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Δευτέρα 17 Ιουλίου 2017

Associations between drugs and small-bowel mucosal bleeding: A multicenter capsule-endoscopy study

Abstract

Objectives

Although several drugs may induce small-bowel mucosal injuries, it is unclear whether these injuries contribute to overt small-bowel bleeding. This study was designed to evaluate the associations between drug use and small-bowel mucosal injury and between these mucosal injuries and overt bleeding in a disease-relevant population.

Methods

We retrospectively studied patients with suspected small-bowel diseases who underwent capsule endoscopy between 2010 and 2013. Drug exposure, the Charlson comorbidity index, smoking, and alcohol consumption were assessed before capsule endoscopy. Adjusted odds ratios (AORs) and confidence intervals (CIs) were estimated for small-bowel mucosal injury and small-bowel overt bleeding.

Results

In total, 850 patients were analyzed during the study period. The median age was 64 years, and 544 patients (64.0%) were men. Among the patients with small-bowel mucosal injury (n = 60) and without mucosal injury (n = 705), the use of NSAIDs (AOR 1.8, 95% CI 1.01–3.31) was significantly associated with an increased risk of small-bowel mucosal injury compared with non-use. The patients with small-bowel mucosal injury with overt bleeding (n = 85) and without overt bleeding (n = 60) were compared, and no significant difference between the groups in the usage rates for NSAIDs, thienopyridine, other antiplatelets, anticoagulants, acetaminophen, tramadol hydrochloride, or steroids was revealed, even after adjusting for confounders.

Conclusions

Although the use of NSAIDs was significantly associated with an increased risk of small-bowel mucosal injury, no significant associations were observed between the use of such drugs and small-bowel overt bleeding.

This article is protected by copyright. All rights reserved.



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Prevention of Post-ERCP Pancreatitis Is More Than Just Suppositories and Stents

Abstract

In this issue of the Journal, Professor Elmunzer provides an outstanding overview of the variable methods of prevention of post-ERCP pancreatitis (PEP) (1). We all recognize the importance of this topic given its morbidity for our patients. His review succinctly summarizes a wealth of both old and new data underscoring previously identified risk factors for PEP which have stood the test of time. In addition, newer interventions are appraised and placed in an appropriate context.

This article is protected by copyright. All rights reserved.



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Re-treatment with radium-223: first experience from an international, open-label, phase I/II study in patients with castration-resistant prostate cancer and bone metastases

Abstract
BackgroundSix radium-223 injections at 4-week intervals is indicated for patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases. However, patients usually develop disease progression after initial treatment. This prospective phase I/II study assessed re-treatment safety and efficacy of up to six additional radium-223 injections.Patients and methodsPatients had CRPC and bone metastases and six initial radium-223 injections with no on-treatment bone progression; all had subsequent radiologic or clinical progression. Concomitant agents were allowed at investigator discretion, excluding chemotherapy and initiation of new abiraterone or enzalutamide. The primary endpoint was safety; additional exploratory endpoints included time to radiographic bone progression, time to total alkaline phosphatase (tALP) and prostate-specific antigen (PSA) progression, radiographic progression-free survival (rPFS), overall survival, time to first symptomatic skeletal event (SSE), SSE-free survival (SSE-FS), and time to pain progression.ResultsAmong 44 patients, 29 (66%) received all six re-treatment injections. Median time from end of initial radium-223 treatment was 6 months. Forty-one (93%) reported ≥1 treatment-emergent adverse event (TEAE). No grade 4-5 hematologic TEAEs occurred. Only one (2%) patient had radiographic bone progression; eight (18%) had radiographic soft tissue tumor progression (three lymph node, five visceral metastases). Median times to tALP and PSA progression were not reached and 2.2 months, respectively. Median rPFS was 9.9 months (12.8-mo maximum follow-up). Five (11%) patients died and eight (18%) experienced first SSEs. Median overall survival, time to first SSE, and SSE-FS were not reached. Five (14%) of 36 evaluable patients (baseline worst pain score ≤7) had pain progression. After 2 years of follow-up, 28 (64%) patients died, and the median overall survival was 24.4 months.ConclusionsRe-treatment with a second course of six radium-223 injections after disease progression is well tolerated, with minimal hematologic toxicity and low radiographic bone progression rates in this small study with limited follow-up. Favorable safety, and early effects on disease progression indicate that radium-223 re-treatment is feasible and warrants further evaluation in larger prospective trials.

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Revival of PI3K inhibitors in Non-Hodgkin lymphoma



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Re: Review of knee arthroscopic practice and coding at a major metropolitan centre



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Newborn Screening for Lysosomal Storage Disorders in Illinois: The Initial 15-Month Experience

To assess the outcomes of newborn screening for 5 lysosomal storage disorders (LSDs) in the first cohort of infants tested in the state of Illinois.

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Longitudinal Association between Obesity and Dental Caries in Adolescents

To investigate the longitudinal association between obesity and dental caries among adolescents.

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Scrofula in a Child

A 4-year-old boy, previously healthy, had a 7-month history of a lesion on his face. He also had left-sided cervical adenopathy, with a diameter of 3.5 × 2.5 cm, which was not painful nor adherent to the overlying skin. Despite several courses of antibiotic therapy (erythromycin, amoxicillin-clavulanic acid, and cefaclor), there was no improvement. Surgical drainage of the lymphadenitis, undertaken after 14 days of illness, led to a chronic draining fistulous tract. Subsequently, he presented with 2 skin lesions, the largest being 2.5 × 2.5 cm (Figure).

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Beyond Folliculitis: Recognizing Herpes Gladiatorum in Adolescent Athletes

A previously healthy 17-year-old adolescent male wrestler presented to the emergency department with right eyelid swelling, worsening pruritic rash on his forehead, headache, and temperature of 100.9°F despite 4 doses of cephalexin. The patient reported sustaining 4 abrasions on his forehead during a wrestling tournament 2 weeks before, but otherwise denied contact with anyone with skin infections. His symptoms began with paresthesia, followed by headache, pruritus, and eruption of the rash. On physical examination, he had pustules spanning his forehead and extending onto his scalp, as well as a confluent area of crusted lesions on his left forehead (Figure).

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Tandem amplification of SCCmec can drive high level methicillin resistance in MRSA [PublishAheadOfPrint]

Hospital-associated methicillin-resistant Staphylococcus aureus strains typically express high level, homogenous (HoR) β-lactam resistance, whereas community-associated MRSA (CA-MRSA) more commonly express low level heterogeneous (HeR) resistance. Expression of the HoR phenotype typically requires both increased expression of the mecA gene, carried on the Staphylococcus cassette chromosome SCCmec element, and additional mutational event(s) elsewhere on the chromosome. Here the oxacillin concentration in a chemostat culture of the CA-MRSA strain USA300 was increased from 8 μg/ml to 130 μg/ml over 13 days to isolate highly oxacillin resistant derivatives. A stable, small colony variant, designated HoR34, which had become established in the chemostat culture was found to have acquired mutations in gdpP, clpX, guaA and camS. Closer inspection of the genome sequence data further revealed that reads covering SCCmec were ~10 times over-represented compared to other parts of the chromosome. qPCR confirmed >10-fold higher levels of mecA DNA on the HoR34 chromosome, and MinION genome sequencing verified the presence of 10 tandem repeats of the SCCmec element. qPCR further demonstrated that sub-culture of HoR34 in varying concentrations of oxacillin (0--100 μg/ml) was accompanied by accordion-like contraction and amplification of the SCCmec element. Although slower growing than USA300, HoR34 out-competed the parent strain in the presence of sub-inhibitory oxacillin. These data identify tandem amplification of the SCCmec element as a new mechanism of high-level methicillin resistance in MRSA, which may provide a competitive advantage for MRSA under antibiotic selection.



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Modeling the kinetics of the permeation of antibacterial agents into growing bacteria and its interplay with efflux [PublishAheadOfPrint]

A mathematical model of the passive permeation of a novel solute into bacteria is developed that explicitly accounts for intracellular dilution through growth. A bacterial cell envelope permeability coefficient of >10-8 cm2.s-1 approx., is predicted to ensure passive permeation into rapidly replicating bacterial cells. The relative importance of the permeability coefficients of the cytoplasmic and outer membranes of Gram-negative bacteria in determining the overall envelope permeability coefficient is analyzed quantitatively. A mathematical description of the balance between passive influx and active efflux is also developed that shows that bacterial expansion through growth can usually be neglected for compounds likely to be prepared in antibacterial drug discovery programs, and the balance between passive inward permeation and active outwardly-directed efflux predominates. A new parameter, efflux efficiency = k/P (where k is the rate coefficient for the efflux pump and P is the permeability coefficient for the membrane across which the pump acts), is introduced and the consequences explored for the efficiency of efflux pumping by a single pump, two pumps in parallel across either the cytoplasmic or outer membrane, and two pumps in series, one across the cytoplasmic membrane and one across the outer membrane of Gram-negative bacteria. The results, showing additive efficiency for two pumps acting across a single membrane, and multiplicative efficiency for two pumps acting in series across the cytoplasmic and outer membranes, can be quantitatively related to the ratios between minimum inhibitory concentrations measured against pump-sufficient and -deletion strains, and agree with previous experimental and theoretical studies.



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Flucloxacillin results in suboptimal voriconazole plasma concentrations [PublishAheadOfPrint]

Combining voriconazole and flucloxacillin is indicated in patient cohorts experiencing both invasive aspergillosis and gram-positive infections (e.g. patients with chronic granulomatous disease or post-influenza pulmonary aspergillosis). We report a highly relevant interaction between voriconazole and flucloxacillin resulting in subtherapeutic voriconazole plasma concentrations in more than 50% of patients, posing a severe threat if not managed properly.



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A Human Biofilm-Disrupting Monoclonal Antibody Potentiates Antibiotic Efficacy in Rodent Models of both Staphylococcus aureus and Acinetobacter baumannii Infections [PublishAheadOfPrint]

Many serious bacterial infections are antibiotic-refractory due to biofilm formation. A key structural component of biofilm is extracellular DNA which is stabilized by bacterial proteins, including those from the DNABII family. TRL1068 is a high affinity human monoclonal antibody against a DNABII epitope conserved across both gram-positive and gram-negative bacterial species. In the current study, the efficacy of TRL1068 for disruption of biofilm was demonstrated in vitro in the absence of antibiotics by scanning electron microscopy. In vivo efficacy of this antibody was investigated in a well-characterized catheter-induced aortic valve infective endocarditis model in rats infected with a methicillin-resistant Staphylococcus aureus (MRSA) strain with the ability to form thick biofilm, obtained from the blood of a patient with a persistent clinical infection. Animals were treated with vancomycin alone or in combination with TRL1068. MRSA burdens in cardiac vegetations, and within intracardiac catheters, kidneys, spleen and liver showed a significant reduction in the combination arm vs vancomycin alone (p<0.001). A trend towards mortality reduction was also observed (p=0.09). In parallel, in vivo efficacy of TRL1068 against a multi-drug resistant clinical Acinetobacter baumannii isolate was explored using an established skin and soft tissue catheter-related biofilm infection mouse model. Catheter segments infected with A. baumannii were implanted subcutaneously in mice; animals were treated with imipenem alone or in combination with TRL1068. The combination showed a significant reduction in catheter-adherent bacteria vs. antibiotic alone (p<0.001). TRL1068 shows excellent promise as an adjunct to standard-of-care antibiotics for a broad range of difficult-to-treat bacterial infections.



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IMPACT OF A CARBAPENEM ANTIMICROBIAL STEWARDSHIP PROGRAM ON PATIENT OUTCOMES [PublishAheadOfPrint]

Antimicrobial stewardship programs (ASPs) aim to improve appropriate antimicrobials use. However, concerns of the negative consequences from accepting ASP interventions exist, particularly when de-escalation or discontinuation of broad-spectrum antibiotics are recommended. Hence, we sought to evaluate the impact on clinical outcomes when ASP interventions for inappropriate carbapenem use were accepted or rejected by primary providers.

We retrospectively reviewed all carbapenem prescriptions deemed inappropriate according to institutional guidelines with ASP interventions between July 2011 and December 2014. Intervention acceptance and outcomes including carbapenem utilization, length-of-stay, hospitalization charges, 30-day readmission and mortality rates were reviewed. Data was analyzed in groups where physicians accepted all interventions ("Accepted") versus rejected ("Rejected").

A total of 158 ASP interventions were made. These included: carbapenem discontinuation (35%), change to narrower-spectrum antibiotic (32%), dose optimization (17%), further investigations (including imaging, procalcitonin) (11%), Infectious Diseases referral (3%), antibiotic discontinuation (other than carbapenem) (1%) and source control (1%).

Of 220 unique patients, carbapenem use was inappropriate in 101 (45.9%). Significant reduction in carbapenem utilization was observed in the "Accepted" group versus "Rejected" group (median defined daily doses: 0.224 versus 0.668 per 1000 patient-days, p<0.001). There was a significant reduction in 30-day mortality in "Accepted" (none) versus "Rejected" group (10 deaths, p=0.015) but there was no difference in length-of-stay, hospitalization charge and 30-day readmission rates. Hypotension was independently associated with mortality in multivariate analysis (odds ratio, 5.25, 95% confidence interval, 1.34-20.6).

In our institution, acceptance of carbapenem ASP interventions did not compromise patient safety in terms of clinical outcomes while reducing consumption.



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Activation of STING in hepatocytes suppresses the replication of hepatitis B virus [PublishAheadOfPrint]

Induction of interferon and proinflammatory cytokines is a hallmark of the infection of many different viruses. However, hepatitis B virus (HBV) does not elicit a detectable cytokine response in infected hepatocytes. In order to investigate the molecular mechanism underlying the innate immune evasion, a functional cGAS-STING pathway was reconstituted in a human hepatoma cell line supporting tetracycline-inducible HBV replication. It was demonstrated that induction of HBV replication neither activated nor inhibited this cytosolic DNA sensing pathway. However, human hepatoma cells as well as immortalized mouse hepatocytes express low levels of STING, which upon activation by cGAMP, the natural ligand of STING, led to induction of a proinflammatory cytokine response. Treatment of immortalized mouse hepatocytes supporting HBV replication with either cGAMP or a small molecule pharmacologic STING agonist significantly reduced viral DNA in a STING- and Janus kinase 1 (JAK1)-dependent manner. Moreover, cGAMP treatment was able to induce inflammatory cytokine gene expression and inhibit the transcription of covalently closed circular (ccc) DNA in HBV-infected human hepatoma cells expressing sodium-taurocholate cotransporting polypeptide (NTCP), an essential receptor for HBV infection of hepatocytes. The studies reported here and previously (Guo, F., et al., Antimicrob Agents Chemother, 59:1273--1281) thus support the notion that pharmacological activation of STING in macrophages and hepatocytes induces host innate responses that can efficiently control HBV replication. Hence, despite not playing a significant role in host innate immune response to HBV infection of hepatocytes, STING is potentially a valuable target for immunotherapy of chronic hepatitis B.



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Transmission of resistant Gram-negative bacteria to Healthcare Worker Gowns and Gloves during Care of Nursing Home Residents in VA Community Living Centers [PublishAheadOfPrint]

Objective: To estimate the risk of transmission of antibiotic resistant Gram-negative bacteria (RGNB) to gowns and gloves (G&G) worn by healthcare workers (HCWs) when providing care to nursing home residents and to identify types of care and resident characteristics associated with transmission.

Methods: A multi-center, prospective observational study was conducted enrolling residents and HCWs from VA nursing homes. Perianal swabs to detect RGNB were collected from residents. HCWs wore G&G during usual care activities and at the end of the interaction the G&G were swabbed in a standardized manner. Transmission of RGNB from a colonized resident to G&G by type of care was measured. Odds ratios (OR) associated with type of care or resident characteristics was estimated.

Results: Fifty-seven of 185 (31%) enrolled residents were colonized with at least one RGNB. RGNB transmission to either HCWs gloves or gowns occurred during 9% of the interactions (n=905). Seven percent of time to only gloves and 2% to gowns. Bathing the resident, as well as providing hygiene and toilet assistance were associated with high-risk of transmission. Glucose monitoring and assistance with feeding or medication were associated with low-risk of transmission. In addition, antibiotic use by the resident was strongly associated with greater transmission (OR 2.51, p<0.01).

Conclusions: RGNB were transferred to HCWs during approximately 9% of visits. High-risk types of care were identified for which use of G&G could be prioritized. Antibiotic use was associated with a 2.5 times greater risk of transmission, emphasizing the importance of antibiotic stewardship.



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NEUROTOXIC CONCENTRATION OF PIPERACILLIN DURING CONTINUOUS INFUSION IN CRITICALLY ILL PATIENTS [PublishAheadOfPrint]

This retrospective cohort study included 53 patients admitted in ICU, of average age 69 years, without neurologic disorder before initiation of piperacillin continuous infusion at standard dose and who underwent piperacillin serum concentration monitoring. Among them, 23 developed neurologic disorder for which the piperacillin causality was chronologically and semiologically suggestive. A concentration threshold of 157.2 mg/L independently predicted neurotoxicity with 96.7% specificity and 52.2% sensitivity and may constitute a limitation when targeting less susceptible pathogens.



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Deletion of sigB Causes Increased Sensitivity to para-Aminosalicylic Acid and Sulfamethoxazole in Mycobacterium tuberculosis [PublishAheadOfPrint]

Although the de novo folate biosynthesis pathway has been well studied in bacteria, little is known about its regulation. In this study, the sigB gene in Mycobacterium tuberculosis (M. tb) was deleted. Subsequent drug susceptibility tests revealed that M. tb sigB was more sensitive to para-aminosalicylic acid (PAS) and sulfamethoxazole (SMX). Comparative transcriptional analysis was performed and down-regulation of pabB was observed in the sigB deleted strain, which was further verified by qRT-PCR and Western blot assay. Then production of para-aminobenzoic acid (pABA) were compared between the sigB deletion mutant and wild type strain, and results showed that sigB deletion resulted in decreased production of pABA. Additionally, SigB was found to be able to recognize the promoter of pabB in vitro. Furthermore, we found that deleting pabC also caused increased susceptibility to PAS. Taken together, our data revealed that, in M. tb, sigB affects susceptibility to antifolates through multiple ways, the most of which is regulating the expression of pabB. To our knowledge, this is the first report showing that SigB modulates pABA biosynthesis and thus affecting susceptibility to antifolates, which broadens our understanding of the regulation of bacterial folate metabolism and mechanisms of susceptibility to antifolates.



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BCG — old workhorse, new skills

M Gengenbacher | NE Nieuwenhuizen | SHE Kaufmann

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Non-human primates as a model for understanding the mechanism of action of toll-like receptor-based vaccine adjuvants

Elizabeth A .Thompson | Karin Loré

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RNA-Seq of Rice Yellow Stem Borer, Scirpophaga incertulas Reveals Molecular Insights During Four Larval Developmental Stages

The yellow stem borer (YSB), Scirpophaga incertulas is a prominent pest in the rice cultivation causing serious yield losses. The larval stage is an important stage in YSB, responsible for maximum infestation. However, limited knowledge exists on biology and mechanisms underlying growth and differentiation of YSB. To understand and identify the genes involved in YSB development and infestation, so as to design pest control strategies, we performed de novo transcriptome at 1st, 3rd, 5th and 7th larval developmental stages employing Illumina Hi-seq. High quality reads of ~229 Mb were assembled into 24,775 transcripts with an average size of 1485bp. Genes associated with various metabolic processes i.e. detoxification mechanism (CYP450, GSTs and CarEs), RNAi machinery (Dcr-1, Dcr-2, Ago-1, Ago-2, Sid-1, Sid-2, Sid-3 and sid-1 related gene), chemoreception (CSPs, GRs, OBPs and ORs) and regulators (TFs and hormones) were differentially regulated during the developmental stages. Identification of stage specific transcripts made possible to determine the essential processes of larval development. Comparative transcriptome analysis revealed that YSB has not much evolved in detoxification mechanism but showed presence of distinct RNAi machinery. Presence of strong specific visual recognition coupled with chemosensory mechanisms supports the monophagous nature of YSB. Designed EST-SSRs will facilitate accurate estimation of genetic diversity of YSB. This is the first report on characterization of YSB transcriptome and identification of genes involved in key processes which will help researchers and industry to devise novel pest control strategies. This study opens a new avenue to develop next generation resistant rice using RNAi or genome editing approaches.



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Annotated Draft Genome Assemblies for the Northern Bobwhite (Colinus virginianus) and the Scaled Quail (Callipepla squamata) Reveal Disparate Estimates of Modern Genome Diversity and Historic Effective Population Size

Northern bobwhite (Colinus virginianus; hereafter bobwhite) and scaled quail (Callipepla squamata) populations have suffered precipitous declines across most of their U.S. ranges. Illumina-based first- (v1.0) and second-generation (v2.0) draft genome assemblies for the scaled quail and the bobwhite produced N50 scaffold sizes of 1.035 Mb and 2.042 Mb, thereby producing a 45-fold improvement in contiguity over the existing bobwhite assembly, and ≥ 90% of the assembled genomes were captured within 1,313 and 8,990 scaffolds, respectively. The scaled quail assembly (v1.0 = 1.045 Gb) was approximately 20% smaller than the bobwhite (v2.0 = 1.254 Gb), which was supported by kmer-based estimates of genome size. Nevertheless, estimates of GC content (41.72%; 42.66%), genome-wide repetitive content (10.40%; 10.43%), and MAKER-predicted protein coding genes (17,131; 17,165) were similar for the scaled quail (v1.0) and bobwhite (v2.0) assemblies, respectively. BUSCO analyses utilizing 3,023 single-copy orthologs revealed a high level of assembly completeness for the scaled quail (v1.0; 84.8%) and the bobwhite (v2.0; 82.5%), as verified by comparison with well-established avian genomes. We also detected 273 putative segmental duplications in the scaled quail genome (v1.0), and 711 in the bobwhite genome (v2.0), including some that were shared among both species. Autosomal variant prediction revealed approximately 2.48 and 4.17 heterozygous variants per Kb within the scaled quail (v1.0) and bobwhite (v2.0) genomes, respectively, and estimates of historic effective population size were uniformly higher for the bobwhite across all time points in a coalescent model. However, large-scale declines were predicted for both species beginning approximately 15-20 kya.



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Regulation of Small Mitochondrial DNA Replicative Advantage by Ribonucleotide Reductase in Saccharomyces cerevisiae

Small mitochondrial genomes can behave as selfish elements by displacing wild-type genomes regardless of their detriment to the host organism. In the budding yeast Saccharomyces cerevisiae, small hypersuppressive mtDNA transiently co-exist with wild-type in a state of heteroplasmy, wherein the replicative advantage of the small mtDNA outcompetes wild-type and produces offspring without respiratory capacity in >95% of colonies. The cytosolic enzyme ribonucleotide reductase (RNR) catalyzes the rate-limiting step in dNTP synthesis and its inhibition has been correlated with increased petite colony formation, reflecting loss of respiratory function. Here, we used heteroplasmic diploids containing wild-type (rho+) and suppressive (rho-) or hypersuppressive (HS rho-) mitochondrial genomes to explore the effects of RNR activity on mtDNA heteroplasmy in offspring. We found that the proportion of rho+ offspring was significantly increased by RNR overexpression or deletion of its inhibitor, SML1, while reducing RNR activity via SML1 overexpression produced the opposite effects. In addition, using Ex Taq and KOD Dash polymerases, we observed a replicative advantage for small over large template DNA in vitro, but only at low dNTP concentrations. These results suggest that dNTP insufficiency contributes to the replicative advantage of small mtDNA over wild-type and cytosolic dNTP synthesis by RNR is an important regulator of heteroplasmy involving small mtDNA molecules in yeast.



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Clinical characteristics and outcomes of Pseudomonas aeruginosa bacteremia in febrile neutropenic children and adolescents with the impact of antibiotic resistance: a retrospective study

Although the proportion of Pseudomonas aeruginosa infections has reduced after the introduction of antibiotics with anti-pseudomonal effects, P. aeruginosa bacteremia still causes high mortality in immunocompromi...

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USP18 protects against hepatic steatosis and insulin resistance via its DUB activity

Abstract

Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, impaired insulin sensitivity and chronic low-grade inflammation. However, the pathogenic mechanism of NAFLD is poorly understood, which hinders the exploration of possible treatments. Here, we first report that ubiquitin-specific protease 18 (USP18), a member of the deubiquitinating (DUB) enzyme family, plays regulatory roles in NAFLD progression. The expression of USP18 was down-regulated in the livers of non-alcoholic steatohepatitis (NASH) patients and high-fat diet (HFD) induced or genetically obese mice. When challenged with HFD, hepatocyte-specific USP18 transgenic (HTG) mice exhibited improved lipid metabolism and insulin sensitivity, whereas mice knocked out of USP18 expression (HKO) showed adverse trends regarding hepatic steatosis and glucose metabolic disorders. Furthermore, the concomitant inflammatory response was suppressed in USP18-HTG mice and promoted in USP18-HKO mice treated with HFD. Mechanistically, hepatocyte USP18 ameliorates hepatic steatosis by interacting with and deubiquitinating TGFβ-activated kinase 1 (TAK1), which inhibits TAK1 activation and subsequently suppresses the downstream JNK and NF-κB signaling pathways. This is further validated by alleviated steatotic phenotypes and highly activated insulin signaling in HFD-fed USP18-HKO mice administered with TAK1 inhibitor. The therapeutic effect of USP18 on NAFLD relies on its deubiquitinating activity because HFD-fed mice injected with active-site mutant USP18 failed to inhibit hepatic steatosis.

Conclusion: USP18 associates with and deubiquitinates TAK1 to protect against hepatic steatosis, insulin resistance and the inflammatory response. This article is protected by copyright. All rights reserved.



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Virtual and Actual Humanoid Robot Control with Four-Class Motor-Imagery-Based Optical Brain-Computer Interface

Motor-imagery tasks are a popular input method for controlling brain-computer interfaces (BCIs), partially due to their similarities to naturally produced motor signals. The use of functional near-infrared spectroscopy (fNIRS) in BCIs is still emerging and has shown potential as a supplement or replacement for electroencephalography. However, studies often use only two or three motor-imagery tasks, limiting the number of available commands. In this work, we present the results of the first four-class motor-imagery-based online fNIRS-BCI for robot control. Thirteen participants utilized upper- and lower-limb motor-imagery tasks (left hand, right hand, left foot, and right foot) that were mapped to four high-level commands (turn left, turn right, move forward, and move backward) to control the navigation of a simulated or real robot. A significant improvement in classification accuracy was found between the virtual-robot-based BCI (control of a virtual robot) and the physical-robot BCI (control of the DARwIn-OP humanoid robot). Differences were also found in the oxygenated hemoglobin activation patterns of the four tasks between the first and second BCI. These results corroborate previous findings that motor imagery can be improved with feedback and imply that a four-class motor-imagery-based fNIRS-BCI could be feasible with sufficient subject training.

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Effects of Angelica Extract on Schwann Cell Proliferation and Expressions of Related Proteins

The present study investigated the effects of Angelica extract (AE) on Schwann cell proliferation and expressions of related proteins, including brain derived neurotrophic factor (BDNF), neural cell adhesion molecule (NCAM), and proliferating cell nuclear antigen (PCNA). Proliferation activity and cell cycles of SCs were evaluated by MTT assay and flow cytometry methods, respectively, after 12 h treatment of AE at different concentrations (62.5, 125, 250, 1000, 2000, 4000, and 8000 mg/L). SCs were treated by 500, 1000, and 2000 mg/L AE for 24 h or 48 h; the related genes mRNA and proteins expressions in SCs were detected by quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) kit. At the concentration range of 125–2000 mg/L, the SC proliferation was induced by AE in a dose-dependent manner, especially 1000 and 2000 mg/L; cells in drug-treated groups showed the most increase. Cells counts were ascended significantly in (G2/M + S) phase compared to control group. BDNF, NCAM, and PCNA protein expressions significantly increased at drug-treated groups. Relative genes mRNA expressions levels were also significantly higher compared to control group. The results indicated that AE facilitated SC proliferation and related genes and proteins expressions, which provided a basic guideline for nerve injury repair in clinic.

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Dystonic neck muscles show a shift in relative autospectral power during isometric contractions

Idiopathic cervical dystonia (CD) is a neurological movement disorder characterized by involuntary neck muscle contractions (Fahn, 1988). The pathophysiology of CD remains unclear, although functional and morphometric changes have been found in several brain areas, such as the cerebral cortex (Draganski et al., 2003; Egger et al., 2007; Obermann et al., 2007; de Vries et al., 2012), superior colliculus (Holmes et al., 2012), thalamus (Krauss et al., 1999; Chang et al., 2002; Butterworth et al., 2003; Kupsch et al., 2006; Vidailhet et al., 2007), and cerebellum (LeDoux and Brady, 2003; Neychev et al., 2008; Sadnicka et al., 2012; Prudente et al., 2013).

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The standardized EEG electrode array of the IFCN

Standardising the position and nomenclature of scalp electrode arrays was an important step in the development of electroencephalography. First, the 10-20 system of the International Federation was developed by Herbert H. Jasper and his co-workers (Jasper, 1958), resulting in the first published guidelines in 1999 (Klem et al, 1999). Early on the lack of proper coverage of the temporal lobe was criticized, resulting in the proposition of the 'Maudsley electrodes' to sample the temporal pole (Binnie et al, 1982).

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Pain processing in atypical parkinsonisms and parkinson disease: A comparative neurophysiological study

Pain is a frequent symptom in Parkinson's Disease (PD) (Beiske et al., 2009), Progressive Sopranuclear Palsy (PSP)(Colosimo et al., 2010; Steele et al., 2014) and Multiple System Atrophy (MSA) (Tison et al., 1996).

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Extreme delta brushes in anti NMDA receptor encephalitis – muscle artefact or an EEG phenomenon? A case report

Extreme delta brushes have been described as an unique electroencephalographic (EEG) phenomenon in anti-NMDA receptor (anti-NMDA-R) encephalitis (Schmitt et al 2012; da Silva-Junior et al 2014; Veciana et al 2015).

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Modulation of motor cortex excitability by paired peripheral and transcranial magnetic stimulation

Peripheral electrical stimulation (PES) over muscles or nerves is commonly used as an intervention to facilitate plastic changes in the motor cortex and spinal cord, enhancing recovery of motor functions (Chipchase et al 2011). Stefan et al (2000) first reported that paired- associativestimulation(PAS), which consists of repetitive low-frequency PES of the median nerve followed by TMS of the contralateral M1 cortex, induced a transient increase in MEP amplitude at rest and in the duration of the cortical silent period (CSP) during contraction.

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Evaluation of Emergency Department Management of Opioid-Tolerant Cancer Patients with Acute Pain

There are no previously published studies examining opioid doses administered to opioid-tolerant cancer patients during Emergency Department (ED) encounters.

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Development of Entrustable Professional Activities for Hospice and Palliative Medicine Fellowship Training in the United States

Entrustable Professional Activities (EPAs) represent the key physician tasks of a specialty. Once a trainee demonstrates competence in an activity, they can then be 'entrusted' to practice without supervision1. A physician workgroup of the American Academy of Hospice and Palliative Medicine (AAHPM) sought to define Hospice and Palliative Medicine (HPM) EPAs.

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The Implementation of Measuring What Matters in Research and Practice: Series Commentary

The joint American Academy of Hospice and Palliative Medicine (AAHPM) and Hospice and Palliative Nurses Association (HPNA) "Measuring What Matters" (MWM) initiative selected and recommended ten quality indicators for hospice and palliative care practice (1) (Table 1). These quality indicators were chosen after a systematic process, relying on the existing evidence base. The intent was identification of a core set of clinically relevant, cross-cutting performance measures for use by palliative care and hospice programs to drive quality improvement efforts.

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Study of Erythrocyte Indices, Erythrocyte Morphometric Indicators, and Oxygen-Binding Properties of Hemoglobin Hematoporphyrin Patients with Cardiovascular Diseases

The current study investigates the functional state of erythrocytes and indices of the oxygen-binding capacity of hemoglobin in blood samples from healthy donors and from patients with coronary artery disease and myocardial infarction before and after treatment. It has been established that, in cardiovascular diseases, erythrocyte morphology and hemoglobin oxygen-transporting disorders are observed. Standard therapy does not result in the restoration of the structure and properties of erythrocytes. The authors believe that it is necessary for future therapeutic treatment to include preparations other than cardiovascular agents to enhance the capacity of hemoglobin to transport oxygen to the tissues.

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Antimicrobial use and antimicrobial susceptibility in Escherichia coli on small- and medium-scale pig farms in north-eastern Thailand

Intensification of livestock production seen in many low- and middle-income countries is often believed to be associated with increased use of antimicrobials, and may hence contribute to the emergence of antim...

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Breast cancer risk after radiotherapy for Hodgkin lymphoma: influence of gonadal hormone exposure

It is unknown whether gonadal hormone exposure affects the risk of radiation-associated breast cancer in female Hodgkin lymphoma survivors. We performed a nested-case control study to assess the separate and joint effects of radiation dose to the breast and hormone exposure on breast cancer risk. Risk increased linearly with radiation dose, decreased with shorter duration of ovarian function, and did not appear to be influenced by hormone use among women with treatment-induced early menopause.

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HDAC1 upregulation by NANOG promotes multidrug resistance and a stem-like phenotype in immune edited tumor cells

Cancer immunoediting drives the adaptation of tumor cells to host immune surveillance. Immunoediting driven by antigen (Ag)-specific T cells enriches NANOG expression in tumor cells, resulting in a stem-like phenotype and immune resistance. Here we identify HDAC1 as a key mediator of the NANOG-associated phenotype. NANOG upregulated HDAC1 through promoter occupancy, thereby decreasing histone H3 acetylation on K14 and K27. NANOG-dependent, HDAC1-driven epigenetic silencing of cell cycle inhibitor CDKN2D and CDKN1B induced stem-like features. Silencing of TRIM17 and NOXA induced immune and drug resistance in tumor cells by increasing anti-apoptotic MCL1. Importantly, HDAC inhibition synergized with Ag-specific adoptive T cell therapy to control immune refractory cancers. Our results reveal that NANOG influences the epigenetic state of tumor cells via HDAC1, and they encourage a rational application of epigenetic modulators and immunotherapy in treatment of NANOG+ refractory cancer types.

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TBK1 Provides Context-Selective Support of the Activated AKT/mTOR Pathway in Lung Cancer

Emerging observations link dysregulation of TANK-binding kinase 1 (TBK1) to developmental disorders, inflammatory disease, and cancer. Biochemical mechanisms accounting for direct participation of TBK1 in host defense signaling have been well described. However, the molecular underpinnings of the selective participation of TBK1 in a myriad of additional cell biological systems in normal and pathophysiological contexts remain poorly understood. To elucidate the context-selective role of TBK1 in cancer cell survival, we employed a combination of broad-scale chemogenomic and interactome discovery strategies to generate data-driven mechanism-of-action hypotheses. This approach uncovered evidence that TBK1 supports AKT/mTORC1 pathway activation and function through direct modulation of multiple pathway components acting both upstream and downstream of the mTOR kinase itself. Furthermore, we identified distinct molecular features in which mesenchymal, Ras-mutant lung cancer is acutely dependent on TBK1-mediated support of AKT/mTORC1 pathway activation for survival.

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MCPIP1 downregulation in clear cell renal cell carcinoma promotes vascularization and metastatic progression

<p>Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer and it forms highly vascularized tumors. The monocyte endoribonuclease MCPIP1 negatively regulates inflammation by degrading mRNA encoding proinflammatory cytokines, such as IL-6, IL-1 and IL-12. MCPIP1 is also a negative regulator of NFκB and AP1 activity and it influences a broad range of miRNA activities. Here we report that MCPIP1 protein levels are decreased during renal cancer progression. In patient-derived tumors, and xenografts established in NOD-SCID or nude mice, low MCPIP1 levels correlated strongly with increased proliferation, tumor outgrowth and vascularity. MCPIP1 activity regulated secretion of VEGF, IL-8, and CXCL12 leading to chemotaxis of microvascular endothelial cells, phosphorylation of VE-cadherin and increased vascular permeability. Mechanistic investigations showed that MCPIP1 regulated ccRCC cell motility, lung metastasis and mesenchymal phenotype by regulating key elements in the EMT signaling axis. Overall, our results illuminate how MCPIP1 serves as a key nodal point in coordinating tumor growth, angiogenesis and metastatic spread in ccRCC. 

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Poor Prognosis Indicated by Venous Circulating Tumor Cell Clusters in Early Stage Lung Cancers

Early detection of metastasis can be aided by circulating tumor cells (CTCs), which also show potential to predict early relapse. Due to the limited CTC numbers in peripheral blood in early stages, we investigated CTCs in pulmonary vein blood accessed during surgical resection of tumors. Pulmonary vein (PV) and peripheral vein (Pe) blood specimens from patients with lung cancer were drawn during the perioperative period and assessed for CTC burden using a microfluidic device. From 108 blood samples analyzed from 36 patients, PV had significantly higher number of CTCs compared to pre-operative Pe (p<0.0001) and intra-operative Pe (p<0.001) blood. CTC clusters with large number of CTCs were observed in 50% of patients, with PV often revealing larger clusters. Long term surveillance indicated that presence of clusters in pre-operative Pe blood predicted a trend toward poor prognosis. Gene expression analysis by RT-qPCR revealed enrichment of p53 signaling and extracellular matrix involvement in PV and Pe samples. Ki67 expression was detected in 62.5% of PV samples and 59.2% of Pe samples, with the majority (72.7%) of patients positive for Ki67 expression in PV having single CTCs as opposed to clusters. Gene ontology analysis revealed enrichment of cell migration and immune-related pathways in CTC clusters, suggesting survival advantage of clusters in circulation. Clusters display characteristics of therapeutic resistance, indicating the aggressive nature of these cells. Thus, CTCs isolated from early stages of lung cancer are predictive of poor prognosis and can be interrogated to determine biomarkers predictive of recurrence.

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CTLA4 promotes Tyk2-STAT3 dependent B cell oncogenecity

Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) is a well-established immune checkpoint for antitumor immune responses. The pro-tumorigenic function of CTLA4 is believed to be limited to T cell inhibition by countering the activity of the T cell co-stimulating receptor CD28. However, as we demonstrate here, there are two additional roles for CTLA4 in cancer, including via CTLA4 overexpression in diverse B cell lymphomas and in melanoma-associated B cells. CTLA4-CD86 ligation recruited and activated the JAK family member Tyk2, resulting in STAT3 activation and expression of genes critical for cancer immunosuppression and tumor growth and survival. CTLA4 activation resulted in lymphoma cell proliferation and tumor growth, whereas silencing or antibody-blockade of CTLA4 in B cell lymphoma tumor cells in the absence of T cells inhibits tumor growth. This inhibition was accompanied by reduction of Tyk2/STAT3 activity, tumor cell proliferation, and induction of tumor cell apoptosis. The CTLA4-Tyk2-STAT3 signal pathway was also active in tumor-associated non-malignant B cells in mouse models of melanoma and lymphoma. Overall, our results show how CTLA4 induced immune suppression occurs primarily via an intrinsic STAT3 pathway and that CTLA4 is critical for B cell lymphoma proliferation and survival.

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Changing the Conversation About Opioid Tapering

Frank and colleagues' systematic review provides helpful information about tapering and discontinuing long-term opioid therapy for chronic pain. The editorialists discuss the findings and how they show that it is possible to reduce opioid use and associated risks while reducing pain and improving function and quality of life.

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The Pharmaceuticalization of the Tobacco Industry

The use and acceptance of e-cigarettes and other noncombustible tobacco products have been growing. The authors point to a concerted effort by tobacco companies to rehabilitate their image as providers of health-related products and argue that such "pharmaceuticalization" of this industry has important consequences for public health.

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Patient Outcomes in Dose Reduction or Discontinuation of Long-Term Opioid Therapy A Systematic Review

Background:
Expert guidelines recommend reducing or discontinuing long-term opioid therapy (LTOT) when risks outweigh benefits, but evidence on the effect of dose reduction on patient outcomes has not been systematically reviewed.
Purpose:
To synthesize studies of the effectiveness of strategies to reduce or discontinue LTOT and patient outcomes after dose reduction among adults prescribed LTOT for chronic pain.
Data Sources:
MEDLINE, EMBASE, PsycINFO, CINAHL, and the Cochrane Library from inception through April 2017; reference lists; and expert contacts.
Study Selection:
Original research published in English that addressed dose reduction or discontinuation of LTOT for chronic pain.
Data Extraction:
Two independent reviewers extracted data and assessed study quality using the U.S. Preventive Services Task Force quality rating criteria. All authors assessed evidence quality using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. Prespecified patient outcomes were pain severity, function, quality of life, opioid withdrawal symptoms, substance use, and adverse events.
Data Synthesis:
Sixty-seven studies (11 randomized trials and 56 observational studies) examining 8 intervention categories, including interdisciplinary pain programs, buprenorphine-assisted dose reduction, and behavioral interventions, were found. Study quality was good for 3 studies, fair for 13 studies, and poor for 51 studies. Many studies reported dose reduction, but rates of opioid discontinuation ranged widely across interventions and the overall quality of evidence was very low. Among 40 studies examining patient outcomes after dose reduction (very low overall quality of evidence), improvement was reported in pain severity (8 of 8 fair-quality studies), function (5 of 5 fair-quality studies), and quality of life (3 of 3 fair-quality studies).
Limitation:
Heterogeneous interventions and outcome measures; poor-quality studies with uncontrolled designs.
Conclusion:
Very low quality evidence suggests that several types of interventions may be effective to reduce or discontinue LTOT and that pain, function, and quality of life may improve with opioid dose reduction.
Primary Funding Source:
Veterans Health Administration. (PROSPERO: CRD42015020347)

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Epidemiological and clinical profile of paediatric malaria: a cross sectional study performed on febrile children in five epidemiological strata of malaria in Cameroon

In the wake of a decline in global malaria, it is imperative to describe the epidemiology of malaria in a country to inform control policies. The purpose of this study was to describe the epidemiological and c...

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Effect of gemfibrozil or rifampicin on the pharmacokinetics of selexipag and its active metabolite in healthy subjects

SUMMARY

Aims

Based on in vitro data CYP2C8 is involved in the metabolism of selexipag and its active metabolite, ACT-333679. The present study evaluated the possible pharmacokinetic interactions of selexipag with gemfibrozil, a strong CYP2C8 inhibitor and rifampicin, an inducer of CYP2C8.

Methods

The study consisted of two independent parts, each conducted according to an open-label, randomized crossover design. The pharmacokinetics and safety of selexipag and ACT-333679 were studied following single-dose administration either alone or in the presence of multiple-dose gemfibrozil (Part I) or rifampicin (Part II) in healthy male subjects.

Results

Gemfibrozil had comparatively small effects on selexipag (less than 2-fold on any pharmacokinetic variable) but, with respect to ACT-333679, increased maximum plasma concentration (Cmax) 3.6 fold (90% CI; 3.1, 4.3), and area under the plasma concentration-time curve from zero to infinity (AUC(0-∞)) 11.1 fold (90% CI; 9.2, 13.4). The marked increased exposure to ACT-333679, which mediates the majority of pharmacological activity of selexipag, was accompanied by significantly more adverse events such as headache, nausea, and vomiting. Co-administration of rifampicin increased Cmax of selexipag 1.8 fold (90% CI; 1.4, 2.2) and its AUC(0-∞) 1.3 fold (90% CI; 1.1, 1.4). A small increase in Cmax (1.3 fold, 90% CI; 1.1, 1.6) and a 63% shortening of t1/2 reduced AUC(0-∞) of ACT-333679 by half (90% CI; 0.45, 0.59).

Conclusion

Concomitant administration of selexipag and strong inhibitors of CYP2C8 must be avoided whereas when co-administered with inducers of CYP2C8 dose adjustments of selexipag should be envisaged.



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Annals for Hospitalists - 18 July 2017



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In moderate-to-severe sciatica, pregabalin did not reduce leg pain intensity or improve quality of life



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Racial Differences in the Relationship of Glucose Concentrations and Hemoglobin A 1c Levels

Background:
Debate exists as to whether the higher hemoglobin A1c (HbA1c) levels observed in black persons than in white persons are due to worse glycemic control or racial differences in the glycation of hemoglobin.
Objective:
To determine whether a racial difference exists in the relationship of mean glucose and HbA1c.
Design:
Prospective, 12-week observational study.
Setting:
10 diabetes centers in the United States.
Participants:
104 black persons and 104 white persons aged 8 years or older who had had type 1 diabetes for at least 2 years and had an HbA1c level of 6.0% to 12.0%.
Measurements:
Mean glucose concentration, measured by using continuous glucose monitoring and compared by race with HbA1c, glycated albumin, and fructosamine values.
Results:
The mean HbA1c level was 9.1% in black persons and 8.3% in white persons. For a given HbA1c level, the mean glucose concentration was significantly lower in black persons than in white persons (P = 0.013), which was reflected in mean HbA1c values in black persons being 0.4 percentage points (95% CI, 0.2 to 0.6 percentage points) higher than those in white persons for a given mean glucose concentration. In contrast, no significant racial differences were found in the relationship of glycated albumin and fructosamine levels with the mean glucose concentration (P > 0.20 for both comparisons).
Limitation:
There were too few participants with HbA1c levels less than 6.5% to generalize the results to such individuals.
Conclusion:
On average, HbA1c levels overestimate the mean glucose concentration in black persons compared with white persons, possibly owing to racial differences in the glycation of hemoglobin. However, because race only partially explains the observed HbA1c differences between black persons and white persons, future research should focus on identifying and modifying barriers impeding improved glycemic control in black persons with diabetes.
Primary Funding Source:
Helmsley Charitable Trust.

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Sitagliptin and Angioedema



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CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration

Chinese herbal medicine (CHM) formulas are the major components of traditional Chinese medicine (TCM) interventions. The general reporting quality of randomized controlled trials (RCTs) of CHM formulas is disappointing, although CONSORT (Consolidated Standards of Reporting Trials) Statement extensions for herbal medicinal interventions and acupuncture interventions are available. A group of TCM clinical experts, methodologists, epidemiologists, and editors has developed this CONSORT Extension for CHM Formulas (CONSORT-CHM Formulas 2017) through a comprehensive process, including publication of the draft version, solicitation of comments, revision, and finalization.The CONSORT 2010 Statement was extended by introducing the idea of TCM Pattern and the features of CHM formulas. One new checklist subitem, keywords, was added to facilitate indexing and data searching. Seven of the 25 CONSORT checklist items, namely title and abstract, background and objectives, participants, interventions, outcomes, generalizability, and interpretation, are now elaborated, and the explanation of harms specific to CHM formulas is revised. Illustrative examples and explanations are also provided. The group hopes that CONSORT-CHM Formulas 2017 can improve the reporting quality of RCTs of CHM formulas.

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Preoperative geriatric assessment reduced hospital stay and complications in patients ≥ 65 y having vascular surgery



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CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration (Simplified Chinese Version)

Editors' Note: This article is the simplified Chinese version of the CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration. (Cheng C, Wu T, Shang H, Li, Y, Altman D, Moher D; CONSORT-CHM Formulas 2017 Group. CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration. Ann Intern Med. 2017;167:112-21. [Epub 27 June 2017]. doi:10.7326/M16-2977).

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Pooled RCTs: Early goal-directed therapy does not reduce mortality more than usual care in early septic shock



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23andMe Paves the Way for Direct-to-Consumer Genetic Health Risk Tests of Limited Clinical Utility

This commentary discusses the limited clinical utility of 23andMe's direct-to-consumer (DTC) genetic test and raises concerns that its approval creates a pathway that could lead to expansive DTC genetic testing of similarly low clinical utility that the public will misunderstand and misuse.

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CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration (Traditional Chinese Version)

Editors' Note: This article is the traditional Chinese version of the CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration. (Cheng C, Wu T, Shang H, Li, Y, Altman D, Moher D; CONSORT-CHM Formulas 2017 Group. CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration. Ann Intern Med. 2017;167:112-21. [Epub 27 June 2017]. doi:10.7326/M16-2977).

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Annals Consult Guys - Let Me Out of Here! How Long to Remain Hospitalized After an MI



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MACRA: Big Fix or Big Problem?

This commentary discusses how the design of the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA) will result in unintended consequences and incentives that will increase health care disparities without reducing costs.

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Yoga, Physical Therapy, or Education for Chronic Low Back Pain



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Missed Opportunities for Measles, Mumps, Rubella Vaccination Among Departing U.S. Adult Travelers Receiving Pretravel Health Consultations

Background:
Measles outbreaks continue to occur in the United States and are mostly due to infections in returning travelers.
Objective:
To describe how providers assessed the measles immunity status of departing U.S. adult travelers seeking pretravel consultation and to assess reasons given for nonvaccination among those considered eligible to receive the measles, mumps, rubella (MMR) vaccine.
Design:
Observational study in U.S. pretravel clinics.
Setting:
24 sites associated with Global TravEpiNet (GTEN), a Centers for Disease Control and Prevention–funded consortium.
Patients:
Adults (born in or after 1957) attending pretravel consultations at GTEN sites (2009 to 2014).
Measurements:
Structured questionnaire completed by traveler and provider during pretravel consultation.
Results:
40 810 adult travelers were included; providers considered 6612 (16%) to be eligible for MMR vaccine at the time of pretravel consultation. Of the MMR-eligible, 3477 (53%) were not vaccinated at the visit; of these, 1689 (48%) were not vaccinated because of traveler refusal, 966 (28%) because of provider decision, and 822 (24%) because of health systems barriers. Most MMR-eligible travelers who were not vaccinated were evaluated in the South (2262 travelers [65%]) or at nonacademic centers (1777 travelers [51%]). Nonvaccination due to traveler refusal was most frequent in the South (1432 travelers [63%]) and in nonacademic centers (1178 travelers [66%]).
Limitation:
These estimates could underrepresent the opportunities for MMR vaccination because providers accepted verbal histories of disease and vaccination as evidence of immunity.
Conclusion:
Of U.S. adult travelers who presented for pretravel consultation at GTEN sites, 16% met criteria for MMR vaccination according to the provider's assessment, but fewer than half of these travelers were vaccinated. An increase in MMR vaccination of eligible U.S. adult travelers could reduce the likelihood of importation and transmission of measles virus.
Primary Funding Source:
Centers for Disease Control and Prevention, National Institutes of Health, and the Steve and Deborah Gorlin MGH Research Scholars Award.

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Why Aren't International Travelers Vaccinated for Measles?

The editorialists discuss Hyle and colleagues' findings on measles immunization in overseas travelers and note that efforts to increase rates are mainly focused on children and that the need to immunize unvaccinated travelers is overlooked.

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In patients receiving DAPT after coronary stents, the PRECISE-DAPT score predicted bleeding moderately well



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EMS in 2030: What technologies will be widely available?

EMS1 contributors and editorial advisory board members predict the future technologies that will transform patient assessment, care and transport

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OK Google, deliver a shock: 5 opportunities for voice-activated devices in EMS

Here's how the technology in Siri, Amazon Echo and Google Home can transform EMS patient assessment, care and documentation

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Why electronic health records will replace EMS patient care reports

Access to patient records through prehospital and hospital EHR integration will help paramedics improve patient outcomes

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Body-worn cameras: 5 key considerations for EMS leaders

Body-worn cameras can provide important support for EMS providers, but it's important to understand the key issues before implementing a BWC program

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Why point-of-care ultrasound should be a mainstay in EMS

A former firefighter/EMT turned medical student describes the functional components, diagnostic uses and roadblocks of using this imaging technology

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Individualistic Practices and Values Increasing Around the World

Individualism is thought to be on the rise in Western countries, but new research suggests that increasing individualism may actually be a global phenomenon. The findings, published in Psychological Science, a journal of the Association for Psychological Science, show that increasing socioeconomic development is an especially strong predictor of increasing individualistic practices and values in a country over time.

"Much of the research on the manifestation of rising individualism—showing, for example, increasing narcissism and higher divorce rates—has focused on the United States. Our findings show that this pattern also applies to other countries that are not Western or industrialized," says psychology researcher Henri C. Santos of the University of Waterloo. "Although there are still cross-national differences in individualism-collectivism, the data indicate that, overall, most countries are moving towards greater individualism."

Drawing from national census data and data collected for the World Values Survey, Santos, senior study author Igor Grossmann (University of Waterloo), and study co-author Michael E.W. Varnum (Arizona State University) were able to examine 51 years' worth of data detailing individualist practices and values in a total of 78 countries.

In general, individualist cultures tend to conceive of people as self-directed and autonomous, and they tend to prioritize independence and uniqueness as cultural values. Collectivist cultures, on the other hand, tend to see people as connected with others and embedded in a broader social context – as such, they tend to emphasize interdependence, family relationships, and social conformity.

To measure individualistic practices across cultures, the researchers examined data on household size, divorce rates, and proportion of people living alone. To measure individualistic values, they examined data on the importance that people place on friends versus family, how important people believe it is to teach children to be independent, and the degree to which people prioritize self-expression as a national goal.

Santos, Varnum, and Grossmann also looked at data on specific socio-ecological factors – including the level of socioeconomic development, disaster frequency, incidence of infectious disease, and extreme temperatures in each country – to examine whether they might account for any shifts in individualism over time.

Overall, the results showed a clear pattern: Both individualistic practices and values increased across the globe over time. Specifically, statistical models indicated that individualism has increased by about 12% worldwide since 1960.

Only 4 countries—Cameroon, Malawi, Malaysia, and Mali—showed a substantial decrease in individualistic practices over time, while 34 out of 41 countries showed a notable increase.

And only 5 countries—Armenia, China, Croatia, Ukraine, and Uruguay—showed a substantial decrease in individualistic values over time, with 39 out of 53 countries showing a substantial increase.

While the data indicated an overarching trend toward greater individualism, the researchers noted that sizable differences between countries remained through 2011.

Several socio-ecological factors — including more frequent disasters, less prevalent infectious disease, and less climatic stress in poorer countries — were linked with individualism, but increased socioeconomic development was most strongly linked with increased individualism over time. Various aspects of development were related to increases in individualism, particularly increases in the proportion of white-collar jobs, in education levels, and in household income.

"The fact that most of the countries that did not show an increase in individualist values were among the lowest in socioeconomic development over the time period examined is consistent with the observation that socioeconomic development drove the rise in individualism," the researchers explain in their paper. "China is an exception to this pattern, showing a decrease in individualist values even though the country has experienced economic growth. Notably, China has a complex socioeconomic history, so it will be worthwhile to investigate this country in more detail in future research."

"I hope that these findings encourage psychologists in a variety of countries to take a more in-depth look at the rise of individualism within their respective countries," says Santos.

Santos and Grossmann are hoping to continue this line of research, studying other predictors of cultural change, including migration and shifts in ethnic diversity, and also the potential consequences that rising individualism may have on a global scale.

Work on this manuscript was supported by Insight Grant 435-2014-0685 from the Social Sciences and Humanities Research Council of Canada to I. Grossmann.

All code and data have been made publicly available at the Open Science Framework. The complete Open Practices Disclosure is available online. This article has received the badge for Open Data.



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Virtual EMS education: Growing pains and lessons learned

By Kelly Grayson I've been an EMS educator for 24 years, and in those 24 years, I've developed a pretty effective schtick. I'm good at breaking down complex concepts into easily understood terms. I can switch gears from inspirational to educational to entertaining and back again, all within the same lecture. I can read an audience with the best of them, and adapt my teaching methods ...

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Determination of the Glycogen Content in Cyanobacteria

56068fig1.jpg

Here, we present a reliable and easy assay to measure the glycogen content in cyanobacterial cells. The procedure entails precipitation, selectable depolymerization, and the detection of glucose residues. This method is suitable for both wildtype and genetically engineered strains and can facilitate the metabolic engineering of cyanobacteria.

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Development of a sandwich enzyme-linked immunosorbent assay for dTMP-GH fusion protein by rational immunogen selection

dTMP-GH is a chimeric protein containing a tandem dimer of thrombopoietin mimetic peptide (dTMP) fused to human growth hormone (hGH) prepared previously by our team. It shows significant bioactivity in promoti...

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NCI’s Technology Transfer Center—Moving Inventions and Ideas from the Lab to Patients: An Interview with Dr. Michael Salgaller

An interview with Dr. Michael Salgaller about how NCI's Technology Transfer Center helps to move new technologies developed by NCI and NIH scientists from the lab to the bedside.



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Assessing Spatial Memory Impairment in a Mouse Model of Traumatic Brain Injury Using a Radial Water Tread Maze

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Here we present a protocol for a mouse-specific test of cognition that does not require swimming. This test can be used to successfully distinguish controlled cortical impact-induced traumatic brain injury mice from sham controls.

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Beta-mangostin demonstrates apoptogenesis in murine leukaemia (WEHI-3) cells in vitro and in vivo

Beta-mangostin (BM) is a xanthone-type of natural compound isolated from Cratoxylum arborescens. This study aimed to examine the apoptosis mechanisms induced by BM in a murine monomyelocytic cell line (WEHI-3) in...

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Ticagrelor mitigates ischemia-reperfusion induced vascular endothelial dysfunction in healthy young males – a randomised, single-blinded study

Abstract

Aim

Animal data suggest that ticagrelor but not clopidogrel protects against tissue injury. It is unclear if this effect of ticagrelor is also detectable in humans. We studied the effect of ticagrelor and clopidogrel at standard clinical doses on endothelial dysfunction in an experimental model of forearm vascular ischemia-reperfusion (IR) injury.

Methods

In a randomised, single-blinded trial 24 subjects underwent forearm blood flow (FBF) measurements in response to the endothelium-dependent vasodilator acetylcholine (ACh) and to glyceryltrinitrate (GTN; endothelium-independent) before and after a 20 min forearm ischemia. FBF reactivity was assessed after an oral loading dose of ticagrelor or clopidogrel and after 14 days of regular intake of maintenance doses of the study medicines. In addition, the effect on platelet inhibition was evaluated using multiple electrode aggregometry.

Results

ACh-induced vasodilation was impaired during reperfusion and not completely normalized by acute or chronic treatment with ticagrelor or clopidogrel (post- vs. pre-ischemia). However, ticagrelor mitigated endothelial dysfunction compared to clopidogrel after loading (FBF AChAUC ratio post- vs. pre-ischemia: 0.83 [0.70; 0.96] vs. 0.64 [0.56; 0.72]; P=0.024) and after chronic administration (FBF AChAUC ratio: 0.86 [0.71; 1.00] vs. 0.66 [0.55; 0.77]; P= 0.027). As expected, GTN-induced vasodilation was not affected by ischemia. Ticagrelor or clopidogrel treatment inhibited platelet activation to a similar degree.

Conclusion

Our data indicate that ticagrelor treatment exerts a greater vascular salutary effect than clopidogrel during reperfusion after an acute vascular occlusion. IR-induced vascular injury cannot be prevented completely by administration of these antiplatelet agents at standard clinical doses.



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Evolution in the surgical management of gastric cancer: is extended lymph node dissection back in vogue in the USA?

Abstract

Background

Gastric cancer remains a formidable treatment challenge. For decades, treatment consisted mostly of surgical intervention for this deadly disease. With improvements in the multi-disciplinary management of solid organ malignancies, the approach to this disease is being stepwise refined.

Main body

One of the prevalent controversies in the surgical management of gastric cancer rests on the need for adequate harvesting of lymph nodes. For decades, lymph node dissection is regarded as a staging technique useful in only upstaging the disease. The adoption of D2 lymphadenectomy has been particularly slow to mature. But with prevailing data from Asia consistently demonstrating a survival benefit from lymphadenectomy, it calls into question the notion of lymphadenectomy as being solely a staging procedure.

Conclusions

As gastric resection techniques are being better defined in western countries and surgical morbidities lowered on its execution, D2 lymphadenectomy is becoming more accepted as the new standard in the management of gastric cancer.



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A Method to Test the Effect of Environmental Cues on Mating Behavior in Drosophila melanogaster

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We demonstrate an assay to analyze the environmental and genetic cues that influence mating behavior in the fruit fly Drosophila melanogaster.

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Intraoperative radiotherapy for extremity soft-tissue sarcomas: can long-term local control be achieved?

Abstract

Background

Intraoperative electron-beam radiation therapy (IOERT) during limb-sparing surgery has the advantage of delivering a single high boost dose to sarcoma residues and surgical bed area near to radiosensitive structures with limited toxicity. Retrospective studies have suggested that IOERT may improve local control compared to standard radiotherapy and we aimed to demonstrate this theory. Therefore, we performed an observational prospective study to determine (1) if it is possible to achieve high local control by adding IOERT to external-beam radiation therapy (EBRT) in extremity soft-tissue sarcomas (STS), (2) if it is possible to improve long-term survival rates, and (3) if toxicity could be reduced with IOERT

Materials and methods

From 1995−2003, 39 patients with extremity STS were treated with IOERT and postoperative radiotherapy. The median follow-up time was 13.2 years (0.7–19). Complications, locoregional control and survival rates were collected.

Results

Actuarial local control was attained in 32 of 39 patients (82%). Control was achieved in 88% of patients with primary disease and in 50% of those with recurrent tumors (p = 0.01). Local control was shown in 93% of patients with negative margins and in 50% of those with positive margins (p = 0.002). Limb-sparing was achieved in 32 patients (82%). The overall survival rate was 64%. 13% of patients had grade ≥3 acute toxicity, and 12% developed grade ≥3 chronic toxicity.

Conclusion

IOERT used as a boost to EBRT provides high local control and limb-sparing rates in patients with STS of the extremities, with less toxicity than EBRT alone.



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Comorbidity and metabolic syndrome in patients with multiple sclerosis from Asturias and Catalonia, Spain

The impact of comorbidity on multiple sclerosis (MS) is a new area of interest. Limited data on the risk factors of metabolic syndrome (MetS) is currently available. The aim of this study was to estimate the p...

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The Comprehensive Post-Acute Stroke Services (COMPASS) study: design and methods for a cluster-randomized pragmatic trial

Patients discharged home after stroke face significant challenges managing residual neurological deficits, secondary prevention, and pre-existing chronic conditions. Post-discharge care is often fragmented lea...

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Loss of DIP2C in RKO cells stimulates changes in DNA methylation and epithelial-mesenchymal transition

Abstract

Background

The disco-interacting protein 2 homolog C (DIP2C) gene is an uncharacterized gene found mutated in a subset of breast and lung cancers. To understand the role of DIP2C in tumour development we studied the gene in human cancer cells.

Methods

We engineered human DIP2C knockout cells by genome editing in cancer cells. The growth properties of the engineered cells were characterised and transcriptome and methylation analyses were carried out to identify pathways deregulated by inactivation of DIP2C. Effects on cell death pathways and epithelial-mesenchymal transition traits were studied based on the results from expression profiling.

Results

Knockout of DIP2C in RKO cells resulted in cell enlargement and growth retardation. Expression profiling revealed 780 genes for which the expression level was affected by the loss of DIP2C, including the tumour-suppressor encoding CDKN2A gene, the epithelial-mesenchymal transition (EMT) regulator-encoding ZEB1, and CD44 and CD24 that encode breast cancer stem cell markers. Analysis of DNA methylation showed more than 30,000 sites affected by differential methylation, the majority of which were hypomethylated following loss of DIP2C. Changes in DNA methylation at promoter regions were strongly correlated to changes in gene expression, and genes involved with EMT and cell death were enriched among the differentially regulated genes. The DIP2C knockout cells had higher wound closing capacity and showed an increase in the proportion of cells positive for cellular senescence markers.

Conclusions

Loss of DIP2C triggers substantial DNA methylation and gene expression changes, cellular senescence and epithelial-mesenchymal transition in cancer cells.



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β-arrestin1 -mediated acetylation of Gli1 regulates Hedgehog/Gli signaling and modulates self-renewal of SHH medulloblastoma cancer stem cells

Abstract

Background

Aberrant Sonic Hedgehog/Gli (Hh/Gli) signaling pathway is a critical regulator of Sonic hedgehog medulloblastoma (SHH-MB). Cancer stem cells (CSCs), thought to be largely responsible for tumor initiation, maintenance, dissemination and relapse, have been identified in SHH-MB. Since we previously demonstrated that Hh/Gli signaling controls CSCs features in SHH-MB and that in these tumors miR-326 is down regulated, here we investigated whether there is a functional link between Hh/Gli signaling and miR-326.

Methods

We evaluated β-arrestin1 (Arrb1) and its intragenic miR-326 levels in CSCs derived from SHH-MB. Subsequently, we modulated the expression of Arrb1 and miR-326 in CSCs in order to gain insight into their biological role. We also analyzed the mechanism by which Arrb1 and miR-326 control Hh/Gli signaling and self-renewal, using luciferase and protein immunoprecipitation assays.

Results

Low levels of Arrb1 and miR-326 represent a feature of CSCs derived from SHH-MB. We observed that re-expression of Arrb1 and miR-326 inhibits Hh/Gli signaling pathway at multiple levels, which cause impaired proliferation and self-renewal, accompanied by down regulation of Nanog levels. In detail, miR-326 negatively regulates two components of the Hh/Gli pathway the receptor Smoothened (Smo) and the transcription factor Gli2, whereas Arrb1 suppresses the transcriptional activity of Gli1, by potentiating its p300-mediated acetylation.

Conclusions

Our results identify a new molecular mechanism involving miR-326 and Arrb1 as regulators of SHH-MB CSCs. Specifically, low levels of Arrb1 and miR-326 trigger and maintain Hh/Gli signaling and self-renewal.



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Identification Of Erythromyeloid Progenitors And Their Progeny In The Mouse Embryo By Flow Cytometry

55305fig1.jpg

While infiltrating macrophages are continuously recruited to adult tissues from circulating precursors, resident macrophages seed their tissue during development, where they are maintained without further input from progenitors. The progenitors for resident macrophages were recently identified. Here, we present methods for the genetic fate mapping of the resident macrophage progenitors.

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Predation in High CO 2 Waters: Prey Fish from High-Risk Environments are Less Susceptible to Ocean Acidification

Abstract
Most studies investigating the effects of anthropogenic environmental stressors do so in conditions that are often optimal for their test subjects, ignoring natural stressors such as competition or predation. As such, the quantitative results from such studies may often underestimate the lethality of certain toxic compounds. A well-known example of this concept is illustrated by the marked increase in the lethality of pesticides when larval amphibians are concurrently exposed to the odor of potential predators. Here, we investigated the interaction between background levels of environmental predation risk (high vs. low) and ocean acidification (ambient vs. elevated CO2) in 2 × 2 design. Wild-caught juvenile damselfish, Pomacentrus amboinensis, were exposed in the laboratory to the different risk and CO2 conditions for 4 days and released onto coral reef patches. Using a well-established field assay, we monitored the in situ behavior and mortality of the damselfish for 2 days. We predicted that juvenile fish exposed to elevated CO2 and high-risk conditions would display more severe behavioral impairments and increased mortality compared to fish exposed to elevated CO2 maintained under low-risk conditions. As expected, elevated CO2 exposure led to impaired antipredator responses and increased mortality in low-risk fish compared to ambient CO2 controls. However, we failed to find an effect of elevated CO2 on the behavior and survival of the high-risk fish. We hypothesized that the results may stem from either a behavioral compensation or a physiological response to high risk. Our results provide insights into the interactive nature of environmental and natural stressors and advance our understanding of the predicted effect of ocean acidification on aquatic ecosystems.

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Newcomers in paediatric GI pathology: childhood enteropathies including very early onset monogenic IBD

Abstract

Childhood enteropathies are a group of diseases causing severe chronic (>2–3 weeks) diarrhoea often starting in the first week of life with the potential for fatal complications for the affected infant. Early identification and accurate classification of childhood enteropathies are, therefore, crucial for making treatment decisions to prevent life-threatening complications. Childhood enteropathies are classified into four groups based on the underlying pathology: (i) conditions related to defective digestion, absorption and transport of nutrients and electrolytes; (ii) disorders related to enterocyte differentiation and polarization; (iii) defects of enteroendocrine cell differentiation; and (iv) disorders associated with defective modulation of intestinal immune response. While the intestinal mucosa is usually normal in enteropathies related to congenital transport or enzyme deficiencies, the intestinal biopsy in other disorders may reveal a wide range of abnormalities varying from normal villous architecture to villous atrophy and/or inflammation, or features specific to the underlying disorder including epithelial abnormalities, lipid vacuolization in the enterocytes, absence of plasma cells, lymphangiectasia, microorganisms, and mucosal eosinophilic or histiocytic infiltration. This review intends to provide an update on small intestinal biopsy findings in childhood enteropathies, the "newcomers", including very early onset monogenic inflammatory bowel disease (IBD), in particular, for the practicing pathologist.



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Mortality differences by surgical volume among patients with stomach cancer: a threshold for a favorable volume-outcome relationship

Abstract

Background

Many studies have assessed the volume-outcome relationship in cancer patients, but most focused on better outcomes in higher volume groups rather than identifying a specific threshold that could assist in clinical decision-making for achieving the best outcomes. The current study suggests an optimal volume for achieving good outcome, as an extension of previous studies on the volume-outcome relationship in stomach cancer patients.

Methods

We used National Health Insurance Service (NHIS) Sampling Cohort data during 2004–2013, comprising healthcare claims for 2550 patients with newly diagnosed stomach cancer. We conducted survival analyses adopting the Cox proportional hazard model to investigate the association of three threshold values for surgical volume of stomach cancer patients for cancer-specific mortality using the Youden index.

Results

Overall, 17.10% of patients died due to cancer during the study period. The risk of mortality among patients who received surgical treatment gradually decreased with increasing surgical volume at the hospital, while the risk of mortality increased again in "high" surgical volume hospitals, resulting in a j-shaped curve (mid-low = hazard ratio (HR) 0.773, 95% confidence interval (CI) 0.608–0.983; mid-high = HR 0.541, 95% CI 0.372–0.788; high = HR 0.659, 95% CI 0.473–0.917; ref = low). These associations were especially significant in regions with unsubstantial surgical volumes and less severe cases.

Conclusion

The optimal surgical volume threshold was about 727.3 surgical cases for stomach cancer per hospital over the 1-year study period in South Korea. However, such positive effects decreased after exceeding a certain volume of surgeries.



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A rare case of intradural and extramedullary epidermoid cyst after repetitive epidural anesthesia: case report and review of the literature

Abstract

Background

Spinal epidermoid cysts are benign tumors, which are rarely seen as an intradural extramedullary spinal cord tumor in the conus medullaris region. Acquired spinal epidermoid cysts are mostly caused by iatrogenic procedures, such as lumbar puncture, and the majority of acquired spinal epidermoid cysts have been reported below the L1 level, because lumbar puncture is usually performed around the iliac crest. Here, we report an extremely rare case of an epidermoid cyst that occurred as an intradural and extramedullary spinal cord tumor attached to the conus medullaris after repetitive epidural anesthesia.

Case presentation

A 67-year-old female presented with a low back pain and left sciatica. Although the patient had experienced occasional mild low back pain for several years, her low back pain markedly worsened 2 months before her visit, as well as newly developed left sciatica resulting in intermittent claudication. She had a history of several abdominal surgeries. All abdominal procedures were performed under general anesthesia with epidural anesthesia in her thoracolumbar spine. Magnetic resonance imaging of her lumbar spine demonstrated an intradural extramedullary spinal cord tumor at the T12–L1 level. Because her symptoms deteriorated, the tumor excision was performed using microscopy. Histological examination of the specimens demonstrated that the cyst walls lined with stratified squamous keratinizing epithelium surrounded by the outer layer of collagenous tissue with the absence of skin adnexa. A diagnosis of epidermoid cysts was confirmed. Her MRI showed complete resection of the tumor, and there was no recurrence at 2-year follow-up.

Conclusions

In this case report, epidermoid cells might be contaminated into the spinal canal during repetitive epidural anesthesia. The patient was successfully treated by complete resection, and there was no recurrence at 2-year follow-up with a good clinical outcome. However, long-term follow-up is required for a potential risk of tumor recurrence.



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Current status of tertiary debulking surgery and prognosis after secondary debulking surgery for recurrent Müllerian epithelial cancer in Japan: a retrospective analysis of 164 patients (KCOG-G1402)

Abstract

Background

This study aimed to evaluate the current status of secondary debulking surgery (SDS) and tertiary debulking surgery (TDS; performed for recurrence after SDS) and to assess the overall survival after recurrence of Müllerian epithelial cancer in Japan. We also evaluated the data of patients who underwent a fourth debulking surgery (i.e., quaternary debulking surgery (QDS)).

Methods

We conducted a retrospective study of 164 patients with recurrent Müllerian epithelial cancers (i.e., ovarian, tubal, and peritoneal cancers). The SDS was performed between January 2000 and September 2014 in 20 Japanese hospitals. Clinicopathological data were collected and analyzed.

Results

Of the 164 patients, 66 patients did not have a recurrence or died after SDS. Ninety-eight patients had a recurrence after SDS. Forty-three of the 98 patients underwent TDS; 55 of the 98 patients did not undergo TDS and were classified into the non-TDS group. The overall survival (OS) after SDS was significantly better in the TDS group than in the non-TDS group. The median OS after SDS was 123 and 42 months in the TDS group and non-TDS group, respectively. Of the 43 patients who received TDS, 11 patients were further treated with QDS. The median OS after SDS was 123 months for patients who underwent QDS.

Conclusions

This multicenter study on the prognosis of post-SDS is apparently the first report on QDS in Japan. Patients undergoing TDS have a good prognosis, compared to patients in the non-TDS group. Novel drugs are being evaluated; however, debulking surgery remains a necessary treatment for recurrence.



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Influence of tumor extent on central lymph node metastasis in solitary papillary thyroid microcarcinomas: a retrospective study of 1092 patients

Abstract

Background

The morbidity of papillary thyroid microcarcinomas is increasing worldwide. Surgery is the main treatment for papillary thyroid microcarcinomas, and the choice of surgical method partly depends on the T stage of the tumor. However, according to the American Joint Commission on Cancer staging system (7th edition), the T stage of papillary thyroid microcarcinomas with different tumor extent is unclear. We aimed to study the effect of tumor extent and other factors on central lymph node metastasis to explore the relationship between tumor extent and T stage and to identify the risk factors predicting central lymph node metastasis in papillary thyroid microcarcinomas.

Methods

We included 1092 patients diagnosed with solitary papillary thyroid microcarcinomas between July 2011 and April 2016. The tumor extent and other central lymph node metastasis risk factors were retrospectively analyzed.

Results

Univariate analysis revealed that capsule invasion and extracapsular extension (P = 0.013, <0.001; respectively) were significantly correlated with central lymph node metastasis. On multivariate analysis, extracapsular extension was independent central lymph node metastasis predictors (odds ratio 3.092, 95% CI 1.744–5.484), while capsule invasion was not (odds ratio 1.212, 95% CI 0.890–1.651). In addition, multivariate analysis revealed that male sex, tumor size >5 mm, and age <45 years were independent central lymph node metastasis predictors (odds ratio 2.072, 2.356, 2.302; 95% CI 1.483–2.894, 1.792–3.099, 1.748–3.031; respectively).

Conclusions

This study supported that capsule invasion and tumor limited to the thyroid in papillary thyroid microcarcinomas were suitable for the lower T1, that is, capsule invasion in papillary thyroid microcarcinomas might not belong to the minimal extrathyroid extension included in T3 of TNM staging. In addition, patients with risk factors of extrathyroid extension, male sex, age <45 years, or tumor size >5 mm in papillary thyroid microcarcinomas should consider a more aggressive surgical treatment.



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Clinical workflow for MR-only simulation and planning in prostate

Abstract

Purpose

To describe the details and experience of implementing a MR-only workflow in the clinic for simulation and planning of prostate cancer patients.

Methods

Forty-eight prostate cancer patients from June 2016 - Dec 2016 receiving external beam radiotherapy were scheduled to undergo MR-only simulation. MR images were acquired for contouring (T2w axial, coronal, sagittal), synthetic-CT generation (3D FFE-based) and fiducial identification (3D bFFE-based). The total acquisition time was 25 min. Syn-CT was generated at the console using commercial software called MRCAT. As part of acceptance testing of the MRCAT package, external laser positioning system QA (< 2 mm) and geometric fidelity QA (< 2 mm within 50 cm LR and 30 cm AP) were performed and baseline values were set. Our current combined CT + MR simulation process was modified to accommodate a MRCAT-based MR-only simulation workflow. An automated step-by-step process using a MIM™ workflow was created for contouring on the MR images. Patient setup for treatment was achieved by matching the MRCAT DRRs with the orthogonal KV radiographs based on either fiducial ROIs or bones. 3-D CBCTs were acquired and compared with the MR/syn-CT to assess the rectum and bladder filling compared to simulation conditions.

Results

Forty-two patients successfully underwent MR-only simulation and met all of our institutional dosimetric objectives that were developed based on a CT + MR-based workflow. The remaining six patients either had a hip prosthesis or their large body size fell outside of the geometric fidelity QA criteria and thus they were not candidates for MR-only simulation. A total time saving of ~15 min was achieved with MR-based simulation as compared to CT + MR-based simulation. An automated and organized MIM workflow made contouring on MR much easier, quicker and more accurate compared with combined CT + MR images because the temporal variations in normal structure was minimal. 2D and 3D treatment setup localization based on bones/fiducials using a MRCAT reference image was successfully achieved for all cases.

Conclusions

MR-only simulation and planning with equivalent or superior target delineation, planning and treatment setup localization accuracy is feasible in a clinical setting. Future work will focus on implementing a robust 3D isotropic acquisition for contouring.



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Ibrutinib, a Bruton’s tyrosine kinase inhibitor, exhibits antitumoral activity and induces autophagy in glioblastoma

Abstract

Background

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, is a novel anticancer drug used for treating several types of cancers. In this study, we aimed to determine the role of ibrutinib on GBM.

Methods

Cell proliferation was determined by using cell viability, colony formation, and 5-ethynyl-2′-deoxyuridine (EdU) assays. Cell cycle and cell apoptosis were analyzed by flow cytometry. Cell migratory ability was evaluated by wound healing assays and trans-well migration assays. ATG7 expression was knocked-down by transfection with Atg7-specific small interfering RNA. Overexpression of active Akt protein was achieved by transfecting the cells with a plasmid expressing constitutively active Akt (CA-Akt). Transmission electron microscopy was performed to examine the formation of autophagosomes in cells. Immunofluorescence and western blot analyses were used to analyze protein expression. Tumor xenografts in nude mice and immunohistochemistry were performed to evaluate the effect of ibrutinib on tumor growth in vivo.

Results

Ibrutinib inhibited cellular proliferation and migration, and induced apoptosis and autophagy in LN229 and U87 cells. Overexpression of the active Akt protein decreased ibrutinib-induced autophagy, while inhibiting Akt by LY294002 treatment enhanced ibrutinib-induced autophagy. Specific inhibition of autophagy by 3-methyladenine (3MA) or Atg7 targeting with small interfering RNA (si-Atg7) enhanced the anti-GBM effect of ibrutinib in vitro and in vivo.

Conclusions

Our results indicate that ibrutinib exerts a profound antitumor effect and induces autophagy through Akt/mTOR signaling pathway in GBM cells. Autophagy inhibition promotes the antitumor activity of ibrutinib in GBM. Our findings provide important insights into the action of an anticancer agent combining with autophagy inhibitor for malignant glioma.



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Retraction Note to: Extranuclear ERα is associated with regression of T47D PKCα-overexpressing, tamoxifen-resistant breast cancer



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Effect of Modified Pulsatilla Powder on Enterotoxigenic Escherichia coli O101-Induced Diarrhea in Mice

MPP can be effective in the treatment of E. coli O101-induced diarrhea in mice. MPP can improve the weight loss caused by diarrhea, increase spleen and thymus indices, and reduce the diarrhea index. MPP can reduce the number of WBC, regulate the level of cytokines, and regulate the intestinal microbial flora. These data suggest that MPP is a promising candidate for treatment of E. coli-induced diarrhea in humans and animals.

http://ift.tt/2urnDbV

A simulation-based approach to measuring team situational awareness in emergency medicine: A multicenter, observational study

Abstract

Objectives

Team situational awareness (TSA) is critical for effective teamwork and supports dynamic decision-making in unpredictable, time-pressured situations. Simulation provides a platform for developing and assessing TSA; but these efforts are limited by suboptimal measurement approaches. The objective of this study was to develop and evaluate a novel approach to TSA measurement in interprofessional emergency medicine teams.

Methods

We performed a multicenter, prospective, simulation-based observational study to evaluate an approach to TSA measurement. Interprofessional emergency medical teams, consisting of emergency medicine resident physicians, nurses, and medical student, were recruited from the University of Washington (Seattle, WA) and Wayne State University (Detroit, MI). Each team completed a simulated emergency resuscitation scenario. Immediately following the simulation, team members completed a TSA measure, a team perception of shared understanding item, and a team leader effectiveness measure. Subject matter expert reviews and pilot testing of the TSA measure provided evidence of content and response process validity. Simulations were recorded and independently coded for team performance using a previously validated measure. The relationships between the TSA measure other variables (team clinical performance, team perception of shared understanding, team leader effectiveness, and team experience) were explored. The TSA agreement metric was indexed by averaging the pairwise agreement for each dyad on a team, and then averaging across dyads to yield agreement at the team level. For the team perception of shared understanding and team leadership effectiveness measures, individual team member scores were aggregated within a team to create a single team score. We computed descriptive statistics for all outcomes. We calculated Pearson's Product-Moment Correlations to determine bivariate correlations between outcome variables with two-tailed significance testing (p < 0.05).

Results

A total of 123 participants were recruited and formed 3-person teams (n = 41 teams). All teams completed the assessment scenario and post-simulation measures. Team situational awareness agreement ranged from 0.19 to 0.9 and had a mean (SD) of 0.61 (0.17). Team situational awareness correlated with team clinical performance (p<0.05) but did not correlate with team perception of shared understanding, team leader effectiveness, or team experience.

Conclusions

Team situational awareness supports adaptive teams and is critical for high reliability organizations such as healthcare systems. Simulation can provide a platform for research aimed at understanding and measuring TSA. This study provides a feasible method for simulation-based assessment of TSA in interdisciplinary teams that addresses prior measure limitations and is appropriate for use in highly dynamic, uncertain situations commonly encountered in emergency department systems. Future research is needed to understand the development of and interactions between individual –, team –, and system (distributed) – level cognitive processes.

This article is protected by copyright. All rights reserved.



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Welcome to the real world: Do the conditions of FDA approval devalue high sensitivity troponin?

In January 2017 the Food and Drug Administration (FDA) approved the first high sensitivity cardiac troponin (hs-cTn) assay for use in the United States: the 5th generation hs-cTnT assay manufactured by Roche Diagnostics. This landmark decision finally enables Americans to benefit from the same improvements in diagnostic technology that the rest of the world has utilized for some six years.

This article is protected by copyright. All rights reserved.



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Platelet–lymphocyte and neutrophil–lymphocyte ratios are prognostic but not predictive of response to abiraterone acetate in metastatic castration-resistant prostate cancer

Abstract

Purpose

Recently neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR) have been reported to be inflammatory parameters that confer poorer outcome in metastatic castration-resistant prostate cancer (mCPRPC). However, these ratios have not been analyzed in patients treated with abiraterone acetate. We explored the relationship between different values of PLR and NLR and survival in mCPRCP treated with abiraterone and their possible relation with a prostate specific antigen (PSA) response.

Methods

We retrospectively analyzed 101 patients with mCRPC treated with abiraterone from January of 2012 to November of 2015 in two different hospitals. A cut-off value of 5 for NLR and 150 for PLR were used to compare survival by Kaplan–Meier method. Moreover, an association between these cut-off values and the PSA response was analyzed by a χ 2 test.

Results

In the case of NLR, the median DFS were 12, 1 months for NLR <5 and 7 months for NLR ≥5, p = 0.061. The median OS were 23.9 months for NLR <5 and 16.3 months for NLR ≥5, p = 0.046. In the case of PLR, the median DFS were 11.8 months for PLR <150 and 10.6 months for PLR ≥150, p = 0.549. The median OS were 27.4 months for PLR <150 and 15.9 months for PLR ≥150, p = 0.005. It was not observed a correlation between the different cut-off values of PLR or NLR and a PSA response ≥25% (p = 0.31).

Conclusions

It is shown a better prognostic relationship between PLR and NLR low values and OS that is statistically significant in mCPRC patients treated with abiraterone. Furthermore, it was not shown a relation between PLR and NLR values and PSA response.



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Cancer survival in adult patients in Spain. Results from nine population-based cancer registries

Abstract

Introduction

With the aim of providing cancer control indicators, this work presents cancer survival in adult (≥15 years) patients in Spain diagnosed during the period 2000–2007 from Spanish cancer registries participating in the EUROCARE project.

Methods

Cancer cases from nine Spanish population-based cancer registries were included and analysed as a whole. All primary malignant neoplasms diagnosed in adult patients were eligible for the analysis. Cancer patients were followed until 31 December 2008. For each type of cancer, 1-, 3- and 5-year observed and relative survival were estimated by sex, age and years from diagnosis. Furthermore, age-standardized 5-year relative survival for the period 2000–2007 has been compared with that of the period 1995–1999.

Results

Skin melanoma (84.6 95% CI 83.0–86.2), prostate (84.6% 95% CI 83.6–85.6) and thyroid (84.2% CI 95% 82.0–86.6) cancers showed the highest 5-year relative survival, whereas the worst prognosis was observed in pancreatic (6% 95% CI 5.1–7.0) and oesophageal (9.4% 95% CI 7.9–11.1) cancers. Overall, survival is higher in women (58.0%) than in men (48.9%). The absolute difference in relative survival between 2000–2007 and 1995–1999 was positive for all cancers as a whole (+4.8% in men, +1.6% in women) and for most types of tumours. Survival increased significantly for chronic myeloid leukaemia, non-Hodgkin's lymphoma and rectum cancer in both sexes, and for acute lymphoid leukaemia, prostate, liver and colon cancers in men and Hodgkin's lymphoma and breast cancer in women. Survival patterns by age were similar in Europe and Spain. A decline in survival by age was observed in all tumours, being more pronounced for ovarian, corpus uteri, prostate and urinary bladder and less for head and neck and rectum cancers.

Conclusion

High variability and differences have been observed in survival among adults in Spain according to the type of cancer diagnosed, from above 84% to below 10%, reflecting high heterogeneity. The differences in prognosis by age, sex and period of diagnosis reveal opportunities for improving cancer care in Spain.



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Serum C-reactive protein increases the risk of venous thromboembolism: a prospective study and meta-analysis of published prospective evidence

Abstract

Evolving debate suggests that C-reactive protein (CRP) might be associated with the development of venous thromboembolism (VTE); however, the evidence is conflicting. We aimed to assess the prospective association of CRP with VTE risk. C-reactive protein was measured in serum samples at baseline from 2420 men aged 42–61 years, from the Kuopio Ischemic Heart Disease study. Within-person variability in CRP levels was corrected for using repeat measurements of CRP taken 11 years after baseline. Incident VTE events (n = 119) were recorded during a median follow-up of 24.7 years. The age-adjusted regression dilution ratio for loge CRP was 0.57 [95% confidence interval (CIs): 0.51–0.64]. In age-adjusted Cox regression analysis, the hazard ratio (95% CIs) for VTE per 1 standard deviation (SD) increase in loge baseline CRP was 1.17 (0.98–1.40). Further adjustment for several established and emerging risk factors did not alter the association. In a meta-analysis of nine population-based studies (including the current study) comprising 81,625 participants and 2225 VTE cases, the fully-adjusted risk estimate for VTE was 1.14 (1.08–1.19) per SD increase in loge baseline CRP. In a pooled dose–response analysis, a linear association between CRP and VTE risk was suggested (P for nonlinearity = 0.272). The pooled risk estimate for VTE per 5 mg/l increment in CRP levels was 1.23 (1.09–1.38). C-reactive protein was only modestly associated with VTE risk in the primary analysis. Pooled evidence, however, suggests that elevated CRP is associated with greater VTE risk, consistent with a linear dose–response relationship.



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