A novel type of putrescine (diamine)-acetylating enzyme from the nematode Ascaris suum.
A cytosolic enzyme catalysing the acetylation of the diamines putrescine, cadaverine, 1,3-diaminopropane and 1,6-diaminohexane has been partially purified from reproductive tissue of the intestinal parasitic nematode Ascaris suum. The enzyme formed N-acetylated derivatives of the above diamines when incubated in the presence of acetyl-CoA. The Michaelis constants (Km) for the above diamines were 0.25 nM, 0.1 mM, 1.25 mM and 0.4 mM respectively, and the apparent Km for acetyl-CoA was 7.7 microM. sym-Norspermidine was also acetylated by this enzyme preparation, and, at a much lower rate, the enzyme acted on sym-norspermine. The common polyamines, spermidine and spermine, and histones were not substrates. Purification steps involved a freezing-and-thawing procedure to release enzyme activity from unknown inhibitors, DEAE-cellulose chromatography and affinity chromatography on cadaverine-Sepharose, from which the enzyme was eluted by increasing ionic strength. The enzyme exhibited an apparent Mr of about 38,000-40,000, and it consisted of at least two subunits, of which the catalytic one had an Mr of about 13,000. The partially purified enzyme showed no deacetylase activity, and its activity was competitively inhibited by the product N-acetylputrescine, but not by CoA. The name putrescine N-acetyltransferase is suggested for this enzyme, which may have an important function in the degradation of diamines of lower eukaryotes.


Downregulation of HLA-I by the molluscum contagiosum virus mc080 impacts NK-cell recognition and promotes CD8+ T-cell evasion.
Molluscum contagiosum virus (MCV) is a common cause of benign skin lesions in young children and currently the only endemic human poxvirus. Following the infection of primary keratinocytes in the epidermis, MCV induces the proliferation of infected cells and this results in the production of wart-like growths. Full productive infection is observed only after the infected cells differentiate. During this prolonged replication cycle the virus must avoid elimination by the host immune system. We therefore sought to investigate the function of the two major histocompatibility complex class-I-related genes encoded by the MCV genes mc033 and mc080. Following insertion into a replication-deficient adenovirus vector, codon-optimized versions of mc033 and mc080 were expressed as endoglycosidase-sensitive glycoproteins that localized primarily in the endoplasmic reticulum. MC080, but not MC033, downregulated cell-surface expression of endogenous classical human leucocyte antigen (HLA) class I and non-classical HLA-E by a transporter associated with antigen processing (TAP)-independent mechanism. MC080 exhibited a capacity to inhibit or activate NK cells in autologous assays in a donor-specific manner. MC080 consistently inhibited antigen-specific T cells being activated by peptide-pulsed targets. We therefore propose that MC080 acts to promote evasion of HLA-I-restricted cytotoxic T cells.


Selection of P2Y12 Inhibitor in Percutaneous Coronary Intervention and/or Acute Coronary Syndrome.
The P2Y12 receptor plays a critical role in the amplification of platelet aggregation in response to various agonists and stable thrombus generation at the site of vascular injury leading to deleterious ischemic complications. Therefore, treatment with a P2Y12 receptor blocker is a major effective strategy to prevent ischemic complications in high-risk patients with acute coronary syndrome (ACS) and patients undergoing percutaneous coronary intervention (PCI). The determination of optimal platelet inhibition is based on maximizing antithrombotic properties while minimizing bleeding risk and is critically dependent on individual patient's propensity for thrombotic and bleeding risks. Immediately after ACS and during PCI, where highly elevated thrombotic activity is present, a loading dose administration with a potent P2Y12 receptor blocker such as ticagrelor or prasugrel is preferred. In stable coronary artery disease patients undergoing PCI, clopidogrel is widely used. In addition, in patients with ST-segment elevation myocardial infraction who cannot take oral medications, a fast acting intravenous glycoprotein IIb/IIIa inhibitor or P2Y12 receptor blocker, cangrelor, may add clinical benefits. During long term therapy, a strategy that prevents ischemic risk while avoiding excessive bleeding risk is similarly desired. Although up to one year dual antiplatelet therapy (DAPT) is recommended in patients undergoing elective stenting, the available data support the anti-ischemic benefit of prolonged DAPT (more than1 year) in patients with prior MI. In addition to the DAPT risk calculator tool, future risk assessment methods that analyze intrinsic thrombogenicity and atherosclerotic coronary burden may further identify the optimal candidate for prolonged DAPT to improve net clinical outcomes.


Exciton Polaritons in a Two-Dimensional Lieb Lattice with Spin-Orbit Coupling.
We study exciton polaritons in a two-dimensional Lieb lattice of micropillars. The energy spectrum of the system features two flat bands formed from S and P_{x,y} photonic orbitals, into which we trigger bosonic condensation under high power excitation. The symmetry of the orbital wave functions combined with photonic spin-orbit coupling gives rise to emission patterns with pseudospin texture in the flat band condensates. Our Letter shows the potential of polariton lattices for emulating flat band Hamiltonians with spin-orbit coupling, orbital degrees of freedom, and interactions.


Rapid and long-lasting increase in sites for synapse assembly during late-phase potentiation in rat hippocampal neurons.
Long-term potentiation in hippocampal neurons has stages that correspond to the stages of learning and memory. Early-phase (10-30 min) potentiation is accompanied by rapid increases in clusters or puncta of presynaptic and postsynaptic proteins, which depend on actin polymerization but not on protein synthesis. We have now examined changes in pre- and postsynaptic puncta and structures during glutamate-induced late-phase (3 hr) potentiation in cultured hippocampal neurons. We find that (1) the potentiation is accompanied by long-lasting maintenance of the increases in puncta, which depends on protein synthesis, (2) most of the puncta and synaptic structures are very dynamic, continually assembling and disassembling at sites that are more stable than the puncta or structures themselves, (3) the increase in presynaptic puncta appears to be due to both rapid and more gradual increases in the number of sites where the puncta may form, and also to the stabilization of existing puncta, (4) under control conditions, puncta of postsynaptic proteins behave similarly to puncta of presynaptic proteins and share sites with them, and (5) the increase in presynaptic puncta is accompanied by a similar increase in presumably presynaptic structures, which may form at distinct as well as shared sites. The new sites could contribute to the transition between the early and late phase mechanisms of plasticity by serving as seeds for the formation and maintenance of new synapses, thus acting as local "tags" for protein synthesis-dependent synaptic growth during late-phase plasticity.


Phosphoenolpyruvate Carboxykinase, a Key Enzyme That Controls Blood Glucose, Is a Target of Retinoic Acid Receptor-Related Orphan Receptor α.
Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes a committed and rate-limiting step in hepatic gluconeogenesis, and its activity is tightly regulated to maintain blood glucose levels within normal limits. PEPCK activity is primarily regulated through hormonal control of gene transcription. Transcription is additionally regulated via a cAMP response unit, which includes a cAMP response element and four binding sites for CCAAT/enhancer-binding protein (C/EBP). Notably, the cAMP response unit also contains a putative response element for retinoic acid receptor-related orphan receptor α (RORα). In this paper, we characterize the effect of the RORα response element on cAMP-induced transcription. Electrophoresis mobility shift assay indicates that RORα binds this response element in a sequence-specific manner. Furthermore, luciferase reporter assays indicate that RORα interacts with C/EBP at the PEPCK promoter to synergistically enhance transcription. We also found that cAMP-induced transcription depends in part on RORα and its response element. In addition, we show that suppression of RORα by siRNA significantly decreased PEPCK transcription. Finally, we found that a RORα antagonist inhibits hepatic gluconeogenesis in an in vitro glucose production assay. Taken together, the data strongly suggest that PEPCK is a direct RORα target. These results define possible new roles for RORα in hepatic gluconeogenesis.


Reading direction influences lateral biases in letter processing.
Humans have a limited capacity to identify concurrent, briefly presented targets. Recent experiments using concurrent rapid serial visual presentation of letters in horizontally displaced streams have documented a deficit specific to the stream in the right visual field. The cause of this deficit might be either prioritization of the left item based on participants' experience reading from left to right, or a right-hemisphere advantage specific to dual stimulation. Here we test the reading-experience hypothesis by using participants who have experience reading both a language written left-to-right (English) and one written right-to-left (Arabic). When tested with English letters, these participants showed a deficit, of a similar magnitude to that found previously, for reporting the item on the right. However, when the stimuli were Arabic letters the deficit was absent. This suggests that reading direction plays a large role in the second-target deficit. The pattern of participants' errors suggests where in the processing stream reading experience affects stimulus processing: Specifically, the error pattern suggests that the limited-capacity stage responsible for the deficit corresponds to a postsampling process such as consolidation into short-term memory. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


A comparative histological study on the skin occlusion performance of a cream made of solid lipid nanoparticles and Vaseline.
The water content of the epidermis is a main factor in maintaining skin smoothness and elasticity and preventing skin dryness. Occlusive products can greatly affect skin hydration by forming a barrier on the skin following the topical administration of oil-based formulations. These products repair the skin barrier by restoring the skin lipids as well. Solid lipid nanoparticles (SLNs) have recently been introduced as a novel carrier with several benefits in pharmaceutics and cosmeceutics. It has been suggested that SLNs may have an occlusive effect following topical application. In this study, the occlusion effects of lipidic particles in different size ranges were investigated in vitro, ex vivo, and in vivo, and the results were compared with the positive (vaseline) and negative (blank) controls. Although larger lipidic particles showed better occlusion properties than nanoparticles in vitro, but ex vivo experiments confirmed the benefits of nanoparticles (almost 30% higher occlusion factor for particles in the range of 170 nm than ones in the range of 600 and 1800 nm). The superiority of SLN formulation to Vaseline as a positive reference was confirmed by the in vivo study. SLN formulation resulted in much thicker stratum corneum than Vaseline. It was indicated that in vitro and ex vivo study methods may not be a good reflective of the in vivo method for determining the occlusive properties of nanoparticulate systems. It was concluded that formulations containing SLNs can be used as efficient skin moisturizer products.


[PROSPECTS OF INFORMATION INTERACTION OF MEDICAL AND PHARMACEUTICAL SPECIALISTS IN ASSISTING GERIATRIC PATIENTS].
The authors substantiate the necessity for information exchange among medical and pharmaceutical specialists in providing health services to elderly people. Mandatory conditions for the implementation of the exchange of information are defined and the conceptual model is proposed for information interaction between the medical and pharmacy organizations. This model reflects the recommended sections, types of information, the sender information (doctor or pharmacist), consumer of information, and the purpose of using the information included in a separate section. Ability to implement the concept is considered by the example of the Perm region.


Analysis of growth directions of columnar stromatolites from Walker Lake, western Nevada.
Samples of digitate, branching, columnar stromatolites were collected from the steep sides and near horizontal top of four in situ boulders located on the southwestern side of Walker Lake, Nevada, to test the widely held assumption that stromatolite column formation represents a phototropic response. We would predict that the columns on the steeply dipping sides of the boulder would bend upwards toward the light during growth if phototropism was significant during stromatolite morphogenesis. Angle of growth measurements on >300 stromatolites demonstrate that the stromatolites grew nearly normal to their growth surface, regardless of the inclination of their growth surface. No significant differences in the distribution of growth angles between north-, south-, east-, or west-facing samples were observed, and stromatolite lamina thickness did not systematically vary with position on the boulder. The lack of a strong phototropic response does not rule out a biological origin for the Walker Lake structures, but it does suggest that phototropic growth was not a dominant factor controlling stromatolite morphogenesis in these stromatolites and that column formation cannot be uniquely attributed as a phototropic response in stromatolites. It is interesting to note that the morphology of the stromatolites on the top of the boulder is identical to stromatolites on the steep sides. Stromatolite morphogenetic models that predict branching typically require a vertically directed sedimentary component, a feature that would have likely affected the stromatolites on the tops of the boulders, but not the sides, suggesting that other factors may be important in stromatolite morphogenesis.


Fibroblast stimulation of blood vessel development and cancer cell invasion in a subrenal capsule xenograft model: stress-induced premature senescence does not increase effect.
Fibroblast cooperation with cancer cells in xenograft development was investigated by transplanting MDA-MB-231 cells under the kidney capsule of immunodeficient mice. Control fibroblasts and fibroblasts subjected to stress-induced premature senescence by treatment with bleomycin were used. In other xenograft models, senescent fibroblasts have shown a growth-stimulatory effect greater than that of control cells. In this model, both types of fibroblasts accelerated the formation and growth of xenografts. Blood vessel development, as evidence by von Willebrand factor staining, was greatly accelerated by the presence of fibroblasts, and invasion into the kidney was also increased. Control and senescent fibroblasts had very similar effects. These actions of fibroblasts were partially recapitulated in in vitro experiments. Both control and senescent fibroblasts stimulated the tubulogenesis of endothelial cells in culture and stimulated the invasion of MDA-MB-231 cells through Matrigel in vitro. In this xenograft model, in which fibroblasts are cotransplanted with a cancer cell into an internal organ rather than subcutaneously, senescence was not an important factor in the effects of cotransplanted fibroblasts on growth, blood vessel development, and invasion. Therefore, cancer promotion by the senescence of adjacent stromal cells may be restricted to certain organ and tissue types.


Cadherin 5 Is a Significant Risk Factor for Hematogenous Recurrence and a Prognostic Factor in Locally Advanced Gastric Cancer.
Cadherin 5 (CDH5) is important for adhesion in epithelial cells, and expressed in tumor cells in several malignancies. In the present study, we evaluated the clinical significance of CDH5 protein expression in locally advanced gastric cancer. Tumor tissues obtained from 113 patients with advanced gastric adenocarcinoma who underwent gastrectomy were analyzed. High CDH5 expression was significantly associated with recurrence (p=0.017), especially hematological recurrence (p=0.022). High CDH5 expression was a significant risk factor for hematogenous recurrence on multivariate analysis (odds ratio[OR]=3.9, confidential interval [CI] 1.0-15, p=0.043). Patients with high CDH5 expression had a significantly shorter progression-free interval (RFI, p=0.010) than patients with low CDH5 expression. High CDH5 expression was an independent prognostic factor on multivariate analysis of RFI (hazard ratio[HR]=2.2, 95% CI 1.1-4.3, p=0.021). CDH5 may play a key role in hematogenous recurrence of advanced gastric cancer and may be a viable treatment target.


Quantification of T cell receptor rearrangement excision circles to estimate thymic function: an important new tool for endocrine-immune physiology.
Although the thymus constitutes a target organ for most protein and steroid hormones, it has been quite difficult to determine the precise control exerted in vivo by the endocrine system upon thymic function. The biological role of the thymus is to ensure the generation of a diversified population of peripheral T cells able to respond to non-self-antigens but nevertheless tolerant to self-antigens. For a long time, thymic function could not be monitored, as a consequence of the absence of adequate technology to differentiate recent thymic emigrants from naive T cells. The generation of T cell receptor (TCR) diversity occurs in the thymus through recombination of gene segments encoding the variable parts of the TCR alpha and beta chains. During these processes, by-products of the rearrangements are generated in the form of TCR excision circles (TRECs). As these molecules are lost upon further cell division, their quantification is actually considered as a very valuable tool to estimate thymic function. The most appropriate TREC is deltaRec-Psi(J)alpha TREC or signal joint TREC resulting from deltaRec-Psi(J)alpha rearrangement (TCRD deletion) that occurs late during thymopoiesis, before V(alpha)-J(alpha) rearrangement. Here we describe how TREC quantification is a powerful and reliable method to evaluate the impact of hormones and endocrine disorders upon thymic function.


Scaphoid (navicular) fracture of the wrist.
This common fracture most frequently affects young males. In most cases, the fracture is found on initial examination. Occasionally, it is missed on the initial radiographic evaluation but becomes apparent on follow-up films. Although most scaphoid fractures respond to conservative therapy, some fail to heal. Nonunion of the scaphoid may respond to various nonoperative and operative techniques. In such cases, consultation with a hand surgeon is useful.


Resistance to flexural fatigue of Reciproc R25 files under continuous rotation and reciprocating movement.
The aim of the present work was to evaluate the resistance to flexural fatigue of Reciproc R25 nickel-titanium files, 25 mm, used in continuous rotation motion or reciprocation motion, in dynamic assays device. Thirty-six Reciproc R25 files were divided into 2 groups (n = 18) according to kinematics applied, continuous rotary (group CR) and reciprocation motion (group RM). The files were submitted to dynamic assays device moved by an electric engine with 300 rpm of speed that permitted the reproduction of pecking motion. The files run on a ring's groove of temperate steel, simulating instrumentation of a curved root canal with 40° and 5 mm of curvature radius. The fracture of file was detected by sensor of device, and the time was marked. The data were analyzed statistically by Student's t test, with level of significance of 95%. The instruments moved by reciprocating movement reached significantly higher numbers of cycles before fracture (mean, 1787.78 cycles) when compared with instruments moved by continuous rotary (mean, 816.39 cycles). The results showed that the reciprocation motion improves flexural fatigue resistance in nickel-titanium instrument Reciproc R25 when compared with continuous rotation movement.


A Systematic Review of Zoonotic Enteric Parasites Carried by Flies, Cockroaches, and Dung Beetles.
Filth flies, cockroaches, and dung beetles have been close neighbors with humans and animals throughout our joint histories. However, these insects can also serve as vectors for many zoonotic enteric parasites (ZEPs). Zoonoses by ZEPs remain a paramount public health threat due to our close contact with animals, combined with poor water, sanitation, and hygiene access, services, and behaviors in many global regions. Our objective in this systematic review was to determine which ZEPs have been documented in these vectors, to identify risk factors associated with their transmission, and to provide effectual One Health recommendations for curbing their spread. Using PRISMA guidelines, a total of 85 articles published from 1926 to 2021 were reviewed and included in this study. Qualitative analysis revealed that the most common parasites associated with these insects included, but were not limited to: Ascaris spp., Trichuris spp., Entamoeba spp., and Cryptosporidium spp. Additionally, prominent risk factors discovered in the review, such as poor household and community WASH services, unsafe food handling, and exposure to domestic animals and wildlife, significantly increase parasitic transmission and zoonoses. The risk of insect vector transmission in our shared environments makes it critically important to implement a One Health approach in reducing ZEP transmission.


Unanswered questions about margin recommendations for primary cutaneous melanoma.
Radical wide excision with appropriate margins based on depth of tumor invasion has been the standard adopted in NCCN and national clinical practice guidelines in oncology based on randomized controlled trial data. When carefully scrutinized, however, questions remain unanswered about what constitute appropriate margins in many frequently encountered clinical situations. In addition to the single characteristic of tumor depth, factors such as primary tumor location, histologic classification, and even specific patient characteristics may all contribute to risk for local recurrence, and therefore should potentially be considered in margin recommendations. This article addresses current uncertainty surrounding optimal margin status in primary cutaneous melanoma.


Immunization in health employees: Relationship of confidence and attitude.
This is a cross-sectional online survey study performed to identify whether the health employees' confidence in the vaccine besides their confidence in the administrators about the vaccine had any effect on their attitudes toward the vaccine. The study was carried out on February 2021 with the participation of 402 health employees working in the pandemic hospitals. Approximately 33% of the participant health employees stated that they did not think of being vaccinated during the COVID-19 pandemic. Insufficient testing for the vaccines that are developed to fight against pandemics, having fear about their side effects, and finding them unreliable give rise to vaccine hesitancy in health employees. Besides, it was identified that the health employees' confidence in the vaccines and their confidence in the administrators about the vaccines affected their attitudes toward vaccination.


Impact of immunosuppressive drugs on the therapeutic efficacy of ex vivo expanded human regulatory T cells.
Immunosuppressive drugs in clinical transplantation are necessary to inhibit the immune response to donor antigens. Although they are effective in controlling acute rejection, they do not prevent long-term transplant loss from chronic rejection. In addition, immunosuppressive drugs have adverse side effects, including increased rate of infections and malignancies. Adoptive cell therapy with human Tregs represents a promising strategy for the induction of transplantation tolerance. Phase I/II clinical trials in transplanted patients are already underway, involving the infusion of Tregs alongside concurrent immunosuppressive drugs. However, it remains to be determined whether the presence of immunosuppressive drugs negatively impacts Treg function and stability. We tested in vitro and in vivo the effects of tacrolimus, mycophenolate and methylprednisolone (major ISDs used in transplantation) on ex vivo expanded, rapamycin-treated human Tregs. The in vitro results showed that these drugs had no effect on phenotype, function and stability of Tregs, although tacrolimus affected the expression of chemokine receptors and IL-10 production. However, viability and proliferative capacity were reduced in a dose-dependent manner by all the three drugs. The in vivo experiments using a humanized mouse model confirmed the in vitro results. However, treatment of mice with only rapamycin maintained the viability, function and proliferative ability of adoptively transferred Tregs. Taken together, our results suggest that the key functions of ex vivo expanded Tregs are not affected by a concurrent immunosuppressive therapy. However, the choice of the drug combination and their timing and dosing should be considered as an essential component to induce and maintain tolerance by Treg.


Executive Summary from the 2017 Emergency Medicine Resident Wellness Consensus Summit.
Physician wellness has recently become a popular topic of conversation and publication within the house of medicine and specifically within emergency medicine (EM). Through a joint collaboration involving Academic Life in Emergency Medicine's (ALiEM) Wellness Think Tank, Essentials of Emergency Medicine (EEM), and the Emergency Medicine Residents' Association (EMRA), a one-day Resident Wellness Consensus Summit (RWCS) was organized. The RWCS was held on May 15, 2017, as a pre-day event prior to the 2017 EEM conference in Las Vegas, Nevada. Seven months before the RWCS event, pre-work began in the ALiEM Wellness Think Tank, which was launched in October 2016. The Wellness Think Tank is a virtual community of practice involving EM residents from the U.S. and Canada, hosted on the Slack digital-messaging platform. A working group was formed for each of the four predetermined themes: wellness curriculum development; educator toolkit resources for specific wellness topics; programmatic innovations; and wellness-targeted technologies. Pre-work for RWCS included 142 residents from 100 different training programs in the Wellness Think Tank. Participants in the actual RWCS event included 44 EM residents, five EM attendings who participated as facilitators, and three EM attendings who acted as participants. The four working groups ultimately reached a consensus on their specific objectives to improve resident wellness on both the individual and program level. The Resident Wellness Consensus Summit was a unique and novel consensus meeting, involving residents as the primary stakeholders. The summit demonstrated that it is possible to galvanize a large group of stakeholders in a relatively short time by creating robust trust, communication, and online learning networks to create resources that support resident wellness.


Proteogenomic integration reveals CXCL10 as a potentially downstream causal mediator for IL-6 signaling on atherosclerosis.
Genetic and experimental studies support a causal involvement of interleukin-6 (IL-6) signaling in atheroprogression. While trials targeting IL-6 signaling are underway, any benefits must be balanced against an impaired host immune response. Dissecting the mechanisms that mediate the effects of IL-6 signaling on atherosclerosis could offer insights about novel drug targets with more specific effects. Leveraging data from 522,681 individuals, we constructed a genetic instrument of 26 variants in the gene encoding the IL-6 receptor (IL-6R) that proxied for pharmacological IL-6R inhibition. Using Mendelian randomization (MR), we assessed its effects on 3,281 plasma proteins quantified with an aptamer-based assay in the INTERVAL cohort (n=3,301). Using mediation MR, we explored proteomic mediators of the effects of genetically proxied IL-6 signaling on coronary artery disease (CAD), large artery atherosclerotic stroke (LAAS), and peripheral artery disease (PAD). For significant mediators, we tested associations of their circulating levels with incident cardiovascular events in a population-based study (n=1,704) and explored the histological, transcriptomic, and cellular phenotypes correlated with their expression levels in samples from human atherosclerotic lesions. We found significant effects of genetically proxied IL-6 signaling on 70 circulating proteins involved in cytokine production/regulation and immune cell recruitment/differentiation, which correlated with the proteomic effects of pharmacological IL-6R inhibition in a clinical trial. Among the 70 significant proteins, genetically proxied circulating levels of CXCL10 were associated with risk of CAD, LAAS, and PAD with up to 67% of the effects of genetically downregulated IL-6 signaling on these endpoints mediated by decreases in CXCL10. Higher midlife circulating CXCL10 levels were associated with a larger number of cardiovascular events over 20 years, whereas higher CXCL10 expression in human atherosclerotic lesions correlated with a larger lipid core and a transcriptomic profile reflecting immune cell infiltration, adaptive immune system activation, and cytokine signaling. Integrating multiomics data, we found a proteomic signature of IL-6 signaling activation and mediators of its effects on cardiovascular disease. Our analyses suggest the interferon-γ-inducible chemokine CXCL10 to be a potentially causal mediator for atherosclerosis in three vascular compartments and as such could serve as a promising drug target for atheroprotection.


Cardiologist Evaluation and Approval Was the Primary Predictor of Kidney Transplant Candidacy and Transplantation Among Patients With Reduced Left Ventricular Ejection Fraction.
End-stage kidney disease patients with concomitant heart failure (HF) with reduced ejection fraction are often denied kidney transplantation. The aims of this study were to explore factors predictive of suitability for kidney transplant and to assess cardiovascular outcomes in patients with impaired left ventricular ejection fraction (LVEF) after transplant. We evaluated 109 consecutive adults with LVEF ≤40% at the time of initial kidney transplant evaluation between 2013 and 2018. Posttransplant cardiovascular outcomes were defined as nonfatal myocardial infarction (MI), admission for HF, cardiovascular death, and all-cause mortality. A cardiologist participated in kidney transplant evaluation for 87% of patients and was present at 49% of transplant selection conferences. Twenty-four patients (22%) were denied by a cardiologist for kidney transplant' and 59 (54%) were denied by the selection committee, of whom 43 were because of cardiovascular risk. Forty-two (38%) patients were approved for kidney transplant. On univariate analysis, the variables associated with denial for kidney transplant included cardiologist denial, higher cardiac troponin T, prior coronary intervention, cardiovascular event, positive stress study, lower ejection fraction, and lower VO2 max (all P < 0.05). Cardiologist denial was the most significant predictor of denial for kidney transplant in different multivariate models. At a median follow-up of 15 mo, 5 (5%) suffered nonfatal MI, 13 (12%) were hospitalized for HF exacerbation, and 17 (16%) died. Only 22 patients, 52% of those approved, underwent kidney transplant. After kidney transplant, there was 1 death, 1 nonfatal MI, and 3 hospitalizations for HF. Median LVEF improved from 38% before listing to 55% posttransplant. Cardiologist denial was the primary predictor of rejection for kidney transplant. Despite careful selection, prevalence of cardiovascular events and mortality after kidney transplant was 23%. There is need for a structured multidisciplinary approach for patients with impaired LVEF.


Survivin is highly expressed in CD34(+)38(-) leukemic stem/progenitor cells and predicts poor clinical outcomes in AML.
Survivin, a member of the inhibitors of apoptosis protein family, plays important roles in cell proliferation and survival and is highly expressed in various malignancies, including leukemias. To better understand its role in acute myeloid leukemia (AML), we profiled survivin expression in samples obtained from 511 newly diagnosed AML patients and in CD34(+)38(-) AML stem/progenitor cells using a validated reverse-phase protein array; we correlated its levels with clinical outcomes and with levels of other proteins in the same sample set. We found that survivin levels were higher in bone marrow than in paired peripheral blood leukemic cells (n = 140, P = .0001) and that higher survivin levels significantly predicted shorter overall (P = .016) and event-free (P = .023) survival in multivariate Cox model analysis. Importantly, survivin levels were significantly higher in CD34(+)38(-) AML stem/progenitor cells than in bulk blasts and total CD34(+) AML cells (P < .05). Survivin expression correlated with the expressions of multiple proteins involved with cell proliferation and survival. Particularly, its expression strongly correlated with HIF1α in the stem/progenitor cell compartment. These results suggest that survivin is a prognostic biomarker in AML and that survivin, which is overexpressed in AML stem/progenitor cells, remains a potentially important target for leukemia therapy.


Association between iron metabolism and SARS-COV-2 infection, determined by ferritin, hephaestin and hypoxia-induced factor-1 alpha levels in COVID-19 patients.
Due to the growing evidence of the importance of iron status in immune responses, the biomarkers of iron metabolism are of interest in novel Coronavirus Disease 2019 (COVID-19). The present prospective study was carried out to compare iron status indicated by levels of ferritin with the levels of two novel biomarkers related to iron homeostasis, hephaestin and hypoxia-inducible factors-1 (HIF-1α) in the serum of patients with COVID-19 in comparison with a control group. Blood samples from 34 COVID-19 patients and from 43 healthy volunteers were collected and the levels of HEPH and HIF-1α were measured by ELISA and compared with levels of serum ferritin. COVID-19 patients had higher serum levels of ferritin than those levels in control group (P < 0.0001). Conversely levels of HIF-1α and HEPH in the COVID-19 group were significantly lower than those of control group (P < 0.0001 for both). An inverse correlation between hephaestin and ferritin as well as between HIF-1α and ferritin was found among all subjects (P < 0.0001), and among COVID-19 patients, but not to statistical significance. Levels of hephaestin and HIF-1α were found to be inversely related levels of ferritin across all participants in the study, and to our knowledge this is the first report of hephaestin and HIF-1α as potential markers of iron status. Further studies are needed to corroborate the findings, utilizing a broader range of markers to monitor inflammatory as well as iron status.


Pediatric Thyroid Eye Disease: Clinical Characteristics and Orbital Decompression Outcomes.
To review the clinical presentation, disease severity, and surgical interventions of children with thyroid eye disease (TED) at a single institution over a 7-year period. Retrospective cohort study of children 0 to 18 years of age with a diagnosis of TED, seen at the Children's Hospital of Philadelphia from 2009 to 2016. Ophthalmic examination findings, neuroimaging study results, and ophthalmological management were recorded. t-Tests were used to test for statistical significance. Institutional Review Board approval was obtained for the study. Sixty-seven subjects with pediatric TED were studied: 59 female and 8 male. The mean age at diagnosis was 11.6 years (SD 4.2, range 2.3-17.9). All subjects had proptosis (67, 100%). Other clinical findings were eyelid retraction in 46 (69%), chemosis in 7 (10%), punctate epithelial erosions in 8 (12%), and strabismus in 1 (1.5%). No subjects had evidence of optic neuropathy. Five subjects with static-phase TED received orbital decompression surgery for exposure keratopathy and disfigurement. All had significant cosmetic improvement and resolution of exposure keratopathy. In this series, children with TED generally exhibit mild ocular signs, which is in agreement with past studies. Our study presented a high incidence of proptosis compared with other studies; however, this may represent a referral bias to our quaternary care center. Pediatric TED patients exhibit mild symptoms, such as proptosis and eyelid retraction without strabismus, vision loss, or optic neuropathy. Some children with TED have severe disfigurement and corneal exposure due to the disease and benefit from orbital decompression.


A new method for hepatic resection and hemostasis: absorbable plaque and suture.
Blunt and penetrating hepatic injuries are conditions that are frequently encountered in emergency surgeries, and they involve high mortality morbidity. In the handling of such injuries, methods ranging from the application of simple cauterization and suturing for hemostasis to hepatic lobectomies, which might involve the removal of the greater part of the organ, have been defined. Due to the organ's fragility and susceptibility to bleeding, elective hepatic resections necessitate both surgical experience and technological equipment. Therefore, the demand still exists for an affordable and easy-to-use-method that could be applied by all centers. To meet this demand, we have developed a method of hemorrhage control via sutures supported by absorbable plaques that provide effective compression and prevent the suture from cutting the tissue during the application of the sutures in the treatment of such fragile organs as the liver. In our method, we have achieved hemostasis by bilaterally compressing the tissue through strong ties after placing, on the part of the tissue on which the sutures are applied, absorbable and flexible plaques that prevent the suture from cutting the tissue during the application of a polyglactin suture to the solid organ. To prevent dislocation of the plaques, we have fastened the sutures by reeving them through the holes made in the plaques. We have demonstrated the success and the practicality of our method by applying it on four pigs; we experimentally inflicted hepatic injuries on two pigs, and we performed resection on the other two pigs. The hepatic hemorrhages we developed in both of the animals were successfully restrained by the use of our method. On the other hand, two resections were performed on the right and left lobes of the other two animals. There were no hemorrhages during the surgery, and the procedure took 45 minutes in total. No postoperative complications occurred. While the liver function test values were high on the seventh day, due to the operation, they were observed to be normal on the thirtieth day. After the laparotomies, performed six months later, we observed that the plaques as well as the sutures were absorbed and that the injured tissues were completely healed. Additionally, it was observed during the pathological examination that the tissues beneath the area of application were healed through fibrosis and that the liver had no other pathologies. In conclusion, we believe that the method can be safely used in hepatic resections or traumatic hemorrhages in the proper locations.


Exchanging health information: local distribution, national coordination.
The fragmentation of our health care system, our need to accommodate the diversity of existing health information exchanges, the lack of consistent implementation of clinical information standards, and the need to protect patients' privacy and maintain trust are all challenges to overcome in achieving broad-scale interoperable health information exchange. We propose several steps to coordinate information sharing among regional and other networks through universal adherence to a basic framework of policies and standards. The critical policy action is the identification of a "common framework" of standards and policies, maintained by a new Standards and Policy Entity that reflects both public- and private-sector participation.


Identification of label-retaining perivascular cells in a mouse model of endometrial decidualization, breakdown, and repair.
The human endometrium is incredibly dynamic, undergoing monthly cycles of growth and regression during a woman's reproductive life. Endometrial repair at the cessation of menstruation is critical for reestablishment of a functional endometrium receptive for embryo implantation; however, little is understood about the mechanisms behind this rapid and highly efficient process. This study utilized a functional mouse model of endometrial breakdown and repair to assess changes in endometrial vasculature that accompany these dynamic processes. Given that adult endometrial stem/progenitor cells identified in human and mouse endometrium are likely contributors to the remarkable regenerative capacity of endometrium, we also assessed label-retaining cells (LRC) as candidate stromal stem/progenitor cells and examined their relationship with endometrial vasculature. Newborn mouse pups were pulse-labeled with bromodeoxyuridine (BrdU) and chased for 5 wk before decidualization, endometrial breakdown, and repair were induced by hormonal manipulation. Mean vessel density did not change significantly throughout breakdown and repair; however, significantly elevated endothelial cell proliferation was observed in decidual tissue. Stromal LRC were identified throughout breakdown and repair, with significantly fewer observed during endometrial repair than before decidualization. A significantly higher percentage of LRC were associated with vasculature during repair than before decidualization, and a proportion were undergoing proliferation, indicative of their functional capacity. This study is the first to examine the endometrial vasculature and candidate stromal stem/progenitor cells in a functional mouse model of endometrial breakdown and repair and provides functional evidence suggesting that perivascular LRC may contribute to endometrial stromal expansion during the extensive remodeling associated with this process.


Secretome of Adipose Tissue-Derived Stem Cells (ASCs) as a Novel Trend in Chronic Non-Healing Wounds: An Overview of Experimental In Vitro and In Vivo Studies and Methodological Variables.
Wound healing is a complex process with a linear development that involves many actors in a multistep timeline commonly divided into four stages: Hemostasis, inflammation, proliferation, and remodeling. Chronic non-healing wounds fail to progress beyond the inflammatory phase, thus precluding the next steps and, ultimately, wound repair. Many intrinsic or extrinsic factors may contribute to such an occurrence, including patient health conditions, age-related diseases, metabolic deficiencies, advanced age, mechanical pressure, and infections. Great interest is being focused on the adipose tissue-derived stem cell's (ASC) paracrine activity for its potential therapeutic impact on chronic non-healing wounds. In this review, we summarize the results of in vitro and in vivo experimental studies on the pro-wound healing effects of ASC-secretome and/or extracellular vesicles (EVs). To define an overall picture of the available literature data, experimental conditions and applied methodologies are described as well as the in vitro and in vivo models chosen in the reported studies. Even if a comparative analysis of the results obtained by the different groups is challenging due to the large variability of experimental conditions, the available findings are undoubtedly encouraging and fully support the use of cell-free therapies for the treatment of chronic non-healing wounds.


Effect of interstitial and/or systemic delivery of tirapazamine on the radiosensitivity of human glioblastoma multiforme in nude mice.
The purpose of this study was to investigate the feasibility and the efficacy of administering tirapazamine by a slow-releasing polymer disc that was implanted interstitially into a U251 (human glioblastoma multiforme) tumor grown in nude mice. Tumor-bearing animals, with a tumor nodule 0.8 cm3 in size, were distributed to groups receiving combinations of empty or drug-containing polymer implants in the tumor or contralateral leg, intraperitoneal (i.p.) drug, and/or irradiation. The drug (i.p.) alone (14 mg/kg x6) or in combination with tumor drug implant (2 mg) did not significantly increase the tumor volume doubling time compared to that of control animals. Given with 12 Gy of irradiation in twice a day 2-Gy fractions, combined i.p. drug and tumor drug implant significantly delayed tumor growth compared to irradiation alone, which was not achieved with either drug treatment alone added to irradiation. Toxicity, as manifested by transient weight loss, was primarily seen in animals receiving radiation and i.p. tirapazamine. These results indicated that a slow-releasing tirapazamine disc can be produced and the addition of an interstitially implanted tirapazamine disc further increased the effectiveness of i.p. tirapazamine.


Accuracy of human motion capture systems for sport applications; state-of-the-art review.
Sport research often requires human motion capture of an athlete. It can, however, be labour-intensive and difficult to select the right system, while manufacturers report on specifications which are determined in set-ups that largely differ from sport research in terms of volume, environment and motion. The aim of this review is to assist researchers in the selection of a suitable motion capture system for their experimental set-up for sport applications. An open online platform is initiated, to support (sport)researchers in the selection of a system and to enable them to contribute and update the overview. systematic review; Method: Electronic searches in Scopus, Web of Science and Google Scholar were performed, and the reference lists of the screened articles were scrutinised to determine human motion capture systems used in academically published studies on sport analysis. An overview of 17 human motion capture systems is provided, reporting the general specifications given by the manufacturer (weight and size of the sensors, maximum capture volume, environmental feasibilities), and calibration specifications as determined in peer-reviewed studies. The accuracy of each system is plotted against the measurement range. The overview and chart can assist researchers in the selection of a suitable measurement system. To increase the robustness of the database and to keep up with technological developments, we encourage researchers to perform an accuracy test prior to their experiment and to add to the chart and the system overview (online, open access).


Fragmentation of the large subunit of ribulose-1,5-bisphosphate carboxylase by reactive oxygen species occurs near Gly-329.
The large subunit (LSU) of ribulose-1,5-bisphosphate carboxylase/oxygenase (rubisco) in the illuminated lysates of wheat (Triticum aestivum L.) chloroplasts is broken down by reactive oxygen radicals into 37- and 16-kDa polypeptides. Analysis of the terminal amino acid residues of both fragments revealed that the C terminus of the 37-kDa fragment was Ser-328 and the N terminus of the 16-kDa fragment was Thr-330. Gly-329, which links the two fragments, was missing, suggesting that the fragmentation of the LSU in the lysates driven by oxygen-free radicals occurs at Gly-329. Purified rubisco, exposed to a hydroxyl radical-generating system, was also cleaved at the same site of the LSU. The cleavage site was positioned at the N-terminal end of the flexible loop (loop 6) within the beta/alpha-barrel domain, constituting the catalytic site of rubisco. The binding of a reaction intermediate analogue, 2-carboxyarabinitol 1,5-bisphosphate, to the active form of rubisco completely protected the enzyme from the fragmentation. The fragmentation was differentially affected by CO2, Mg2+, ribulose 1, 5-bisphosphate, or 2-carboxyarabinitol 1,5-bisphosphate. All these results indicate that the conformation of the catalytic site of the enzyme is involved as an important factor determining the breakdown of rubisco by reactive oxygen species. Reactive oxygen species generated at its catalytic site by a Fenton-type reaction may trigger the site-specific degradation of the LSU in the lysates of chloroplasts in the light.


Overstaging of cartilage invasion by multidetector CT scan for laryngeal cancer and its potential effect on the use of organ preservation with chemoradiation.
The two currently acceptable treatment options for locally advanced laryngeal cancer are total laryngectomy and organ preservation using chemoradiation. To facilitate therapeutic decision making, the accurate pre-treatment evaluation of cartilage invasion is of paramount importance. The purpose of this study was to evaluate the positive predictive value (PPV) and negative predictive value (NPV) of detecting neoplastic cartilage invasion in laryngeal cancer patients using fast-speed multidetector CT (MDCT). 61 consecutive patients with clinically staged T3 or T4 squamous cell carcinoma of the larynx or hypopharynx who underwent total laryngectomy were analysed. All patients had MDCT of the neck within 2 weeks prior to surgery. Central radiographic and pathological review was performed in an attempt to correlate findings. MDCT invasion of cartilage was graded based on objective criteria. MDCT scan was found to have a PPV of 78% and an NPV of 100% for detection of invasion through cartilage, with sensitivity being 100% and specificity 96%. For detection of any cartilage invasion (minor, major or through cartilage invasion), PPV and NPV were 63% and 92%, respectively. The sensitivity was 85% and specificity was 75%. For the detection of tumour invasion through cartilage or major cartilage invasion, MDCT scan had a PPV of 53% and an NPV of 95%. 47% (9/19) patients were down-staged from T4 to T3 after central pathology review. The low PPV for cartilage destruction using MDCT suggests that a significant proportion of patients who were treated by total laryngectomy could have been appropriately offered organ preservation if more accurately staged at initial diagnosis.


Pre-discharge growth pattern of very low birth weight infants (VLBW): A 5 year single center experience.
Very low birth weight infants born prematurely are at greater risk for growth delays that lead to Ex-utero Growth Restriction (EUGR) during vulnerable periods of organ structural and functional development. There is considerable evidence that early growth failure has adverse effects on long term neurodevelopment in children which often persists into adulthood. This is a single-center cross-sectional study on live newborn infants with birth weight ranges from 500 to 1500 grams (VLBW) and gestational age (GA) between 24-32 weeks who were admitted to NICU at KAMC-Jeddah over a 5 year period (2009-2013). This study aims to evaluate predischarge growth pattern of VLBW infants in terms of weight, head circumference (HC) and length and to identify important variables that have influenced such growth pattern. Of the 135 infants included in the final analysis, 68 (50.4%) were male and 67 (49.6%) were female and the mean gestational age was 28.83±2.064 weeks and the mean birth weight 1166.74±256 grams. Ninety-two infants (68%) had discharge weight at ≤10th percentile and forty four (32%) had their weight >10th percentile. HC was the lowest affected among the anthropometric measurements with 42% ≤10th percentile. In terms of linear growth, 62% had their length ≤10th percentile. Amongst infants born ≤750 grams, 71% and 70% had HC and height at ≤10th percentile respectively, at the time of discharge. BPD was significantly associated with EUGR (p = 0.026). This study demonstrates that almost 2/3rd of VLBW infants born at KAMC-Jeddah with birth weight ≤750 grams were discharged home with EUGR as demonstrated by their weight, length, and HC ≤10th percentile. BPD was found to be significantly associated with EUGR amongst post-natal factors influencing EUGR.


Emergency management of inherited metabolic diseases.
Inherited metabolic diseases with acute severe manifestations can be divided into five categories: (1) disorders of the intoxication type, (2) disorders with reduced fasting tolerance, (3) disorders with disturbed energy metabolism, (4) disorders of neurotransmission and (5) disorders in which no specific emergency treatment is available. Diagnostic emergency laboratory evaluation should cover all differential diagnoses that are therapeutically relevant and should always include ammonia, glucose, lactate and acid-base status as well as testing the urine for ketones. These are indispensable for planning and conducting the first steps of metabolic emergency treatment and should be available within 30 min. According to the clinical situation and biochemical derangement, special metabolic investigations must be initiated in parallel. These include acylcarnitine profiling with tandem mass spectrometry (in plasma or dried blood spots) and analysis of amino acids in plasma and of organic acids in urine. The results of all laboratory investigations relevant to the diagnosis of metabolic disorders for which specific emergency therapy exists should be available within 24 h. There is general agreement with regard to some therapeutic strategies that are clearly explained by pathophysiology: in disorders with endogenous intoxication, anabolism must be promoted and specific detoxification measures initiated. In disorders with reduced fasting tolerance, administration of glucose at the rate of hepatic glucose production forms the basis of treatment. Correction of acidosis is a major goal in disorders with disturbed mitochondrial energy metabolism, while glucose supply may have to be limited. Many current therapeutic strategies are based on case reports and personal experiences at different metabolic centres. The aim of devising the 'best' management is often hampered by the lack of objective evidence of efficacy.


Biotin-decorated all-HPMA polymeric micelles for paclitaxel delivery.
To avoid poly(ethylene glycol)-related issues of nanomedicines such as accelerated blood clearance, fully N-2-hydroxypropyl methacrylamide (HPMAm)-based polymeric micelles decorated with biotin for drug delivery were designed. To this end, a biotin-functionalized chain transfer agent (CTA), 4-cyano-4-[(dodecylsulfanylthiocarbonyl)-sulfanyl]pentanoic acid (biotin-CDTPA), was synthesized for reversible addition-fragmentation chain-transfer (RAFT) polymerization. Amphiphilic poly(N-2-hydroxypropyl methacrylamide)-block-poly(N-2-benzoyloxypropyl methacrylamide) (p(HPMAm)-b-p(HPMAm-Bz)) with molecular weights ranging from 8 to 24 kDa were synthesized using CDTPA or biotin-CDTPA as CTA and 2,2'-azobis(2-methylpropionitrile) as initiator. The copolymers self-assembled in aqueous media into micelles with sizes of 40-90 nm which positively correlated to the chain length of the hydrophobic block in the polymers, whereas the critical micelle concentrations decreased with increasing hydrophobic block length. The polymer with a molecular weight of 22.1 kDa was used to prepare paclitaxel-loaded micelles which had sizes between 61 and 70 nm, and a maximum loading capacity of around 10 wt%. A549 lung cancer cells overexpressing the biotin receptor, internalized the biotin-decorated micelles more efficiently than non-targeted micelles, while very low internalization of both types of micelles by HEK293 human embryonic kidney cells lacking the biotin receptor was observed. As a consequence, the paclitaxel-loaded micelles with biotin decoration exhibited stronger cytotoxicity in A549 cells than non-targeted micelles. Overall, a synthetic pathway to obtain actively targeted poly(ethylene glycol)-free micelles fully based on a poly(HPMAm) backbone was established. These polymeric micelles are promising systems for the delivery of hydrophobic anticancer drugs.


Kinetics of Serological Response in Patients with Severe Fever with Thrombocytopenia Syndrome.
Severe fever with thrombocytopenia syndrome (SFTS) is caused by SFTS virus (SFTSV). We investigated the detailed kinetics of serologic response in patients with SFTS. Twenty-eight patients aged ≥18 years were enrolled between July 2015 and October 2018. SFTS was confirmed by detecting SFTSV RNA in their plasma using reverse transcription polymerase chain reaction. SFTSV-specific IgG and IgM were measured using immunofluorescence assay (IFA) and enzyme-linked immunosorbent assay (ELISA). We found that SFTSV-specific IgG was detected at days 5-9 after symptom onset, and its titer was rising during the course of disease. SFTSV-specific IgM titer peaked at around week 2-3 from symptom onset. The SFTSV-specific seropositive rates for days 5-9, 10-14, 15-19, and 20-24 from symptom onset using IFA and ELISA were 63%, 76%, 90%, and 100%, and 58%, 86%, 100%, and 100%, respectively, for IgG, whereas they were 32%, 62%, 80%, and 100%, and 53%, 62%, 70%, and 100%, respectively, for IgM. The delayed IgM response could be attributed to the low sensitivity of SFTSV-specific IgM IFA or ELISA and/or impaired immune responses. The IgM test using IFA or ELISA that we used in this study is, therefore, insufficient for the early diagnosis of SFTS.


Dexamethasone potentiates hypoxic vasoconstriction in salt solution-perfused rat lungs.
Isolated rat lungs perfused with blood or plasma develop good hypoxic pressor reactivity, but those flushed of blood and perfused solely with physiological salt solution (PSS) show decreased or no hypoxic vasoconstriction. Because the handling of rats during collection of blood increases the plasma corticosterone levels, we wondered whether the difference between blood and PSS perfusion was due partly to higher glucocorticoid activity with blood than with PSS. Treatment of lung donors with the synthetic glucocorticoid dexamethasone (2 mg/kg im 3 h before isolation) or addition of dexamethasone (4.2 X 10(-6) M) to the perfusate increased markedly the hypoxic pressor reactivity of rat lungs perfused with PSS plus albumin (4 g/100 ml). In comparison, dexamethasone did not cause a significant increase in the already vigorous hypoxic pressor reactivity of blood-perfused lungs, but it reversed the blunted pressor reactivity of lungs perfused with blood collected from adrenalectomized rats. The potentiation of hypoxic vasoconstriction by dexamethasone required greater than 40 min to develop and was inhibited by a 100-fold higher concentration of progesterone, a glucocorticoid receptor antagonist. Although dexamethasone and the cyclooxygenase blocker meclofenamate (3.1 X 10(-5) M) caused similar decreases in perfusate levels of cyclooxygenase metabolites, the glucocorticoid was much more effective in inducing hypoxic vasoconstriction in PSS-perfused lungs. Thus a reduction of cyclooxygenase metabolism might have contributed to, but did not fully account for, the glucocorticoid effect. Dexamethasone also caused small increases in base-line perfusion pressure and in pressor reactivity to angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)


Sensitivity of single contrast barium enema with regard to colorectal disease as diagnosed by colonoscopy.
The results of single contrast barium enema were retrospectively correlated with colonoscopically diagnosed colorectal disease in 54 patients (75 lesions). Altogether 66 lesions (88%) were correctly diagnosed. The sensitivity of barium enema for polyps was 81% (26/32). There were three perceptive errors and three polyps 5 mm or less in size were not demonstrated by barium enema. Twenty-nine cases of inflammatory disorders were all correctly diagnosed. One of 12 malignancies was missed by perceptive error. In two cases with vascular malformations the barium enema was normal. 4/9 (44%) of missed lesions were perceptive errors and could have been probably avoided by a second independent reading of films.


Augmentation in two stages of atrophic alveolar bone prior to dental rehabilitation: a case report.
The aim of this report is to describe a significantly deficient case of alveolar bone that was managed by alveolar bone augmentation using a technique of distraction osteogensis and onlay bone grafting prior to dental implant placement. Injury to the teeth and alveolar ridge of the maxillary anterior region can cause a severe alveolar ridge deficiency resulting in ridge atrophy and maxillary retrognathism. The loss of these teeth and alveolar bone together with fibrotic scar formation can result in adverse changes of the interarch space, occlusal plane, arch relationship, and arch form which complicates rehabilitation and can compromise the esthetic outcome. While implant dentistry has become a new paradigm in oral reconstruction and replacement of missing teeth, ideal implant positioning can be compromised by inadequate alveolar bone in terms of bone height, width, and quality of the bone itself. Correction of osseous deficiencies with ridge augmentation allows ideal implant placement and creates a more natural soft tissue profile which influences crown anatomy and esthetics. A 20-year-old female presented with a complaint of poor esthetics resulting from oral injuries incurred in a traffic accident six years previously. In addition to a mandibular parasymphyseal fracture, five maxillary anterior teeth and the most of the alveolar ridge were lost. Clinical examination revealed severe loss of bone in the maxillary anterior region, an absence of a labial sulcus, loss of upper lip support, and a slight over eruption of the mandibular anterior teeth. In preparation for dental implants a distraction osteogenesis surgical procedure was done to lengthen the height of the alveolar ridge. After a three-month healing period, the width of the residual ridge was found to be insufficient for implant placement. To correct this deficiency, a bone graft of a cortiocancellous block was harvested from the chin and fixed to the labial aspect of the ridge. To facilitate revascularization, small perforations were made in the cortical bone of the alveolar ridge at the recipient site before cancellous bone retrieved from the donor site was gently placed between the bone block and the ridge. The patient was then appropriately medicated and healing was uneventful. After three months, the width of the residual ridge was assessed to be adequate for endosseous implants. The clinical result reported here has shown several procedures may be necessary for the rehabilitation of a trauma patient. Distraction osteogenesis per se may not always satisfactorily improve the anatomical alveolar anatomy but it has advantages over other methods of augmentation. It can improve the height and also expand the soft tissue for further bone grafting. Augmentation of the alveolar bone with an onlay bone graft often provides the desired gain of bone, allows for the ideal placement of dental implants, and improves any discrepancy between the upper and lower arches.


An ovalbumin-IL-12 fusion protein is more effective than ovalbumin plus free recombinant IL-12 in inducing a T helper cell type 1-dominated immune response and inhibiting antigen-specific IgE production.
Optimal treatment of allergic diseases requires that the cytokine profile of allergen-specific T cells be redirected, with the conversion of Th2 profiles into Th1 cytokine profiles. This conversion, however, is difficult, since Th2 effector cells have relatively fixed cytokine profiles. To more effectively redirect the cytokine profiles of T cells, we constructed a cytokine fusion protein that contained the Ag OVA, fused to IL-12. Immunization with the OVA-IL-12 fusion protein induced anti-OVA IgG2a Ab and large quantities of OVA-specific IFN-gamma production. The Ag specificity of this response was dependent upon covalent linkage of Ag and IL-12, since immunization of mice with OVA alone induced little or no IFN-gamma, while immunization with OVA and free rIL-12 enhanced T cell production of IFN-gamma, but the IFN-gamma production was not OVA specific. To examine the effects of OVA-IL-12 in reversing ongoing Th2-dominated immune responses, BALB/c mice previously primed with OVA in alum to induce a Th2-dominated response, were vaccinated with the OVA-IL-12 protein. In such mice, OVA-IL-12 was much more effective than OVA plus free rIL-12 in significantly increasing Ag-specific IFN-gamma production and significantly decreasing Ag-specific IL-4 production. Moreover, OVA-IL-12 increased serum anti-OVA IgG2a and decreased anti-OVA IgE. These studies indicate that OVA-IL-12 can convert immune responses characterized by high IL-4 and high IgE synthesis into Th1-dominated responses in an Ag-specific manner.


A multiple stress-responsive gene ERD15 from Solanum pennellii confers stress tolerance in tobacco.
Wild species often show more tolerance to environmental stress factors than their cultivated counterparts. An early responsive-to-dehydration gene was cloned from a drought- and salt-tolerant wild tomato Solanum pennellii (SpERD15). SpERD15 transcript accumulated differentially in different organs, and was remarkably induced by dehydration, salinity, cold and treatment with plant growth regulators. The protein encoded by SpERD15 was predominantly localized in the nucleus. Interestingly, we found that the majority of the transgenic tobacco plants were co-suppressed along with the overexpressing line. Overexpressing plants manifested stress tolerance accompanied by the accumulation of more soluble sugars and proline, and limited lipid peroxidation compared with co-suppression lines, which were more sensitive than the wild type. The differential contents of these compatible solutes in different transgenic lines were related to the changes in the expression of the genes involved in the production of some important osmolytes (P5CS and Sucrose synthase). Reduced lipid peroxidation over a broad range of stress factors was in agreement with increased expression of stress-responsive genes (ADH and GAPDH). Overexpression of SpERD15 increased the efficiency of PSII (F(v)/F(m)) in transgenic tobacco plants by maintaining PSII quinone acceptors in a partially oxidized form. The results show that SpERD15 augments stress tolerance by enhancing the efficiency of PSII through the protection of cellular membranes, as conferred by the accumulation of compatible solutes and limited lipid peroxidation.


Ischemic brain metabolism in patients with chronic cerebrovascular disease: Increased oxygen extraction fraction and cerebrospinal fluid lactate.
The aim of the present study is to elucidate the existence of chronically ischemic metabolism concomitant with misery perfusion of the brain in patients with chronic cerebrovascular disease. For this purpose, we measured cerebral blood flow (CBF) and oxygen metabolism by positron emission tomography (PET) and also determined cerebrospinal fluid (CSF) lactate as an indicator of the ischemic brain metabolism. Twenty-eight patients with chronic ischemic stroke and transient ischemic attack (TIA), who had angiographically occlusive (n = 11), stenotic (n = 10), and nonstenotic changes (n = 7) of the carotid artery and/or the intracranial major artery, were selected for this study. CBF, oxygen extraction fraction (OEF), cerebral metabolic rate for oxygen (CMRO2), and cerebral blood volume (CBV) were determined by PET, and CSF lactate and pyruvate were determined by enzymatic method in the patients with various grades of stenotic changes of the carotid artery. There were no significant differences in PET parameters and CSF variables among the groups of the occlusive, stenotic, and nonstenotic carotid artery. However, CSF lactate was correlated negatively with mean bilateral hemispheric (m)CBF (R(2) = 0.229, P<.01), positively with mOEF (R(2) = 0.278, P<.005) and more highly with mCMRO2/CBF (absolute extraction of oxygen content to the brain) (R(2) = 0.473, P<.0001) in all patients. There was no correlation between CSF lactate and mCMRO2 or mCBV. None of the cases in the nonstenotic group showed mOEF greater than 0.45, or mCMRO2/CBF greater than 7.9 vol%, while 80% of the cases in the stenotic group and 82% of the cases in the occlusive group showed mOEF and mCMRO2/CBF exceeding the above-mentioned values, respectively. The present findings, that increased mOEF and mCMRO2/CBF were significantly correlated with increased CSF lactate, indicate the brain to be in a metabolically ischemic state or increased anaerobic glycolysis with oxygen metabolism maintained in patients with chronic ischemic stroke.


In Vivo Measurement of Granzyme Proteolysis from Activated Immune Cells with PET.
The biology of human granzymes remains enigmatic in part due to our inability to probe their functions outside of in vitro assays or animal models with divergent granzyme species. We hypothesize that the biology of human granzymes could be better elaborated with a translational imaging technology to reveal the contexts in which granzymes are secreted and biochemically active in vivo. Here, we advance toward this goal by engineering a Granzyme targeting Restricted Interaction Peptide specific to family member B (GRIP B) to measure secreted granzyme B (GZMB) biochemistry with positron emission tomography. A proteolytic cleavage of 64Cu-labeled GRIP B liberates a radiolabeled form of Temporin L, which sequesters the radioisotope by binding to adjacent phospholipid bilayers. Thus, at extended time points postinjection (i.e., hours, not seconds), tissue biodistribution of the radioisotope in vivo reflects relative units of the GZMB activity. As a proof of concept, we show in three syngeneic mouse cancer models that 64Cu-GRIP B detects GZMB from T cells activated with immune checkpoint inhibitors (CPI). Remarkably, the radiotracer detects the proteolysis within tumors but also in lymphoid tissue, where immune cells are activated by a systemic CPI. Control experiments with an uncleavable analogue of 64Cu-GRIP B and tumor imaging studies in germline GZMB knockout mice were applied to show that 64Cu-GRIP B is specific for GZMB proteolysis. Furthermore, we explored a potential noncytotoxic function for GZMB by applying 64Cu-GRIP B to a model of pulmonary inflammation. In summary, we demonstrate that granzyme biochemistry can be assessed in vivo using an imaging modality that can be scaled vertically into human subjects.


Enhanced cardiac vagal tone in mental fatigue: Analysis of heart rate variability in Time-on-Task, recovery, and reactivity.
Heart Rate Variability (HRV) has been suggested as a useful tool to assess fatigue-sensitive psychological operations. The present study uses a between and within-subject design with a cognitively demanding task and a documentary viewing condition, to examine the temporal profile of HRV during reactivity, Time-on-Task (ToT), and recovery. In the cognitive task group, participants worked on a bimodal 2-back task with a game-like character (the Gatekeeper task) for about 1.5 hours, followed by a 12-minute break, and a post-break block of performance (about 18 min). In the other group, participants watched documentaries. We hypothesized an increasing vagal-mediated HRV as a function of Time spent on the Gatekeeper task and no HRV change in the documentary viewing group. We also analyzed the trial-based post-response cardiac activity as a physiological associate of task-related motivation. Relative to the documentary-viewing, ToT was associated with an elevated level of subjective fatigue, decreased heart rate, and increased HRV, particularly in the vagal-mediated components. Based on fatigued participants' post-error cardiac slowing, and post-error reaction time analyses, we found no evidence for motivation deficits. The present findings suggest that the parasympathetic branch of the autonomous nervous system functioning as a relaxation system tends to be activated under increasing mental fatigue. In addition, the study shows that many HRV indices also seem to change when individuals are engaged in a prolonged, less fatiguing activity (e.g. documentary viewing). This finding emphasizes the relevance of comparisons/control conditions in ToT experiments.


A prospective international observational prevalence study on prone positioning of ARDS patients: the APRONET (ARDS Prone Position Network) study.
While prone positioning (PP) has been shown to improve patient survival in moderate to severe acute respiratory distress syndrome (ARDS) patients, the rate of application of PP in clinical practice still appears low. This study aimed to determine the prevalence of use of PP in ARDS patients (primary endpoint), the physiological effects of PP, and the reasons for not using it (secondary endpoints). The APRONET study was a prospective international 1-day prevalence study performed four times in April, July, and October 2016 and January 2017. On each study day, investigators in each ICU had to screen every patient. For patients with ARDS, use of PP, gas exchange, ventilator settings and plateau pressure (Pplat) were recorded before and at the end of the PP session. Complications of PP and reasons for not using PP were also documented. Values are presented as median (1st-3rd quartiles). Over the study period, 6723 patients were screened in 141 ICUs from 20 countries (77% of the ICUs were European), of whom 735 had ARDS and were analyzed. Overall 101 ARDS patients had at least one session of PP (13.7%), with no differences among the 4 study days. The rate of PP use was 5.9% (11/187), 10.3% (41/399) and 32.9% (49/149) in mild, moderate and severe ARDS, respectively (P = 0.0001). The duration of the first PP session was 18 (16-23) hours. Measured with the patient in the supine position before and at the end of the first PP session, PaO2/FIO2 increased from 101 (76-136) to 171 (118-220) mmHg (P = 0.0001) driving pressure decreased from 14 [11-17] to 13 [10-16] cmH2O (P = 0.001), and Pplat decreased from 26 [23-29] to 25 [23-28] cmH2O (P = 0.04). The most prevalent reason for not using PP (64.3%) was that hypoxemia was not considered sufficiently severe. Complications were reported in 12 patients (11.9%) in whom PP was used (pressure sores in five, hypoxemia in two, endotracheal tube-related in two ocular in two, and a transient increase in intracranial pressure in one). In conclusion, this prospective international prevalence study found that PP was used in 32.9% of patients with severe ARDS, and was associated with low complication rates, significant increase in oxygenation and a significant decrease in driving pressure.


beta-adrenergic receptor gene polymorphisms and beta-blocker treatment outcomes in hypertension.
Numerous studies have demonstrated that beta(1)- and beta(2)-adrenergic receptor gene (ADRB1 and ADRB2) variants influence cardiovascular risk and beta-blocker responses in hypertension and heart failure. We evaluated the relationship between ADRB1 and ADRB2 haplotypes, cardiovascular risk (death, nonfatal myocardial infarction (MI), and nonfatal stroke), and atenolol-based vs. verapamil sustained-release (SR)-based antihypertensive therapy in 5,895 coronary artery disease (CAD) patients. After an average of 2.8 years, death rates were higher in patients carrying the ADRB1 Ser49-Arg389 haplotype (hazard ratio (HR) 3.66, 95% confidence interval (95% CI) 1.68-7.99). This mortality risk was significant in patients randomly assigned to verapamil SR (HR 8.58, 95% CI 2.06-35.8) but not atenolol (HR 2.31, 95% CI 0.82-6.55), suggesting a protective role for the beta-blocker. ADRB2 haplotype associations were divergent within the treatment groups but did not remain significant after adjustment for multiple comparisons. ADRB1 haplotype variation is associated with mortality risk, and beta-blockers may be preferred in subgroups of patients defined by ADRB1 or ADRB2 polymorphisms.


Clinical and neuropsychological correlates of the P300 in schizophrenia.
We investigated the relationship between the P300, neuropsychological test performance and symptomatology in recent-onset schizophrenic patients (n = 45) to gain insight into underlying mechanisms of abnormal P300 in schizophrenia. The P300 was recorded in two sessions with an intermission of five minutes, at the midline frontal, central and parietal electrode site. P300 amplitude and latency were compared with those obtained in 25 controls. Twenty patients were treated with olanzapine and 19 patients with risperidone. P300 amplitude was smaller and latency longer in patients than in controls. In the patient group, parietal P300 amplitude reduction was related to poorer performance on neuropsychological tests of memory. Frontal P300 amplitude reduction was related to impaired selective attention. In patients with negative symptomatology, P300 amplitude was reduced in the second P300 session compared with the first. Patients on risperidone demonstrated a smaller parietal P300 amplitude than patients using olanzapine. Reduced parietal P300 amplitude could signify a dysfunction in the continuous memory updating of current events. Negative symptomatology may be associated with a time dependent decrease in neuronal firing, as indicated by reduced P300 amplitude in the second P300 session.


Factors associated with declaration of disability in medical students and junior doctors, and the association of declared disability with academic performance: observational study using data from the UK Medical Education Database, 2002-2018 (UKMED54).
To examine factors associated with declaration of disability by medical students and doctors, and the association of declared disability with academic performance. Observational study using record-linked data collected between 2002 and 2018. UK Medical Education Database is a repository of data relating to training of medical students and doctors. Disability and other data are record-linked. All students starting at a UK medical school between 2002 and 2018 (n=135 930). Declared disability was categorised by the Higher Education Statistics Authority. Outcomes related to undergraduate academic performance included scores in the educational performance measure (EPM), prescribing safety assessment and situational judgement test. Performance in postgraduate examinations was studied, as well as prior attainment in school examinations and aptitude tests. Specific learning disability (SLD) was the most commonly declared disability (3.5% compared with the next most commonly declared disability at 1.0% of n=129 345 all cases in the study), and during the period covered by the data, SLD declarations increased from 1.4% (n=6440 for students starting in 2002) to 4.6% (n=8625 for students starting in 2018). In a logistic regression, the following factors predicted recording of SLD on entry to medical school ((exp(B)±95% CI), p<0.0001 unless otherwise stated): attendance at a fee-paying school (2.306±0.178), graduate status (1.806±0.205), participation of local areas quintile (1.089±0.030), age (1.034±0.012). First year medical students were less likely to declare SLD if they were from a non-white ethnic background (Asian/Asian British 0.324±0.034, black/black British 0.571±0.102, mixed 0.731±0.108, other ethnic groups 0.566±0.120), female (0.913±0.059; p=0.007) or from a low index of multiple deprivation quintile (0.963±0.029); p=0.017. In univariate analysis with Bonferroni corrections applied for multiple tests, no significant difference was observed in the recording of SLD according to socioeconomic class (χ2=5.637, p=1), whether or not a student's parents had a higher education (χ2=0.140, p=1), or whether or not a student had received a United Kingdom Clinical Aptitude Test (UKCAT) bursary (χ2=7.661, p=0.068). Students who declared SLD at some point in medical school (n=4830) had lower EPM normalised deviate values (-0.390) than those who did not (-0.119) (F=189.872, p<0.001). Those for whom SLD was recorded were as likely to complete the course successfully as those who did not declare disability (93.0% successful completion by those for whom SLD declared from year 1 (n=2480), 92.2% by those for whom SLD declared after year 1 (n=2350), 91.6% by those for whom SD not declared at any point (n=85 180)) (χ2=6.905, p=0.032). Of 3580 first year students who declared SLD, 43.1% had not sat the UKCAT Special Educational Needs aptitude test (which gives extra time for those with special educational needs), while 28% of 2400 registrants for whom SLD was recorded as medical students did not declare it at General Medical Council registration. Substantial increases in declaration of SLD may reflect changes in the social and legal environment during the period of the study. Those who declare SLD are just as likely to gain a primary medical qualification as those who do not. For some individuals, disability declaration appears to depend on context, based on differences in numbers declaring SLD before, during and after medical school.


C-shaped nanoaperture-enhanced germanium photodetector.
We present a C-shaped nanoaperture-enhanced Ge photodetector that shows 2-5 times the photocurrent enhancement over that from a square aperture of the same area at 1310 nm wavelength. We demonstrate the polarization dependence of the C-aperture photodetector over a wide wavelength range. Our experimental observation agrees well with finite-difference time-domain simulation results.


MR imaging of hyperacute intracranial hemorrhage in the cat.
Hyperacute intracerebral hematomas were successfully created in five cats by injecting a prepared blood sample in which the oxygen (O2) saturation ranged from 0-80%. T1- and T2-weighted spin-echo sequences and T2-weighted gradient refocused scans were obtained 2.5-10 hr after injection on a 1.5-T imaging system. Detailed histology or electron microscopy was performed on each brain to confirm the presence of intact red blood cells in a retracted clot matrix. Areas of the hematoma were hypointense relative to brain in all five cats on the gradient refocused scans. The hematoma was isointense relative to brain on the T1- and T2-weighted spin-echo scans in all cats except one, which suffered a seizure/respiratory arrest and died during the scanning procedure. Portions of the hematoma in this animal had a hypointense T2-weighted signal and a hyperintense T1-weighted signal, which corresponded to the predicted MR properties of intracellular methemoglobin. We hypothesize that acute (less than 10 hr old) hematomas that contain virtually 100% intracellular deoxyhemoglobin may not appear hypointense relative to brain on T2-weighted scan sequences at 1.5 T unless surrounding tissue hypoxia and/or anoxia promote additional changes, one of which may be the formation of intracellular methemoglobin.


Predictors of pneumococcal conjugate vaccine immunogenicity among infants and toddlers in an American Indian PnCRM7 efficacy trial.
Pneumococcal conjugate vaccines are important for the prevention of serious illness and death among infants. Factors associated with pneumococcal conjugate vaccine immunogenicity have not been explored. Children <24 months of age received 2, 3, or 4 doses of 7-valent pneumococcal conjugate vaccine (PnCRM7) or control vaccine depending on age at enrollment. Serum samples were tested for serotype-specific antibodies by enzyme-linked immunosorbant assay. Multiple linear regression was used to determine predictors of immunogenicity. Among 315 PnCRM7-vaccinated subjects and 295 control subjects enrolled at <7 months of age, geometric mean concentrations (GMCs) of antibodies were significantly higher after dose 3 than after dose 2 for all serotypes except type 4. The proportion of subjects with antibody concentrations > or =5.0 micro g/mL was higher for all serotypes, but the proportion with concentrations > or =0.35 micro g/mL was higher only for types 6B and 23F. Three-dose and 2-dose regimens for those 7-11 and 12-23 months of age, respectively, were highly immunogenic. Increased maternal antibody concentrations were associated with reduced responses to dose 1 and 3 but not to dose 4 of PnCRM7. Maternal antibody is associated with a reduced infant response to PnCRM7 but does not interfere with immune memory. In infants, a third priming dose increases the antibody GMC and the proportion achieving an antibody concentration > or =5.0 micro g/mL but has little impact on the proportion achieving a concentration > or =0.35 micro g/mL.


A Comparison of Nonobese Versus Obese Emergency Department Patient Satisfaction Scores Utilizing Standard U.S. Hospital Survey Query Methodology.
Prior research reveals that overweight patients have higher emergency department (ED) utilization rates, longer length of stay, and face increased misdiagnosis risk. The objective of this study was to evaluate the association between obesity and ED patient satisfaction. This study was a cross-sectional study. A convenience sample of inner-city ED patients completed a written survey, then rated overall satisfaction with ED care (10-point scale), and rated components of satisfaction (4-point scale; never to always). Body mass index (BMI) was calculated using triage records (obesity = BMI >30). Five hundred and sixty-four patients were included in the study group (50.5%: obese, 55.4%: female, mean age: 43.2 ± 25.4 years). With respect to overall visit satisfaction (rating 8 or greater on 10-point scale), bivariate analysis revealed no differences between nonobese versus obese patients (74.6% vs. 73.9%; P = 0.85). There were no significant differences for score of 4 (always) for components of ED satisfaction: physician courtesy (87.9% vs. 90.4%; P = 0.34), nurse courtesy/respect (89.2% vs. 88.7%; P = 0.87), doctor listened (85.4% vs. 87.1%; P = 0.5), doctor explained (80.2% vs. 85.0%; P = 0.14), and recommend to friend (72.5% vs. 81.1%; P = 0.02). Within our multivariate model, obesity was not associated with overall satisfaction (scores of 8 or greater) (P = 0.97; odds ratio = 0.99 [95% confidence interval = 0.65-1.5]). Despite research that suggests that overweight patients have characteristics of their ED visit that might increase dissatisfaction risk, we found no difference in satisfaction scores between nonobese and obese patients.


Increased risk of osteoporotic fractures in Swedish patients with rheumatoid arthritis despite early treatment with potent disease-modifying anti-rheumatic drugs: a prospective general population-matched cohort study.
Objective: To study the difference in incidence and risk of fragility fractures between rheumatoid arthritis (RA) patients followed up early in the disease and the general population in Sweden; and the fracture risk changes in RA patients diagnosed in the 1990s and 2000s because of earlier, more potent pharmacological treatment in the later period.Method: Patients with early RA were recruited from the BARFOT cohort, a Swedish multicentre observational study of early RA patients (n = 2557). All patients fulfilled 1987 American College of Rheumatology criteria and were included between 1992 and 2006. Each patient was matched by gender, age, and residential area with four controls from the general population (n = 10 228). Fractures of forearm, upper arm, and hip were identified by ICD-9 and ICD-10 codes through Swedish national medical registries.Results: During follow-up of 12.9 ± 4.7 years (mean ± sd), 14% (n = 470) of RA patients and 11% (n = 1418) of controls experienced a fracture (p < 0.001). When dividing the patients and controls into two groups according to inclusion period, an 8 year follow-up time was used. RA patients included in the 1990s had a higher incidence rate (IR) of hip and other fractures. RA patients included in the 2000s had a higher IR of all fracture sites. The hazard ratio of fractures was 1.4 in the total RA cohort, and the risk was increased in both the 1990s and 2000s.Conclusion: We observed an increased risk of fragility fractures in RA patients diagnosed in both the 1990s and 2000s, despite patients in the 2000s obtaining potent pharmacological treatment early in the disease.


Endocarditis in the setting of IDU: multidisciplinary management.
The purpose of this article is to provide a brief overview of the medical and surgical management of infective endocarditis secondary to IDU, with a focus on the underlying substance use disorder. Patients with infective endocarditis secondary to IDU are often young with unique comorbidities including mental illness, chronic hepatitis C, HIV infection, which are often compounded by limited social and familial supports. The focus of management has been treatment of endocarditis using IV antibiotics alongside surgery. Surgical outcomes compare favorably with those of infective endocarditis in the general population but long-term outcomes of IDUs are significantly worse. This is primarily due to the high rate of recidivism of drug use and the risk of prosthetic valve infective endocarditis. Contemporary management of addiction utilizes an integrative approach, combining both pharmacologic and nonpharmacologic strategies while remaining patient-centered. Given the complexity of care required, we advocate for a multidisciplinary team-based approach including psychiatry, infectious disease, cardiology, cardiac surgery and social services. Infective endocarditis secondary to IDU remains a medical and surgical challenge with dismal outcomes. Here we offer practical suggestions on the multidisciplinary management of this challenging and high-risk patient cohort.


Standardised packaging, minimum excise tax, and RYO focussed tax rise implications for UK tobacco pricing.
Standardised packaging for factory made (FM) and roll your own (RYO) tobacco was fully implemented in the UK in May 2017. Around the same time, several changes to the tax system were applied (a Minimum Excise Tax (MET) for FM products and tax increases weighted towards RYO products). The tobacco industry claims that standardised packaging will lower prices (a disincentive for quitting) by commoditising the product, yet had itself taken advantage of the previous tax regime to achieve large profits from premium brands while also keeping some products' prices relatively low. Here we evaluate the impact of standardised packaging, the MET and the RYO focussed tax changes on price and industry profitability. Nielsen electronic point of sale (EPOS) data (May 2015 to April 2018) were used to calculate real (inflation adjusted) monthly price per stick overall, by cigarette type (FM and RYO) and by seven market segments. Trend estimation, using additive mixed models, assessed weighted average price (weighted by volume of sales) and tobacco industry net revenue changes. The beginning and end of the data series were compared in terms of: (a) average monthly price growth, (b) average monthly net revenue growth, and (c) undershifting and overshifting patterns after tax changes. FM and RYO real prices changed little over the 3-year period-overall prices rose by about 1p per stick. There was no evidence of commoditisation with prices of all FM segments (but not RYO) rising faster after the implementation of standardised packaging than immediately beforehand. The prices of the cheapest FM brands rose with the implementation of the MET. RYO price increases did not close the gap to FM pricing levels despite RYO focussed tax increases. Tax changes following the implementation of standardised packaging and the MET were more widely and quickly passed on to smokers in the form of higher prices than the tax change pre-implementation. The main limitations are first that because we do not know the exact mechanism by which Nielsen scales up sample data to provide UK estimates, we could only use data for a set three year period during which the same adjustments are made. Second, the tax and standardised packaging events were sometimes too close in time to separate their consequences statistically. Third, tobacco prices may also be affected by external factors such as changes in smokers' disposable income or availability of electronic nicotine delivery systems. There was no long-term lowering of tobacco prices after the implementation of standardised packaging as predicted by the industry. The introduction of the MET was successful in increasing the price of the cheapest FM cigarettes and narrowing the price gap between FM brands. The RYO tax increases were, however, insufficient to narrow the price gap between RYO and FM. Overall, undershifting became less extensive indicating that tobacco industry manipulation of the tax system which had previously kept cheap products available had declined. This suggests that standardised packaging and a MET will likely contribute to further declines in UK tobacco use.


[Environmental factors associated with habitat preferences by caddisfly larvae in tropical dry forest watersheds (Tolima, Colombia)].
River ecosystems, mainly those draining tropical dry forests, are among the most endangered tropical ecosystems and a major conservation priority in South America, as elsewhere. In this study, we assessed the influence of environmental factors (e.g., precipitation) and riparian vegetation on Trichoptera larval assemblages colonizing four substrates (rock, gravel, sand, and litter) in the Venadillo and Opia watersheds (Tolima, Colombia). In each river, five 20m reaches nested into two 100m segments (one at -550 and another at -250masl), were surveyed for benthic invertebrates in the above mentioned substrates. In addition, water samples were collected for physicochemical analyses and the QBR index ("qualitat del bosc de ribera" or riparian forest quality) was applied in both rivers. A total of 6,282 larvae were collected, belonging to 11 families and 22 genera, representing 73.30% and 43.13% of the Trichoptera fauna reported to Colombia, respectively. The most abundant families were Hydropsychidae (49.86%) and Philopotamidae (25.44%) and the least abundant Odontoceridae (0.16%) and Hydrobiosidae (0.06%). The genera Smicridea, Chimarra, Protoptila, Neotrichia, and Leptonema, were common during dry and rainy seasons. The main factors related to changes in composition, richness, and abundance of larval Trichoptera were seasonality and riparian vegetation, which can influence organic matter supply, availability and stability of substrates, and colonization and population dynamics. Trichoptera assemblages showed no significant differences among substrates. However sampling points located at high elevation and in non-urbanized areas offered the largest variety of substrates and richness. Our results indicate that Trichoptera larvae are an important biotic element in freshwater ecosystems and that they are sensitive to environmental changes. Hence, our study suggests that caddisflies may be used as potential organisms for the biomonitoring of tropical dry forest rivers. The implementation of these studies is urgent, considering that degradation of freshwater ecosystems tends to be severe and persistent in dry forest.


Systematic review of anticoagulant treatment of catheter-related thrombosis.
Central venous catheter-related thrombosis (CRT) is a complication seen in patients requiring long-term intravenous access. Treatment of CRT is not standardized and international guidelines for treatment are based on extrapolation of evidence from lower extremity thrombosis. We performed a systematic review of the literature to evaluate if duration of anticoagulation affects the risk of recurrent venous thrombosis, post-thrombotic syndrome, or major hemorrhage. We searched PubMed, Embase, Medline, CINAHL, Cochrane, and ACP Journal club for studies of CRT treated with anticoagulation. Of 1648 titles and abstracts, 23 studies met our inclusion criteria. No randomized trials were identified. Duration of anticoagulation varied from 8 days to more than 6 months. Outcomes of patients with upper extremity thrombosis due to CRT or other etiologies were often combined. The incidence of post-thrombotic syndrome varied between 0 and 75% depending on the definition used. Seven percent of patients with upper extremity thrombosis treated with anticoagulation experienced recurrent deep vein thrombosis and 2.8% experienced pulmonary embolism. Major hemorrhage was reported in 2.8-4.9% of anticoagulated patients. Prospective studies evaluating the optimal duration of anticoagulation in patients with CRT are needed.


Circ_0000253 promotes the progression of osteosarcoma via the miR-1236-3p/SP1 axis.
Circular RNAs (circRNAs) play important roles in modulating tumour progression. This study investigated the role of circ_0000253 in osteosarcoma (OS). We downloaded the chip dataset GSE140256 from the Gene Expression Omnibus database and the circRNAs differentially expressed in OS tissue and normal tissue samples were analysed. Quantitative real-time PCR (qRT-PCR) was carried out to examine circ_0000253 expression in OS tissues and cells. Cell counting kit-8, BrdU and flow cytometry assays were performed to verify the effects of circ_0000253 on OS cell growth and apoptosis. Bioinformatics analysis was conducted to predict, and RNA immunoprecipitation assay and dual-luciferase reporter gene assay were performed to verify the targeted relationships of miR-1236-3p with circ_0000253 and Sp1 transcription factor (SP1) mRNA 3'UTR. The effects of miR-1236-3p and circ_0000253 on SP1 expression in OS cells were detected through Western blot. Circ_0000253 was upregulated in OS tissues and cell lines. Circ_0000253 overexpression facilitated OS cell growth and suppressed apoptosis, whereas knocking down circ_0000253 inhibited OS cell growth and facilitated apoptosis. Circ_0000253 targeted miR-1236-3p directly and negatively modulated its expression. SP1 was miR-1236-3p's target gene and positively regulated by circ_0000253. Circ_0000253 promotes OS cell proliferation and suppresses cell apoptosis via regulating the miR-1236-3p/SP1 molecular axis.