes were removed 1 day post surgery in 167 patients and 4 days post surgery in 120 patients. Compared with the laparotomy group, we determined the laparoscopy group to have a significantly lower prevalence of lymphocyst (6.2% vs 20.2%, p = 0.002) but a similar prevalence of lymphedema (4.9% vs 5.2%), and symptomatic lymphocyst (2.5% vs 4.5%). The two laparotomy groups did not differ significantly with respect to the prevalence of lymphedema (4.8% vs 5.8%), lymphocyst (20.4% vs 20.0%), or symptomatic lymphocyst (4.2% vs 5.0%). Our results suggest that routine drainage should be omitted, especially in cases involving laparoscopic surgery.


The role of psychiatric symptoms and environmental vulnerability factors in explaining the relationship between child maltreatment and suicidality: A prospective investigation.
Childhood maltreatment has been associated with suicide thoughts and attempts; however, few longitudinal studies have assessed risk of suicidality into adulthood. Fewer have examined potential mediators (psychiatric symptoms and environmental vulnerability factors). Prospective cohort design. Children with documented cases of maltreatment (N = 495, ages 0-11) were matched with non-maltreated children (N = 395) and followed up into adulthood. Psychiatric symptoms (depression, anxiety, dysthymia, post-traumatic stress,antisocial personality,and substance use) and environmental vulnerability (social isolation, physical disability/illness, and homelessness) were assessed at mean age 29 and suicide thoughts and attempts at 39. Structural equation models tested for mediation, controlling for age, sex, race, and IQ. Childhood maltreatment predicted suicide attempts (Beta = 0.44, p<0.001), but not suicide thoughts only.Individuals with only suicide thoughts differed significantly from those with suicide attempts in psychiatric symptoms, physical disability/ illness, and homelessness. There were significant paths from child maltreatment to suicide attempts through psychiatric symptoms (0.18, p<0.001), ASPD (0.13, p<0.001), substance use (0.07, p<0.01), and homelessness (0.10, p<0.05). Court cases of child maltreatment may not generalize to middle- or upper- class and non-reported cases.Effect sizes were small but significant. Psychiatric risk factors for suicide are well recognized. These new results provide strong evidence that environmental vulnerability factors, particularly homelessness, are associated with increased risk for suicide attempts and warrant attention.Although many people report suicide thoughts, maltreated children with more psychiatric symptoms and experience homelessness are more likely to attempt suicide and warrant targeted interventions.


Baseline staging in cutaneous malignant melanoma.
Baseline staging in patients with primary cutaneous malignant melanoma (MM) is routine, but the diagnostic accuracy and the impact on clinical outcome are still unclear. To evaluate the sensitivity and specificity of baseline staging in the early detection of regional lymph node metastases or distant metastases in patients with MM. One hundred consecutive patients with MM of Breslow's tumour thickness over 1.0 mm were enrolled. All patients had an extensive baseline staging including physical examination, ultrasound (US) of the abdomen and regional lymph nodes, chest X-ray, whole-body positron emission tomography (PET) and sentinel lymph node biopsy. The sensitivity and specificity of detection of macroscopic or microscopic metastases in the regional lymph nodes or at distant sites were calculated for each method. Sentinel lymph node biopsy was positive in 26 patients. US detected two of 26 histologically tumour-positive sentinel nodes (sensitivity 8%, specificity 88%) and PET two of 26 (sensitivity 8%; specificity 100%). There were three lymph node metastases with a diameter > 4 mm. All of them were found suspect at physical examination. Two of them were detectable with US, two with PET, and all were identified with either US or PET. Nine patients had suspect findings at distant sites, which were all false positive on further investigation (specificity of the combined staging procedures 91%). At 18 (6-37) months' follow-up, five of 26 (19%) patients with a positive sentinel node and four of 74 (5%) of patients with a negative sentinel node had recurrent or progressive disease. The combination of physical examination and lymph node US detects the great majority of patients with macroscopic lymph node metastasis (approximately 3% of patients at baseline). Only 10% of patients who have a histologically tumour-positive sentinel node are macroscopically detectable. Altogether, approximately 25% of patients have a positive sentinel node biopsy, among 90% microscopic. The value of whole body staging at baseline remains limited, since distant metastases can hardly ever be detected. The survival benefit of baseline staging and surveillance in patients with cutaneous MM remains to be established by comparative prospective trials.


Neonatal intensive care and child psychiatry inpatient care: do different working conditions influence stress levels?
Introduction. Nurses often experience work-related stress. High stress can negatively affect job satisfaction and lead to emotional exhaustion with risk of burnout. Aim. To analyse possible differences in biological stress markers, psychosocial working conditions, health, and well-being between nurses working in two different departments. Methods. Stress was evaluated in nurses working in a neonatal intensive care unit (NICU) (n = 33) and nurses working in a child and adolescent psychiatry inpatient ward (CAP) (n = 14) using salivary cortisol and HbA1c. Salivary cortisol was measured three times a day on two consecutive days during two one-week periods, seven weeks apart (= 12 samples/person). Psychosocial working conditions, health, and well-being were measured once. Results. NICU nurses had better social support and more self-determination. CAP nurses had a lower salivary cortisol quotient, poorer general health, and higher client-related burnout scores. Conclusion. When comparing these nurses with existing norm data for Sweden, as a group their scores reflect less work-related stress than Swedes overall. However, the comparison between NICU and CAP nurses indicates a less healthy work situation for CAP nurses. Relevance to Clinical Practice. Healthcare managers need to acknowledge the less healthy work situation CAP nurses experience in order to provide optimal support and promote good health.


Clustering metagenomic sequences with interpolated Markov models.
Sequencing of environmental DNA (often called metagenomics) has shown tremendous potential to uncover the vast number of unknown microbes that cannot be cultured and sequenced by traditional methods. Because the output from metagenomic sequencing is a large set of reads of unknown origin, clustering reads together that were sequenced from the same species is a crucial analysis step. Many effective approaches to this task rely on sequenced genomes in public databases, but these genomes are a highly biased sample that is not necessarily representative of environments interesting to many metagenomics projects. We present SCIMM (Sequence Clustering with Interpolated Markov Models), an unsupervised sequence clustering method. SCIMM achieves greater clustering accuracy than previous unsupervised approaches. We examine the limitations of unsupervised learning on complex datasets, and suggest a hybrid of SCIMM and supervised learning method Phymm called PHYSCIMM that performs better when evolutionarily close training genomes are available. SCIMM and PHYSCIMM are highly accurate methods to cluster metagenomic sequences. SCIMM operates entirely unsupervised, making it ideal for environments containing mostly novel microbes. PHYSCIMM uses supervised learning to improve clustering in environments containing microbial strains from well-characterized genera. SCIMM and PHYSCIMM are available open source from http://www.cbcb.umd.edu/software/scimm.


A Web-Based Registry for Familial Hypercholesterolaemia.
Familial hypercholesterolaemia (FH) is the most common and serious monogenic disorder of lipoprotein metabolism that leads to premature coronary heart disease. Patients with FH are often under-treated, and many remain undiagnosed. The deployment of the FH Australasia Network Registry is a crucial component of the comprehensive model of care for FH, which aims to provide a standardised, high-quality and cost-effective system of care that is likely to have the highest impact on patient outcomes. The FH Australasia Network Registry was customised using a registry framework that is an open source, interoperable system that enables the efficient customisation and deployment of national and international web-based disease registries that can be modified dynamically as registry requirements evolve. The FH Australasia Network Registry can be employed to improve health services for FH patients across the Australasia-Pacific region, through the collation of data to facilitate clinical service planning, clinical trials, clinical audits, and to inform clinical best practice.


Nerve conduction studies: clinical challenges and engineering solutions.
Nerve conduction studies (NCSs) have played an important role in the evaluation of neuromuscular disease for the past 50 years. When patients present with complaints of pain, numbness, tingling, or weakness, NCS is often one of the earliest tests obtained by physicians, because it enables the quantitative assessment of peripheral nerve and muscle function and, therefore, aid the physician in identifying the physiological source of the patient's symptoms. NCSs involve the delivery of electric stimuli to peripheral nerves at accessible locations on the human body and the recording of electrophysiological responses. This article reviews how NCS is traditionally performed. This paper also examines technical challenges associated with each step of performing an NCS and describes how engineering solutions could be realized to meet these challenges. The engineering goals were several: improvement in NCS workflow, use of prefabricated electrode arrays to standardize NCS technique and reduce the errors associated with electrode placement, and improvement of the overall accuracy and reliability of NCS.


Color consilience: color through the lens of art practice, history, philosophy, and neuroscience.
Paintings can be interpreted as the product of the complex neural machinery that translates physical light signals into behavior, experience, and emotion. The brain mechanisms responsible for vision and perception have been sculpted during evolution and further modified by cultural exposure and development. By closely examining artists' paintings and practices, we can discover hints to how the brain works, and achieve insight into the discoveries and inventions of artists and their impact on culture. Here, I focus on an integral aspect of color, color contrast, which poses a challenge for artists: a mark situated on an otherwise blank canvas will appear a different color in the context of the finished painting. How do artists account for this change in color during the production of a painting? In the broader context of neural and philosophical considerations of color, I discuss the practices of three modern masters, Henri Matisse, Paul Cézanne, and Claude Monet, and suggest that the strategies they developed not only capitalized on the neural mechanisms of color, but also influenced the trajectory of western art history.


A conserved docking motif for CK1 binding controls the nuclear localization of NFAT1.
In resting cells, the NFAT1 transcription factor is kept inactive in the cytoplasm by phosphorylation on multiple serine residues. These phosphorylated residues are primarily contained within two types of serine-rich motifs, the SRR-1 and SP motifs, which are conserved within the NFAT family. Several different kinases have been proposed to regulate NFAT, but no single candidate displays the specificity required to fully phosphorylate both types of motifs; thus, the identity of the kinase that regulates NFAT activity remains unclear. Here we show that the NFAT1 serine motifs are regulated by distinct kinases that must coordinate to control NFAT1 activation. CK1 phosphorylates only the SRR-1 motif, the primary region required for NFAT1 nuclear import. CK1 exists with NFAT1 in a high-molecular-weight complex in resting T cells but dissociates upon activation. GSK3 does not phosphorylate the SRR-1 region but can target the NFAT1 SP-2 motif, and it synergizes with CK1 to regulate NFAT1 nuclear export. We identify a conserved docking site for CK1 in NFAT proteins and show that mutation of this site disrupts NFAT1-CK1 interaction and causes constitutive nuclear localization of NFAT1. The CK1 docking motif is present in proteins of the Wnt, Hedgehog, and circadian-rhythm pathways, which also integrate the activities of CK1 and GSK3.


Adaptive Motor Imagery: A Multimodal Study of Immobilization-Induced Brain Plasticity.
The consequences of losing the ability to move a limb are traumatic. One approach that examines the impact of pathological limb nonuse on the brain involves temporary immobilization of a healthy limb. Here, we investigated immobilization-induced plasticity in the motor imagery (MI) circuitry during hand immobilization. We assessed these changes with a multimodal paradigm, using functional magnetic resonance imaging (fMRI) to measure neural activation, magnetoencephalography (MEG) to track neuronal oscillatory dynamics, and transcranial magnetic stimulation (TMS) to assess corticospinal excitability. fMRI results show a significant decrease in neural activation for MI of the constrained hand, localized to sensorimotor areas contralateral to the immobilized hand. MEG results show a significant decrease in beta desynchronization and faster resynchronization in sensorimotor areas contralateral to the immobilized hand. TMS results show a significant increase in resting motor threshold in motor cortex contralateral to the constrained hand, suggesting a decrease in corticospinal excitability in the projections to the constrained hand. These results demonstrate a direct and rapid effect of immobilization on MI processes of the constrained hand, suggesting that limb nonuse may not only affect motor execution, as evidenced by previous studies, but also MI. These findings have important implications for the effectiveness of therapeutic approaches that use MI as a rehabilitation tool to ameliorate the negative effects of limb nonuse.


Do auditory responses recorded from awake animals reflect the anatomical parcellation of the auditory thalamus?
Previous studies performed in anesthetized animals have shown differences between the acoustic responses of neurons recorded from the different divisions of the medial geniculate body (MGB). This study aimed at determining whether or not such differences are also expressed when neurons are recorded from awake animals. The auditory responses of 130 neurons of the auditory thalamus were determined in awake, restrained guinea pigs while the state of vigilance of the animals was continuously monitored. There were significantly more 'on' phasic evoked responses and significantly fewer 'non-responsive' or 'labile' cells in the ventral division of the MGB (MGv) than in the other divisions. The response latencies and the variability of the latencies were smaller in the MGv than in the other divisions. The tuning of the neurons obtained from MGv and from the lateral part of the posterior complex were significantly sharper than those coming from the dorsal division of the MGB and the medial division. The mean threshold and the percentage of monotonic vs. non-monotonic intensity functions were not different in the subdivisions of the auditory thalamus. When compared with previous studies, the quantifications of the acoustic responses obtained in the present study gave values that differed from those reported under deep anesthesia, but were close to those reported under light anesthesia. Lastly, even if none of the physiological characteristic makes it possible, by itself, to determine the locus of recordings in the auditory thalamus, we conclude that the physiological characteristics of the evoked responses obtained in MGv differ from those of other divisions.


Substance use, gender inequity, violence and sexual risk among couples in Cape Town.
Alcohol and other drug use, gender power inequities and violence are key contributors to sexual risks for HIV among South African men and women. Little is known about the intersection between these sex-risk behaviours among couples in established heterosexual relationships. We conducted 10 focus-group discussions with men and women in relationships of 1 year or longer recruited from shebeens (informal taverns) in Cape Town, South Africa. Participants described: high levels of alcohol consumption at shebeens; low levels of condom use with main and casual sex partners; gender roles disfavouring women's condom negotiating power that also promoted economic dependency on male partners; men often spending a portion of the household income on alcohol and other drugs and sex with others in shebeens; loss of household income driving women to trade sex to provide for their families; and sexual violence and the exploitation of women occurring in shebeens. Findings highlight how the social contexts of alcohol and other drug use, gender inequitable norms and gender violence promote HIV risk within established heterosexual relationships in South African communities. Evidence of this kind should inform the design of HIV-risk-reduction interventions tailored to heterosexual couples who drink alcohol in shebeens.


TU-E-218-01: PET/CT QA/QC and Acceptance Testing.
Combined PET/CT imaging has become a routine imaging technique in diagnostic radiology and nuclear medicine alike. In this regard a thorough understanding of this modality's quality assurance and control procedures including acceptance testing is a necessary pre-requisite to ensure the optimal performance of this imaging modality. This session is designed to explain the QA and QC procedures for a PET/CT scanner with examples from two different manufacturers. The session will also cover the frequency of these tests and the elements to implement a QA/QC program for PET/CT imaging. Finally the session will cover the NEMA standard for acceptance testing of PET scanners and their meanings as well as additional recommended tests for hybrid (PET/CT) systems. 1. Summarize the signal processing steps for coincidence detection 2. Understand the components of a daily QA procedure 3. Identify and trouble shoot possible sources of failure in daily QA 4. List the recommended frequency of QA/QC tests 5. Describe the process of scanner calibration 6. Name the different components of the NEMA test used for PET acceptance testing 7. Understand the meaning of the results of the NEMA tests.


Periodontal health knowledge and smoking are associated with periodontal treatment need according to tooth brushing levels.
The aim of this study is to determine whether periodontal health knowledge is associated with frequency of tooth brushing and periodontal treatment need. Four hundred and two subjects participated in the study. Data on sociodemographic variables (age, gender, marital status, income, and education), general health, smoking behaviour tooth cleaning habits and knowledge on periodontal health/disease were collected with a questionnaire. Periodontal treatment need was examined using the Community Periodontal Index of Treatment Needs (CPITN). According to the CPITN scores, the treatment needs were grouped as minimum (CPITN = 0), low-level (CPITN = 1-2), or high-level (CPITN = 3-4). Statistical differences were found between the frequency of tooth brushing and smoking status, marital status, periodontal health knowledge and periodontal treatment needs. Gender (females), place of residence (urban areas), education and periodontal health knowledge had positive relationship with tooth brushing frequency, while smoking and periodontal treatment need had negative relationship. When multivariate logistic regression analysis was applied, age, marriage and poor periodontal knowledge were associated with increased low-level periodontal treatment needs, and age, marriage and smoking were associated with increased high-level periodontal treatment need. In the limits of this study, we suggest that gender, smoking habits, marital status, place of residence, education and periodontal health knowledge are determining factors related to tooth brushing frequency. Periodontal knowledge and smoking are associated with periodontal treatment needs.


[Risk factors for multiple intestinal parasites in an indigenous community of the State of Pernambuco, Brazil].
An investigation into the ethno-epidemiological profile of the Pankararu indigenous group in the State of Pernambuco, Brazil, identified multiple intestinal parasites in nearly all members of the community. To detect possible environmental risk factors, we used the data base from a previous survey to test relations between daily living conditions (housing, sanitation, water supply and treatment, and garbage disposal) and the number of different parasite species found in the same household. The sample consisted of 84 families from the original sample of 112. Selection was based on the number of stool tests performed in the family. The mean number of parasite species was 5.0 per family, for a mean family size of 6.1 members. This number was greater for wattle-and-daub houses (mean 6.0 parasite species vs. 4.9 for brick houses; p < 0.03) and when water used in the household was not treated (mean 5.1 parasite species, vs. 4.5 for treated water; p < 0.05). Other household characteristics and hygienic habits did not significantly influence this number. We concluded that multiple intestinal parasitism in the Pernambuco Pankararu community is frequent, to the point of being the rule, and that it relates essentially to water source and treatment.


Involvement of Conserved Amino Acids in the C-Terminal Region of LINE-1 ORF2p in Retrotransposition.
Long interspersed element 1 (L1) is the only currently active autonomous retroelement in the human genome. Along with the parasitic SVA and short interspersed element Alu, L1 is the source of DNA damage induced by retrotransposition: a copy-and-paste process that has the potential to disrupt gene function and cause human disease. The retrotransposition process is dependent upon the ORF2 protein (ORF2p). However, it is unknown whether most of the protein is important for retrotransposition. In particular, other than the Cys motif, the C terminus of the protein has not been intensely examined in the context of retrotransposition. Using evolutionary analysis and the Alu retrotransposition assay, we sought to identify additional amino acids in the C terminus important for retrotransposition. Here, we demonstrate that Gal4-tagged and untagged C-terminally truncated ORF2p fragments possess residual potential to drive Alu retrotransposition. Using sight-directed mutagenesis we identify that while the Y1180 amino acid is important for ORF2p- and L1-driven Alu retrotransposition, a mutation at this position improves L1 retrotransposition. Even though the mechanism of the contribution of Y1180 to Alu and L1 mobilization remains unknown, experimental evidence rules out its direct involvement in the ability of the ORF2p reverse transcriptase to generate complementary DNA. Additionally, our data support that ORF2p amino acids 1180 and 1250-1262 may be involved in the reported ORF1p-mediated increase in ORF2p-driven Alu retrotransposition.


Extrahepatic metabolism of 4-methylumbelliferone and lidocaine in the anhepatic rabbit.
Extrahepatic drug metabolism was studied in an anhepatic rabbit model. Plasma concentrations of 4-methylumbelliferone (4-MU) and its major metabolites, 4-methylumbelliferyl-O-glucuronide and 4-methyumbelliferyl sulfate, along with lidocaine and its major metabolites, monoethylglycinexylidide and 3-hydroxylidocaine, were measured in sham rabbits (n = 4) and anhepatic rabbits (n = 4) following bolus intravenous administration of each drug. Along with concentration profiles of the drugs and metabolites, pharmacokinetic analyses of 4-MU metabolism and lidocaine metabolism were used to assess the extrahepatic metabolism of these classical substrates. Total body clearance of 4-MU in the anhepatic rabbits was about 50% that of the sham animals. Extensive extrahepatic glucuronidation of 4-MU was revealed by comparing the AUC ratios of 4-methylumbelliferyl-O-glucuronide and 4-MU in anhepatic and sham rabbit groups. Sulfation of 4-MU was reduced significantly in the anhepatic group, although some extrahepatic sulfation was observed. Total body clearance of lidocaine was reduced 3-fold in anhepatic animals. 3-Hydroxylidocaine was only detected in plasma samples from sham animals. These results emphasize the importance of extrahepatic sites in drug metabolism, especially glucuronidation of phenolic compounds such as 4-MU.


Comparison of minisatellites.
In the class of repeated sequences that occur in DNA, minisatellites have been found polymorphic and became useful tools in genetic mapping and forensic studies. They consist of a heterogeneous tandem array of a short repeat unit. The slightly different units along the array are called variants. Minisatellites evolve mainly through tandem duplications and tandem deletions of variants. Jeffreys et al. (1997) devised a method to obtain the sequence of variants along the array in a digital code and called such sequences maps. Minisatellite maps give access to the detail of mutation processes at work on such loci. In this paper, we design an algorithm to compare two maps under an evolutionary model that includes deletion, insertion, mutation, tandem duplication, and tandem deletion of a variant. Our method computes an optimal alignment in reasonable time; and the alignment score, i.e., the weighted sum of its elementary operations, is a distance metric between maps. The main difficulty is that the optimal sequence of operations depends on the order in which they are applied to the map. Taking the maps of the minisatellite MSY1 of 609 men, we computed all pairwise distances and reconstructed an evolutionary tree of these individuals. MSY1 (DYF155S1) is a hypervariable locus on the Y chromosome. In our tree, the populations of some haplogroups are monophyletic, showing that one can decipher a microevolutionary signal using minisatellite maps comparison.


Volumetric myelographic magnetic resonance imaging to localize difficult-to-find spinal dural arteriovenous fistulas.
Although more prevalent in males in the 6th and 7th decade of life, spinal dural arteriovenous fistulas (SDAVFs) are an uncommon cause of progressive myelopathy. Magnetic resonance imaging and more recently Gd bolus MR angiography have been used to diagnose, radiographically define, and preprocedurally localize the contributing lumbar artery. Three-dimensional myelographic MR imaging sequences have recently been developed for anatomical evaluation of the spinal canal. The authors describe 3 recent cases in which volumetric myelographic MR imaging with a 3D phase-cycled fast imaging employing steady state acquisition (PC-FIESTA) and a 3D constructive interference steady state (CISS) technique were particularly useful not only for documenting an SDAVF, but also for providing localization when CT angiography, MR imaging, MR angiography, and spinal angiography failed to localize the fistula. In a patient harboring an SDAVF at T-4, surgical exploration was performed based on the constellation of findings on the PC-FIESTA images as well as the fact that the spinal segments leading to T-4 were the only ones that the authors were unable to catheterize. In a second patient, who harbored an SDAVF at T-6, after 2 separate angiograms failed to demonstrate the fistula, careful assessment of the CISS images led the authors to focus a third angiogram on the left T-6 intercostal artery and to perform superselective microcatheterization. In a third patient with an SDAVF originating from the lateral sacral branch, the PC-FIESTA sequence demonstrated the arterialized vein extending into the S-1 foramen, leading to a second angiogram and superselective internal iliac injections. The authors concluded that myelographic MR imaging sequences can be useful not only as an aid to diagnosis but also for localization of an SDAVF in complex cases.


Dermoscopic features of basal cell carcinomas: differences in appearance under non-polarized and polarized light.
Basal cell carcinomas (BCCs) can be diagnosed using different dermoscopic modalities. To evaluate dermoscopic features of BCCs using nonpolarized and polarized dermoscopy to highlight similarities and differences between dermoscopic modalities. Retrospective study of 149 BCCs under nonpolarized dermoscopy (NPD), polarized contact dermoscopy (PCD), and polarized noncontact dermoscopy (PNCD). Images were evaluated for a range of dermoscopic colors, structures, and vessels. Features were compared according to histopathologic subtype. The most common dermoscopic structures in BCCs across all modalities included globules (50.3-51.0%), dots (49.7-50.3%), white structureless areas (63.1-74.5%), structureless gray-brown areas (24.2-24.8%), and ulcerations (28.2%). The most frequently observed vasculature included arborizing vessels (18.8-38.3%), short fine telangiectasias (SFTs) (73.8-82.6%), and vascular blush (41.6-83.2%). Structures with higher levels of agreement across modalities included pigmented structures and ulcerations. Lower levels of agreement existed between contact and noncontact modalities for certain vascular features. White shiny structures, which include shiny white lines (chrysalis and crystalline structures) (0-69.1%), shiny white areas (0-25.5%), and rosettes (0-11.4%), exhibited no agreement between NPD and polarized modalities. This study highlights differences in dermoscopic features of BCCs under three dermoscopic modalities. Shiny white lines (chrysalis and crystalline structures) and shiny white areas may be used as additional criteria to diagnose BCCs.


Randomized controlled trial of a home-based palliative approach for people with severe multiple sclerosis.
Evidence on the efficacy of palliative care in persons with severe multiple sclerosis (MS) is scarce. To assess the efficacy of a home-based palliative approach (HPA) for adults with severe MS and their carers. Adults with severe MS-carer dyads were assigned (2:1 ratio) to either HPA or usual care (UC). At each center, a multi-professional team delivered the 6-month intervention. A blind examiner assessed dyads at baseline, 3 months, and 6 months. Primary outcome measures were Palliative care Outcome Scale-Symptoms-MS (POS-S-MS) and Schedule for the Evaluation of Individual Quality of Life-Direct Weighting (SEIQoL-DW, not assessed in severely cognitively compromised patients). Of 78 dyads randomized, 76 (50 HPA, 26 UC) were analyzed. Symptom burden (POS-S-MS) significantly reduced in HPA group compared to UC ( p = 0.047). Effect size was 0.20 at 3 months and 0.32 at 6 months, and statistical significance was borderline in per-protocol analysis ( p = 0.062). Changes in SEIQoL-DW index did not differ in the two groups, as changes in secondary patient and carer outcomes. HPA slightly reduced symptoms burden. We found no evidence of HPA efficacy on patient quality of life and on secondary outcomes.


Voluntary Fasting to Control Post-Ramadan Weight Gain among Overweight and Obese Women.
This study aimed to examine the effectiveness of an Islamic voluntary fasting intervention to control post-Ramadan weight gain. This study was conducted between July and November 2011. Two weight loss intervention programmes were developed and implemented among groups of overweight or obese Malay women living in the Malaysian cities of Putrajaya and Seremban: a standard programme promoting control of food intake according to national dietary guidelines (group B) and a faith-based programme promoting voluntary fasting in addition to the standard programme (group A). Participants' dietary practices (i.e., voluntary fasting practices, frequency of fruit/vegetable consumption per week and quantity of carbohydrates/protein consumed per day), body mass index (BMI), blood pressure, fasting blood high-density lipoprotein cholesterol (HDL-C) and total cholesterol (TC):HDL-C ratio were assessed before Ramadan and three months post-Ramadan. Voluntary fasting practices increased only in group A (P <0.01). Additionally, the quantity of protein/carbohydrates consumed per day, mean diastolic pressure and TC:HDL-C ratio decreased only in group A (P <0.01, 0.05, 0.02 and <0.01, respectively). Frequency of fruit/vegetable consumption per week, as well as HDL-C levels, increased only in group A (P = 0.03 and <0.01, respectively). Although changes in BMI between the groups was not significant (P = 0.08), BMI decrease among participants in group A was significant (P <0.01). Control of post-Ramadan weight gain was more evident in the faith-based intervention group. Healthcare providers should consider faith-based interventions to encourage weight loss during Ramadan and to prevent post-Ramadan weight gain among patients.


Meropenem versus imipenem-cilastatin for the treatment of hospitalized patients with complicated skin and skin structure infections: results of a multicenter, randomized, double-blind comparative study.
Meropenem, a broad-spectrum carbapenem with potent in vitro activity, is postulated to be an effective monotherapy for the treatment of complicated skin and skin structure infections (cSSSI). This multicenter, international, double-blind, randomized, prospective study of hospitalized patients with cSSSI evaluated the efficacy, safety, and tolerability of meropenem (500 mg IV q8h) versus imipenem-cilastatin (500 mg IV q8h). The primary efficacy endpoint was clinical outcome at follow-up in the clinically evaluable (CE) and modified intent-to-treat populations (MITT; patients who met eligibility criteria and received at least one dose of study drug). The study aimed to demonstrate non-inferiority (delta of 10%, 95% confidence intervals) in clinical response in the CE population. Clinical responses for all pathogens at follow-up were assessed in the fully evaluable population (CE population with baseline pathogen and follow-up cultures). In total, 1,076 patients were enrolled. Of these, 692 patients comprised the MITT population (334 and 358 patients randomized to meropenem and imipenem-cilastatin, respectively) and 548 the CE population (261 and 287 patients randomized to meropenem and imipenem-cilastatin, respectively). Cure rates were 86.2% (meropenem) and 82.9% (imipenemcilastatin; 95% CI, -2.8, 9.3) in the CE population and 73.1% (meropenem) and 74.9% (imipenem-cilastatin; 95% CI, -8.4, 4.7) in the MITT population. The frequencies of adverse events and drug-related adverse events were similar between treatment groups. In one of the largest studies conducted to date of hospitalized patients with cSSSI, meropenem, 500 mg IV q8h had comparable safety and efficacy to imipenem-cilastatin, 500 mg IV q8h.


Modeling polymer crystallisation induced by a moving heat sink.
Recent experimental work has shown that polymer crystallisation can be used to "move" and organize nanoparticles (NP). As a first effort at modeling this situation, we consider the classical Stefan problem but with the modification that polymer crystallisation does not occur at a single temperature. Rather, the rate of crystallisation is proportional to its subcooling, and here we employ a form inspired by the classical Avrami model to describe this functional form. Our results for the movement of the polymer crystallisation front, as defined as the point where the crystallinity is 50%, closely track the results of the classical Stefan problem. Thus, at this level of approximation, the crystallisation kinetics of the polymer do not cause qualitative changes to the physics of this situation. Inspired by this fact we study the more interesting situation where the directional recrystallisation of a polymer melt is considered, e.g., through the application of a moving heat sink over an initially molten polymer, reminiscent of a processing technique termed zone annealing. The polymer crystallisation shows that a steady state exists for a range of sink velocities. The solid-melt interface moves slightly ahead of the sink but at the same velocity. The steady-state distance between the sink and the interface decreases with increasing sink velocity - this is a consequence of the excess cooling provided by the sink over what is required to crystallise the melt. The most interesting new result is that the temperature of the crystal-melt interface decreases with increasing sink velocity. This is in line with the ansatz of Lovinger and Gryte who suggested that larger zone annealing velocities correspond to progressively larger effective undercoolings at which polymer crystallisation occurs.


A systematic review of electronic audit and feedback: intervention effectiveness and use of behaviour change theory.
Audit and feedback is a common intervention for supporting clinical behaviour change. Increasingly, health data are available in electronic format. Yet, little is known regarding if and how electronic audit and feedback (e-A&F) improves quality of care in practice. The study aimed to assess the effectiveness of e-A&F interventions in a primary care and hospital context and to identify theoretical mechanisms of behaviour change underlying these interventions. In August 2016, we searched five electronic databases, including MEDLINE and EMBASE via Ovid, and the Cochrane Central Register of Controlled Trials for published randomised controlled trials. We included studies that evaluated e-A&F interventions, defined as a summary of clinical performance delivered through an interactive computer interface to healthcare providers. Data on feedback characteristics, underlying theoretical domains, effect size and risk of bias were extracted by two independent review authors, who determined the domains within the Theoretical Domains Framework (TDF). We performed a meta-analysis of e-A&F effectiveness, and a narrative analysis of the nature and patterns of TDF domains and potential links with the intervention effect. We included seven studies comprising of 81,700 patients being cared for by 329 healthcare professionals/primary care facilities. Given the extremely high heterogeneity of the e-A&F interventions and five studies having a medium or high risk of bias, the average effect was deemed unreliable. Only two studies explicitly used theory to guide intervention design. The most frequent theoretical domains targeted by the e-A&F interventions included 'knowledge', 'social influences', 'goals' and 'behaviour regulation', with each intervention targeting a combination of at least three. None of the interventions addressed the domains 'social/professional role and identity' or 'emotion'. Analyses identified the number of different domains coded in control arm to have the biggest role in heterogeneity in e-A&F effect size. Given the high heterogeneity of identified studies, the effects of e-A&F were found to be highly variable. Additionally, e-A&F interventions tend to implicitly target only a fraction of known theoretical domains, even after omitting domains presumed not to be linked to e-A&F. Also, little evaluation of comparative effectiveness across trial arms was conducted. Future research should seek to further unpack the theoretical domains essential for effective e-A&F in order to better support strategic individual and team goals.


Refugee's agency and coping strategies in refugee camps during the coronavirus pandemic: ethnographic perspectives.
The global spread of the coronavirus pandemic has particularly dramatic consequences for the lives of migrants and refugees living in already marginalised and restricted conditions, whose ongoing crisis is at risk of being overlooked. But refugees are not only extremely vulnerable and at risk of infection, as several reports show, quickly develop their own protection measures like the production of hygienic products, the publication of their situation and calls for action and help. Therefore, this paper aims to research the effects of the coronavirus crisis on refugees in camp settings with a special ethnographic focus on how refugees actively deal with this crisis and if they, through already developed resilience, are capable of adapting to the restrictions as well as inventing strategies to cope with the difficult situation. To account for the variety of refugee camps as well as the different living conditions due to their locality, history and national asylum politics, we will look at three different locations, namely refugee asylum homes in Germany, hotspots on the Greek islands as well as one refugee camp in Kenya. The main questions will be how, under structurally and institutionally framed conditions of power and victimisation in refugee camps, forms of agency are established, made possible or limited. The goal is to show which strategies refugees apply to cope with the enhanced restrictions and exclusion, how they act to protect themselves and others from the virus and how they present and reflect their situation during the coronavirus pandemic. Finally, this discussion offers a new perspective to consider refugees not only as vulnerable victims, but also as actively engaged individuals.


High-throughput mutation analysis in patients with a nephronophthisis-associated ciliopathy applying multiplexed barcoded array-based PCR amplification and next-generation sequencing.
To identify disease-causing mutations within coding regions of 11 known NPHP genes (NPHP1-NPHP11) in a cohort of 192 patients diagnosed with a nephronophthisis-associated ciliopathy, at low cost. Mutation analysis was carried out using PCR-based 48.48 Access Array microfluidic technology (Fluidigm) with consecutive next-generation sequencing. We applied a 10-fold primer multiplexing approach allowing PCR-based amplification of 475 amplicons (251 exons) for 48 DNA samples simultaneously. After four rounds of amplification followed by indexing all of 192 patient-derived products with different barcodes in a subsequent PCR, 2 × 100 paired-end sequencing was performed on one lane of a HiSeq2000 instrument (Illumina). Bioinformatics analysis was performed using 'CLC Genomics Workbench' software. Potential mutations were confirmed by Sanger sequencing and shown to segregate. Bioinformatics analysis revealed sufficient coverage of 30 × for 168/192 (87.5%) DNA samples (median 449 ×) and of 234 out of 251 targeted coding exons (sensitivity: 93.2%). For proof-of-principle, we analysed 20 known mutations and identified 18 of them in the correct zygosity state (90%). Likewise, we identified pathogenic mutations in 34/192 patients (18%) and discovered 23 novel mutations in the genes NPHP3 (7), NPHP4 (3), IQCB1 (4), CEP290 (7), RPGRIP1L (1), and TMEM67 (1). Additionally, we found 40 different single heterozygous missense variants of unknown significance. We conclude that the combined approach of array-based multiplexed PCR-amplification on a Fluidigm Access Array platform followed by next-generation sequencing is highly cost-efficient and strongly facilitates diagnostic mutation analysis in broadly heterogeneous Mendelian disorders.


Using genomic data to revisit an early example of reproductive character displacement in Haitian Anolis lizards.
The pattern of reproductive character displacement (RCD)-in which traits associated with reproductive isolation are more different where two species occur together than where they occur in isolation-is frequently attributed to reinforcement, a process during which natural selection acting against maladaptive mating events leads to enhanced prezygotic isolation between species or incipient species. One of the first studies of RCD to include molecular genetic data was described 40 years ago in a complex of Haitian trunk anole lizards using a small number of allozyme loci. In this example, Anolis caudalis appears to experience divergence in the color and pattern of an extensible throat fan, or dewlap, in areas of contact with closely related species at the northern and southern limits of its range. However, this case study has been largely overlooked for decades; meanwhile, explanations for geographic variation in dewlap color and pattern have focused primarily on adaptation to local signalling environments. We reinvestigate this example using amplified fragment length polymorphism (AFLP) genome scans, mtDNA sequence data, information on dewlap phenotypes and GIS data on environmental variation to test the hypothesis of RCD generated by reinforcement in Haitian trunk anoles. Together, our phenotypic and genetic results are consistent with RCD at the southern and northern limits of the range of A. caudalis. We evaluate the evidence for reinforcement as the explanation for RCD in Haitian trunk anoles, consider alternative explanations and provide suggestions for future work on the relationship between dewlap variation and speciation in Haitian trunk anoles.


Activation of discoidin domain receptor 1 on CD14-positive bronchoalveolar lavage fluid cells induces chemokine production in idiopathic pulmonary fibrosis.
Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase activated by collagen. We previously reported the functional expression of DDR1 on human monocyte-derived macrophages in vitro; however, information regarding its role in diseases is limited. Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease, and the lesions contain an abundance of collagen. In this study, we examined DDR1 expression on bronchoalveolar lavage fluid (BALF) cells and investigated its functionality using samples obtained from 28 IPF patients, 13 chronic obstructive pulmonary disease patients, and 14 healthy volunteers. The DDR1 expression level in CD14-positive BALF cells was higher in IPF patients than in chronic obstructive pulmonary disease patients or healthy volunteers. The predominant isoform was DDR1b in the IPF group, while DDR1a was predominant in the other two groups. Using immunohistochemical analysis, we also detected DDR1 expression on infiltrating inflammatory cells in the IPF lesion. In IPF patients, DDR1 activation induced the production of MCP-1, IL-8, MIP-1 alpha, and matrix metalloproteinase-9 (MMP-9) from CD14-positive BALF cells in a p38 MAPK-dependent manner. In contrast, DDR1 activation of CD14-positive BALF cells in the other groups did not induce the production of these chemokines or MMP-9. These chemokines and MMP-9 contribute to the development of IPF and, therefore, we suggest that DDR1 might be associated with the pathogenesis of IPF in the tissue microenvironment.


High-speed videotopographic measurement of tear film build-up time.
To detect tear film regularity changes in the 15 seconds after a blink, by using a new high-speed videotopographic method. The new system, based on a standard corneal topograph, allows registration of four photokeratoscopic images per second. Altogether, 15 eyes of 15 healthy volunteers and 7 eyes of 7 patients with dry eye were examined in this prospective preliminary study. The main outcome measures were changes in surface regularity index (SRI), surface asymmetry index (SAI), and corneal power. The corneal surface became more regular in the first few seconds after a blink. In healthy eyes, the trend line of SRI and SAI decreased (improved) significantly (P < 0.001) after a blink, in 10 of 15 eyes for the SRI and in 13 of 15 for the SAI. In the typical cases, the trend line for SRI reached its minimum level, on average, at 7.1 +/- 3.9 seconds after a blink and that for the SAI at 5.4 +/- 2.7 seconds. Similar trends were found in the dry-eye group. The changes in keratometric measures were small (mean range, <1.5% of the absolute value) and showed no definite trends. High-speed videotopography provides the possibility of quantitative measurement of tear-film dynamics and may have clinical value in the management of ocular surface disorders. After a blink, it takes the tear film approximately 3 to 10 seconds (tear film build-up time) to reach the most regular state. However, despite surface-regularity changes, the measured corneal powers are stable.


Mentoring as an intervention to promote gender equality in academic medicine: a systematic review.
Mentoring is frequently suggested as an intervention to address gender inequalities in the workplace. To systematically review evidence published since a definitive review in 2006 on the effectiveness of mentoring interventions aimed at achieving gender equality in academic medicine. Systematic Review, using the Template for Intervention Description and Replication as a template for data extraction and synthesis. Studies were included if they described a specific mentoring intervention in a medical school or analogous academic healthcare organisation and included results from an evaluation of the intervention. Mentoring was defined as (1) a formally organised intervention entailing a supportive relationship between a mentor, defined as a more senior/experienced person and a mentee defined as a more junior/inexperienced person; (2) mentoring intervention involved academic career support (3) the mentoring relationship was outside line management or supervision of performance and was defined by contact over an extended period of time. The impact of mentoring was usually reported at the level of individual participants, for example, satisfaction and well-being or self-reported career progression. We sought evidence of impact on gender equality via reports of organisation-level effectiveness, of promotion or retention, pay and academic performance of female staff. We identified 32 publications: 8 review articles, 20 primary observational studies and 4 randomised controlled trials. A further 19 discussed mentoring in relation to gender but did not meet our eligibility criteria. The terminology used, and the structures and processes reported as constituting mentoring, varied greatly. We identified that mentoring is popular with many who receive it; however, we found no robust evidence of effectiveness in reducing gender inequalities. Primary research used weak evaluation designs. Mentoring is a complex intervention. Future evaluations should adopt standardised approaches used in applied health research to the design and evaluation of effectiveness and cost-effectiveness.


Significance of the urokinase-type plasminogen activator and its receptor in the progression of focal segmental glomerulosclerosis in clinical and mouse models.
suPAR biomarker generally considered a pathogenic factor in FSGS. However, studies have been published that dispute this conclusion. The current study was designed to investigate the roles of uPA and suPAR in FSGS in clinical and mouse models. Clinical subjects including those with biopsy-proven FSGS and MCD were enrolled. To verify the role of uPA in FSGS, Adriamycin was used to induce FSGS in uPA knockout (uPA(-/-)) and BALB/c (WT) mice. Proteinuria and suPAR, the cleaved/intact forms of the circulating suPAR, and possible proteases involving cleavage of the suPAR were also studied. FSGS clinical cases presented significantly higher serum levels of suPAR and Cr and lower serum levels of uPA. In the mice model, the uPA(-/-) group exhibited faster disease progression and worsening proteinuria than the WT group. In addition, the uPA(-/-) group had higher plasma suPAR levels, glomerular cell apoptosis, and dysregulation of the Th1/Th2 balance. In an analysis of suPAR variants in FSGS, both the intact and cleaved forms of the suPAR were higher in clinical subjects and the mouse model. However, the process of suPAR cleavage was not mediated by enzymatic activities of the uPA, elastase, or cathepsin G. A deficiency of uPA accelerated the progression of Adriamycin-induced mouse FSGS model. Decrease of serum uPA levels may be an indicator of the progression of FSGS in clinical subjects and animal models.


Clinical outcomes of state-of-the-art percutaneous coronary revascularization in patients with de novo three vessel disease: 1-year results of the SYNTAX II study.
To investigate if recent technical and procedural developments in percutaneous coronary intervention (PCI) significantly influence outcomes in appropriately selected patients with three-vessel (3VD) coronary artery disease. The SYNTAX II study is a multicenter, all-comers, open-label, single arm study that investigated the impact of a contemporary PCI strategy on clinical outcomes in patients with 3VD in 22 centres from four European countries. The SYNTAX-II strategy includes: heart team decision-making utilizing the SYNTAX Score II (a clinical tool combining anatomical and clinical factors), coronary physiology guided revascularisation, implantation of thin strut bioresorbable-polymer drug-eluting stents, intravascular ultrasound (IVUS) guided stent implantation, contemporary chronic total occlusion revascularisation techniques and guideline-directed medical therapy. The rate of major adverse cardiac and cerebrovascular events (MACCE [composite of all-cause death, cerebrovascular event, any myocardial infarction and any revascularisation]) at one year was compared to a predefined PCI cohort from the original SYNTAX-I trial selected on the basis of equipoise 4-year mortality between CABG and PCI. As an exploratory endpoint, comparisons were made with the historical CABG cohort of the original SYNTAX-I trial. Overall 708 patients were screened and discussed within the heart team; 454 patients were deemed appropriate to undergo PCI. At one year, the SYNTAX-II strategy was superior to the equipoise-derived SYNTAX-I PCI cohort (MACCE SYNTAX-II 10.6% vs. SYNTAX-I 17.4%; HR 0.58, 95% CI 0.39-0.85, P = 0.006). This difference was driven by a significant reduction in the incidence of MI (HR 0.27, 95% CI 0.11-0.70, P = 0.007) and revascularisation (HR 0.57, 95% CI 0.37-0.9, P = 0.015). Rates of all-cause death (HR 0.69, 95% CI 0.27-1.73, P = 0.43) and stroke (HR 0.69, 95% CI 0.10-4.89, P = 0.71) were similar. The rate of definite stent thrombosis was significantly lower in SYNTAX-II (HR 0.26, 95% CI 0.07-0.97, P = 0.045). At one year, clinical outcomes with the SYNTAX-II strategy were associated with improved clinical results compared to the PCI performed in comparable patients from the original SYNTAX-I trial. Longer term follow-up is awaited and a randomized clinical trial with contemporary CABG is warranted. NCT02015832.


Biological clustering supports both "Dutch" and "British" hypotheses of asthma and chronic obstructive pulmonary disease.
Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases. We sought to determine, in terms of their sputum cellular and mediator profiles, the extent to which they represent distinct or overlapping conditions supporting either the "British" or "Dutch" hypotheses of airway disease pathogenesis. We compared the clinical and physiological characteristics and sputum mediators between 86 subjects with severe asthma and 75 with moderate-to-severe COPD. Biological subgroups were determined using factor and cluster analyses on 18 sputum cytokines. The subgroups were validated on independent severe asthma (n = 166) and COPD (n = 58) cohorts. Two techniques were used to assign the validation subjects to subgroups: linear discriminant analysis, or the best identified discriminator (single cytokine) in combination with subject disease status (asthma or COPD). Discriminant analysis distinguished severe asthma from COPD completely using a combination of clinical and biological variables. Factor and cluster analyses of the sputum cytokine profiles revealed 3 biological clusters: cluster 1: asthma predominant, eosinophilic, high TH2 cytokines; cluster 2: asthma and COPD overlap, neutrophilic; cluster 3: COPD predominant, mixed eosinophilic and neutrophilic. Validation subjects were classified into 3 subgroups using discriminant analysis, or disease status with a binary assessment of sputum IL-1β expression. Sputum cellular and cytokine profiles of the validation subgroups were similar to the subgroups from the test study. Sputum cytokine profiling can determine distinct and overlapping groups of subjects with asthma and COPD, supporting both the British and Dutch hypotheses. These findings may contribute to improved patient classification to enable stratified medicine.


The binding specificity and affinity determinants of family 1 and family 3 cellulose binding modules.
Cellulose binding modules (CBMs) potentiate the action of cellulolytic enzymes on insoluble substrates. Numerous studies have established that three aromatic residues on a CBM surface are needed for binding onto cellulose crystals and that tryptophans contribute to higher binding affinity than tyrosines. However, studies addressing the nature of CBM-cellulose interactions have so far failed to establish the binding site on cellulose crystals targeted by CBMs. In this study, the binding sites of CBMs on Valonia cellulose crystals have been visualized by transmission electron microscopy. Fusion of the CBMs with a modified staphylococcal protein A (ZZ-domain) allowed direct immuno-gold labeling at close proximity of the actual CBM binding site. The transmission electron microscopy images provide unequivocal evidence that the fungal family 1 CBMs as well as the family 3 CBM from Clostridium thermocellum CipA have defined binding sites on two opposite corners of Valonia cellulose crystals. In most samples these corners are worn to display significant area of the hydrophobic (110) plane, which thus constitutes the binding site for these CBMs.


Age-specific risk factor profiles of adenocarcinomas of the esophagus: A pooled analysis from the international BEACON consortium.
Esophageal (EA) and esophagogastric junction (EGJA) adenocarcinoma have been steadily increasing in frequency in younger people; however, the etiology of these cancers is poorly understood. We therefore investigated associations of body mass index (BMI), cigarette smoking, alcohol consumption, gastroesophageal reflux and use of nonsteroidal anti-inflammatory drugs (NSAIDs) in relation to age-specific risks of EA and EGJA. We pooled individual participant data from eight population-based, case-control studies within the international Barrett's and Esophageal Adenocarcinoma Consortium (BEACON). The analysis included 1,363 EA patients, 1,472 EGJA patients and 5,728 control participants. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for age-specific (<50, 50-59, 60-69, ≥70 years) cancer outcomes, as well as interactions by age. BMI, smoking status and pack-years, recurrent gastroesophageal reflux and frequency of gastroesophageal reflux were positively associated with EA and EGJA in each age group. Early-onset EA (<50 years) had stronger associations with recurrent gastroesophageal reflux (OR = 8.06, 95% CI: 4.52, 14.37; peffect modification = 0.01) and BMI (ORBMI ≥ 30 vs . <25 = 4.19, 95% CI: 2.23, 7.87; peffect modification = 0.04), relative to older age groups. In contrast, inverse associations of NSAID use were strongest in the oldest age group (≥70 years), although this apparent difference was not statistically significant. Age-specific associations with EGJA showed similar, but slightly weaker patterns and no statistically significant differences by age were observed. Our study provides evidence that associations between obesity and gastroesophageal reflux are stronger among earlier onset EA cancers.


Flavonoids: hemisynthesis, reactivity, characterization and free radical scavenging activity.
Phenolic compounds form one of the main classes of secondary metabolites. They display a large range of structures and they are responsible for the major organoleptic characteristics of plant-derived-foods and beverages, particularly color and taste properties and they also contribute to the nutritional qualities of fruits and vegetables. Phenolic compounds are also highly unstable compounds which undergo numerous enzymatic and chemical reactions during postharvest food storage and processing thus adding to the complexity of plant polyphenol composition. Among these compounds flavonoids constitute one of the most ubiquitous groups of all plant phenolics. Owing to their importance in food organoleptic properties and in human health, a better understanding of their structures, their reactivity and chemical properties in addition to the mechanisms generating them appears essential to predict and control food quality. The purpose of this work is an overview of our findings concerning the hemisynthesis, the reactivity and the enzymatic oxidation of some flavonoids and shed light on the mechanisms involved in some of these processes and the structures of the resulting products. The free radical scavenging activity of some of the synthesized compounds is also presented and a structure-activity relationship is discussed. The first part of this review concerns the synthesis and structural characterization of modified monomeric flavanols. The use of these compounds as precursor for the preparation of natural and modified dimeric procyanidin derivatives was then explored through different coupling reactions. The full characterization of the synthesized compounds was achieved by concerted use of NMR and ESI-MS techniques. The free radical scavenging activity of some of the synthesized compounds was investigated. The second part of this review concerns the enzymatic oxidation of several flavonols by Trametes versicolor laccase. Most of the major oxidation products have been isolated as pure compounds and their structures unambiguously established through spectroscopic methods. Correlation between the structure of the oxidation product and the substitution pattern of the starting materials allows mechanistic features of this transformation to be elucidated.


Influence of carvedilol on hospitalizations in heart failure: incidence, resource utilization and costs. U.S. Carvedilol Heart Failure Study Group.
Carvedilol reduces disease progression in heart failure, but to our knowledge, its effects on hospitalizations and costs have not been evaluated. We examined the effects on hospitalization frequency and costs in the U.S. Carvedilol Heart Failure Trials Program. This program consisted of four concurrent, multicenter, double-blind, placebo-controlled studies involving 1,094 patients with New York Heart Association class II to IV heart failure, which treated patients with placebo or carvedilol for up to 15 months (median, 6.5 months). Detailed resource utilization data were collected for all hospitalizations occurring between randomization and the end of follow-up. In-patient care costs were estimated based on observed levels of resource use. Compared with placebo, carvedilol reduced the risk of hospitalization for any reason by 29% (p = 0.009), cardiovascular hospitalizations by 28% (p = 0.034) and heart failure hospitalizations by 38% (p = 0.041). Carvedilol also decreased the mean number of hospitalizations per patient (for cardiovascular reasons 30% [p = 0.02], for heart failure 53% [p = 0.03]). Among hospitalized patients, carvedilol reduced severity of illness during hospital admission, as reflected by shorter length of stay and less frequent use of intensive care. For heart failure hospital admissions, carvedilol decreased mean length of stay by 37% (p = 0.03) and mean number of intensive care unit/coronary care unit days by 83% (p = 0.001), with similar effects on cardiovascular admissions. As a result, estimated inpatient care costs with carvedilol were 57% lower for cardiovascular admissions (p = 0.016) and 81% lower for heart failure admissions (p = 0.022). Carvedilol added to angiotensin-converting enzyme inhibition reduces hospitalization risk as well as severity of illness and resource utilization during admission in patients with chronic heart failure.


Determining bronchial morphology for the purposes of segregating so-called heterotaxy.
Introduction Heterotaxy is a unique clinical entity in which lateralisation of the thoraco-abdominal organs is abnormal, typically with isomerism of the bronchial tree and atrial appendages. This study was carried out to determine whether routine clinical imaging such as chest radiographs, angiographic images, and CT/MRI can determine bronchial isomerism, and how sidedness of bronchial isomerism correlates with overall features anticipated in hearts with isomeric atrial appendages. Methods and results We identified 73 patients with heterotaxy, in whom imaging clearly demonstrated the bronchial tree, seen at our institution since 1998. We calculated bronchial angles and lengths using all the available imaging modalities to determine the presence and sidedness of bronchial isomerism. This was then compared with the anticipated presence of isomeric atrial appendages based on the overall clinical findings, as the appendages themselves had not specifically been imaged. The ratio of bronchial lengths revealed bronchial isomerism in all patients, with bronchial angles permitting distinction of right as opposed to left isomerism. We noted discordances between the identified bronchial isomerism and the presumed arrangement of the atrial appendages in nearly 20% of the patients in our cohort. Routine clinical imaging with chest radiographs, angiographic imaging, and CT/MRI can determine the presence of bronchial isomerism in patients with so-called heterotaxy. Right as opposed to left isomerism can be distinguished based on bronchial angles. The finding of bronchial isomerism correlates well, but not totally, with the presumed isomerism of the atrial appendages as predicted from the identified intra-cardiac morphology.


[Surgical targets in Psychiatric disorders. From movement to emotions].
Deep brain stimulation (DBS) for psychiatric disorders refractory to conventional treatments are currently been performed based on the knowledge obtained in the motor disorder surgery and mainly in Parkinson's disease. Depression, obsessive-compulsive disorder (OCD) and Tourette syndrome, all of them are cortico-striato-thalamo-cortical pathological process involved in the limbic loop of the basal ganglia. This review describes the different targets in these pathological neuro-psychiatric disorders. For OCD there are currently two targets, ventral striatum (VS) Accumbens nucleus (Nacc) and the subthalamic nucleus (STN). In refractory depression the subgenual area (25 Brodmann area) and VS/Nacc. For Tourette syndrome the ventralis oralis internus and centromedianum/parafascicularis of the thalamus (Voi and CM/Pf) and the internal part of the globus pallidus (GPi). Currently there are no specific surgical target for each pathological disorder because clinical results reported are very similar after stimulation surgery. In other point, a selected surgical target also may improve different pathologies.