Cancers, Vol. 9, Pages 111: Translocation Renal Cell Carcinoma: An Update on Clinicopathological and Molecular Features

Cancers, Vol. 9, Pages 111: Translocation Renal Cell Carcinoma: An Update on Clinicopathological and Molecular Features

Cancers doi: 10.3390/cancers9090111

Authors: Kentaro Inamura

Microphthalmia-associated transcription (MiT) family translocation renal cell carcinoma (tRCC) comprises Xp11 tRCC and t(6;11) RCC. Due to the presence of fusion genes, Xp11 tRCC and t(6;11) RCC are also known as TFE3- and TFEB-rearranged RCC, respectively. TFE3 and TFEB belong to the MiT family, which regulates melanocyte and osteoclast differentiation, and TFE3- and TFEB-rearranged RCC show characteristic clinicopathological and immunohistochemical features. Recent studies identified the fusion partner-dependent clinicopathological and immunohistochemical features in TFE3-rearranged RCC. Furthermore, RCC with chromosome 6p amplification, including TFEB, was identified as a unique subtype of RCC, along with ALK-rearranged RCC. This review summarizes these recent advancements in our tRCC-related knowledge.

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Clonality and mutational profiling of a case of composite hairy cell leukemia and chronic lymphocytic leukemia

Abstract

We report a unique case of composite hairy cell leukemia (HCL) and monoclonal B-cell lymphocytosis with chronic lymphocytic leukemia (CLL) phenotype evaluated comprehensively through cell sorting and deep sequencing. The patient presented with decreased exercise tolerance and complete blood count revealed neutropenia, monocytopenia, and thrombocytopenia. The peripheral blood film was suggestive of HCL. However, a bone marrow evaluation was suspicious for composite HCL and CLL. Flow cytometry not only confirmed monoclonal kappa light chain restricted HCL and CLL populations, but also identified a kappa restricted population with co-expression of bright CD20, bright CD22, and CD11c without CD25 or CD103. Each population was isolated by cell sorting and subsequent B-cell receptor gene rearrangement analysis showed distinct rearrangements in each population. Likewise, next-generation sequencing (NGS) showed distinct mutation patterns in each of the monoclonal B-cell populations. The HCL clone harbored the signature BRAF V600E mutation, the CLL clone harbored an RB1 (L343fs*6) mutation, and the third clone was essentially negative for either mutation. In HCL, the BRAF V600E has been found in hematopoietic stem cells, raising the possibility of a common stem cell origin for composite HCL/CLL. However, our findings suggest a process of independent clonal development of multiple neoplastic B-cell populations in composite lymphoma, likely occurring somewhere after the common lymphoid progenitor stage.

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The Impact of Volatile Anesthetic Choice on Postoperative Outcomes of Cardiac Surgery: A Meta-Analysis

Objectives. To evaluate the impact of volatile anesthetic choice on clinically relevant outcomes of patients undergoing cardiac surgery. Methods. Major databases were systematically searched for randomized controlled trials (RCTs) comparing volatile anesthetics (isoflurane versus sevoflurane) in cardiac surgery. Study-level characteristics, intraoperative events, and postoperative outcomes were extracted from the articles. Results. Sixteen RCTs involving 961 patients were included in this meta-analysis. There were no significant differences between both anesthetics in terms of intensive care unit length of stay (SMD −0.07, 95% CI −0.38 to 0.24, ), hospital length of stay (SMD 0.06, 95% CI −0.33 to 0.45, ), time to extubation (SMD 0.29, 95% CI −0.08 to 0.65, ), S100 (at the end of surgery: SMD 0.08, 95% CI −0.33 to 0.49, ; 24 hours after surgery: SMD 0.21, 95% CI −0.23 to 0.65, ), or troponin (at the end of surgery: SMD −1.13, 95% CI −2.39 to 0.13, ; 24 hours after surgery: SMD 0.74, 95% CI −0.15 to 1.62, ). CK-MB was shown to be significantly increased when using isoflurane instead of sevoflurane (SMD 2.16, 95% CI 0.57 to 3.74, ). Conclusions. The volatile anesthetic choice has no significant impact on postoperative outcomes of patients undergoing cardiac surgery.

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Minimal Residual Disease Eradication in CML: Does It Really Matter?

Abstract

BCR-ABL1 tyrosine kinase inhibitors (TKIs) have improved the prognosis of chronic phase chronic myeloid leukemia (CP-CML) to an extent that survival is largely determined by non-CML mortality. Monitoring for minimal residual disease by measuring BCR-ABL1 messenger RNA is a key component of CML management. CP-CML patients who achieve a stable deep molecular response may discontinue (TKIs) with an ~ 50% chance of entering treatment-free remission (TFR). So far discontinuation of TKIs has largely been limited to clinical trials, but is on the verge of becoming a part of wider clinical practice. Careful patient selection, dense molecular monitoring, and prompt reinstitution of treatment in the event of relapse are all vital to reproduce the same level of success. Much effort has been dedicated to identifying therapeutic strategies to eliminate CML stem cells and enable to TFR in more patients. Unfortunately, despite promising preclinical data, as yet, none of the various approaches have entered clinical practice.

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Takayasu arteritis presenting as embolic stroke

A 52-year-old Caucasian woman presented to the emergency department with symptoms of acute ischaemic stroke (right-side weakness, confusion and aphasia) that resolved completely after administration of tissue plasminogen activator. During stroke work-up, she was found to have an enhancing infiltrate of the aorta at the level of the take-off of the great vessels, most consistent with early Takayasu arteritis. After being discharged home on steroids and dual antiplatelet therapy, she returned 2 days later with re-presentation of weakness and aphasia. Further work-up revealed two intraluminal clots in the left common carotid and left internal carotid arteries that had not been discovered during previous testing. This case illustrates the need to screen for sources of embolic stroke in patients with Takayasu arteritis, especially those with recurring symptoms.

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Oesophageal mastocytosis: eosinophilic oesophagitis without eosinophils?

A 59-year-old male with a history of lifelong asthma, allergic rhinitis and hypercholesterolaemia presented to the emergency department for management of severe substernal chest pain with radiating pain to his left arm, nausea and diaphoresis. Physical examination was unrevealing and a cardiac workup including cardiac enzymes, ECG, chest radiographs were negative for an underlying ischaemic event. A subsequent gastrointestinal workup including oesophageal manometry and oesophagogastroduodenoscopy revealed elevated lower oesophageal pressures and histopathology suggestive of mast cell proliferation, respectively. These findings were suggestive of oesophageal mastocytosis. Treatment with omeprazole-sodium bicarbonate, cetirizine, montelukast and oral budesonide promptly ameliorated his symptoms which have not recurred.

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Continuous remission of renal cell carcinoma with tumour thrombus after severe adverse events following short-term treatment with sunitinib

A 64-year-old Japanese man with renal cell carcinoma (RCC) and tumour thrombus in the inferior vena cava was treated with sunitinib. Two weeks after treatment, he was hospitalised for disturbance of consciousness. Laboratory tests revealed high-grade hypoglycaemia, hyponatraemia, liver dysfunction and thrombocytopaenia with disseminated intravascular coagulation. Sunitinib was discontinued and the patient recovered after a protracted platelet transfusion. At 5 months after treatment, CT revealed that the tumour thrombus had disappeared and other lesions had regressed. MRI at 15 months revealed further regression and suggested the possibility of histological remission according to the signal intensity of fibrosis. A partial response persisted at 20 months after treatment, despite residual accumulation in the renal tumour evident on positron emission tomography. In summary, we present a case of locally advanced RCC accompanied by severe adverse events that showed a significant and durable response to treatment with sunitinib for just 2 weeks.

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The 150 most important questions in cancer research and clinical oncology series: questions 50–56

Since the beginning of 2017, Chinese Journal of Cancer has published a series of important questions in cancer research and clinical oncology, which sparkle diverse thoughts, interesting communications, and poten...

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Adipose-tissue regulatory T cells: Critical players in adipose-immune crosstalk

Obesity and type-2 diabetes (T2D) are associated with metabolic defects and inflammatory processes in fat depots. FoxP3⁺ regulatory T cells (Tregs) control immune tolerance, and have an important role in controlling tissue-specific inflammation. In this mini-review we will discuss current insights into how cross-talk between T cells and adipose tissue shapes the inflammatory environment in obesity-associated metabolic diseases, focusing on the role of CD4⁺T cells and Tregs. We will also highlight potential opportunities for how the immunoregulatory properties of Tregs could be harnessed to control inflammation in obesity and T2D and emphasize the critical need for more research on humans to establish mechanisms that are conserved in both mice and humans.

This article is protected by copyright. All rights reserved

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Oral Ivermectin: Regaining a Drug for the Treatment of Scabies

G. Blasco Morente
Actas Dermosifiliogr.2017;108:606

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Variability in Therapeutic Decision Making: Evaluation of the Validity of an Information and Communication Technology Tool

F. Rivas Ruiz
Actas Dermosifiliogr.2017;108:607

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Buried Sutures to Facilitate the Closure of Facial Defects

G. Romero, P. Cortina
Actas Dermosifiliogr.2017;108:607-8

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Other Faces of Darier Disease

E. del Rio
Actas Dermosifiliogr.2017;108:608

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Autoinflammatory Diseases in Pediatric Dermatology-Part 1: Urticaria-like Syndromes, Pustular Syndromes, and Mucocutaneous Ulceration Syndromes

S. Hernández-Ostiz, L. Prieto-Torres, G. Xirotagaros, L. Noguera-Morel, Á. Hernández-Martín, A. Torrelo
Actas Dermosifiliogr.2017;108:609-19

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Autoinflammatory Diseases in Pediatric Dermatology–Part 2: Histiocytic, Macrophage Activation, and Vasculitis Syndromes

S. Hernández-Ostiz, G. Xirotagaros, L. Prieto-Torres, L. Noguera-Morel, A. Torrelo
Actas Dermosifiliogr.2017;108:620-9

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Diagnostic and Prognostic Relevance of the Cutaneous Manifestations of Neurofibromatosis Type 2

A. Plana-Pla, I. Bielsa-Marsol, C. Carrato-Moñino
Actas Dermosifiliogr.2017;108:630-6

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Impact of Vitiligo on Quality of Life

M.A. Morales-Sánchez, M. Vargas-Salinas, M.L. Peralta-Pedrero, M.G. Olguín-García, F. Jurado-Santa Cruz
Actas Dermosifiliogr.2017;108:637-42

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Treatment of Human Scabies with Oral Ivermectin. Eczematous Eruptions as a New Non-Reported Adverse Event

J. Sanz-Navarro, C. Feal, E. Dauden
Actas Dermosifiliogr.2017;108:643-9

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Reliability of the MDi Psoriasis Application to Aid Therapeutic Decision-Making in Psoriasis

D. Moreno-Ramírez, J.M. Herrerías-Esteban, T. Ojeda-Vila, J.M. Carrascosa, G. Carretero, P. de la Cueva, C. Ferrándiz, M. Galán, R. Rivera, L. Rodríguez-Fernández, R. Ruiz-Villaverde, L. Ferrándiz
Actas Dermosifiliogr.2017;108:650-6

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Guitar-String Suture to Facilitate Closure of a Finger-like Flap for Reconstruction of the Nose

E. Querol-Cisneros, P. Redondo
Actas Dermosifiliogr.2017;108:657-64

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Acral Hemorrhagic Darier Disease

M.Á. Flores-Terry, M. García-Arpa, M. Llamas-Velasco, C. Mendoza-Chaparro, C. Ramos-Rodríguez
Actas Dermosifiliogr.2017;108:e49-52

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A reddish plaque in the forehead

P. Friedman, E. Cohen Sabban, H. Cabo
Actas Dermosifiliogr.2017;108:665-6

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Slow-Growing Keratotic Tumor on the Eyelid

F.J. Navarro-Triviño, J. Aneiros-Fernández, A.M. Almodóvar-Real
Actas Dermosifiliogr.2017;108:667-8

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RF-Acral Melanoma and Repetitive Injury to the Sole of the Foot

P. Martín-Carrasco, M.T. Monserrat-García, A. Ortiz-Prieto, J. Conejo-Mir
Actas Dermosifiliogr.2017;108:669-70

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Coexistence of Sutton and Meyerson Nevi

I. Vázquez-Osorio, M. González-Sabín, E. Rodríguez-Díaz
Actas Dermosifiliogr.2017;108:671

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Isolated Anterior Cervical Hypertrichosis

G. Blasco-Morente, I. Sánchez-Carpintero
Actas Dermosifiliogr.2017;108:672

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Edematous Dermatomyositis with Probable Evans Syndrome

M.Á. Flores-Terry, M. García-Arpa, J. Anino-Fernández, M.D. Mínguez-Sánchez
Actas Dermosifiliogr.2017;108:673-5

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Reticulate Acropigmentation of Kitamura and Nevus of Ito

M. García-Arpa, M. Franco-Muñoz, M.A. Flores-Terry, C. Ramos-Rodríguez
Actas Dermosifiliogr.2017;108:675-7

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Melanomas Arising on Tattoos: A Casual Association with Practical Implications

M. Armengot-Carbó, N. Barrado-Solís, C. Martínez-Lahuerta, E. Gimeno-Carpio
Actas Dermosifiliogr.2017;108:678-80

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Vaborbactam: Spectrum of Beta-Lactamase Inhibition and Impact of Resistance Mechanisms on Activity in Enterobacteriaceae [PublishAheadOfPrint]

Vaborbactam (formerly RPX7009) is a new beta-lactamase inhibitor based on a cyclic boronic acid pharmacophore. The spectrum of beta-lactamase inhibition by vaborbactam and the impact of bacterial efflux and permeability on its activity were determined using a panel of strains with cloned beta-lactamases from various classes and a panel of Klebsiella pneumoniae carbapenemase (KPC)-3 producing isogenic strains with various combinations of efflux and porin mutations. Vaborbactam is a potent inhibitor of class A carbapenemases such as KPC as well as an inhibitor of other class A (CTX-M, SHV, TEM) and class C (P99, MIR, FOX) beta-lactamases. Vaborbactam does not inhibit class D or class B carbapenemases. When combined with meropenem, vaborbactam had the highest potency compared to combinations with other antibiotics in strains producing KPC beta-lactamase. Consistent with broad-spectrum beta-lactamase inhibition, vaborbactam reduced meropenem MICs in engineered isogenic strains of K. pneumoniae with increased meropenem MICs due to a combination of ESBLs, class C beta-lactamase production and reduced permeability due to porin mutations. Vaborbactam crosses the outer membrane of K. pneumoniae using both OmpK35 and OmpK36, but OmpK36 is the preferred porin. Efflux by the multidrug resistance efflux pump AcrAB-TolC has minimal impact on vaborbactam activity. Investigation of the vaborbactam concentration necessary for restoration of meropenem potency shows that vaborbactam at 8 μg/ml results in meropenem MICs ≤2 μg/ml in the most resistant engineered strains, containing multiple mutations. Vaborbactam is a highly active beta-lactamase inhibitor that restores activity of meropenem and other beta-lactam antibiotics in beta-lactamase-producing bacteria, particularly KPC-producing CRE.

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Real-Time PCR Targeting penA Mosaic XXXIV Type for Prediction of Extended-Spectrum Cephalosporins Susceptibility in Clinical Neisseria gonorrhoeae Isolates [PublishAheadOfPrint]

N. gonorrhoeae with decreased susceptibility to extended-spectrum cephalosporins (ESCs) are increasing. We developed an assay to predict N. gonorrhoeae susceptibility to ESCs by targeting penA mosaic XXXIV, an allele prevalent among U.S. isolates with elevated ESC MICs. The assay was 97% sensitive and 100% specific in predicting at least one ESC minimum inhibitory concentration (MIC) above CDC alert value among clinical isolates, and could be multiplexed with previously validated gyrA PCR to predict ciprofloxacin susceptibility.

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Genomic Characterization of VIM metallo-{beta}-lactamase-producing Alcaligenes faecalis from GAZA, Palestine [PublishAheadOfPrint]

Carbapenemase-producing Gram-negative bacteria (CP-GNB) have increasingly spread worldwide, and different families of carbapenemases have been identified in various bacterial species. Here we report the identification of five VIM metallo-β-lactamase-producing Alcaligenes faecalis, associated with a small outbreak in a large hospital in GAZA, Palestine. Next generation sequencing analysis showed bla_VIM-2 is harbored by a chromosomal genomic island among three strains, while bla_VIM-4 is carried by a novel plasmid in two strains.

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Extinction of West Nile virus by Favipiravir through lethal mutagenesis. [PublishAheadOfPrint]

Favipiravir is an antiviral agent effective against several RNA viruses. The drug has been shown to protect mice against experimental infection with a lethal dose of West Nile virus (WNV), a mosquito-borne flavivirus responsible for outbreaks of meningitis and encephalitis for which no antiviral therapy has been licensed; however, the mechanism of action of the drug is still not well understood. Here, we describe the potent in vitro antiviral activity of favipiravir against WNV, showing that it decreases the virus-specific infectivity and drives the virus to extinction. Two passages of WNV in the presence of 1mM favipiravir -a concentration which is more than 10-fold lower than its cytotoxic concentration 50 (CC₅₀)- resulted in a significant increase of mutation frequency in the mutant spectrum, and in a bias towards A-to-G and G-to-A transitions relative to the population passaged in absence of the drug. These data, together with the fact that the drug is already licensed in Japan against influenza virus and in clinical trial against Ebola virus, point to favipiravir as a promising antiviral agent to fight medically relevant flaviviral infections, such as that caused by WNV.

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Chromosome-Mediated mcr-3 Variants in Aeromonas veronii from Chicken Meat [PublishAheadOfPrint]

Two adjacent colistin resistance gene variants, termed mcr-3.2 and mcr-3-like, were identified in the chromosome of an Aeromonas veronii isolated from retail chicken meat. The variants showed 95.20% and 84.19% nucleotide sequence identity, respectively, to mcr-3 from porcine Escherichia coli. Functional cloning indicated that only mcr-3.2 conferred polymyxin resistance in both E. coli and Aeromonas salmonicida. The mcr-3.2-mcr-3-like segment was also observed in other Aeromonas species, including A. media, A. caviae, and A. hydrophila.

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Pharmacological Basis of CD101 Efficacy: Exposure Shape Matters [PublishAheadOfPrint]

CD101 is a novel echinocandin with concentration-dependent fungicidal activity in vitro and a long half-life (~133 hours in humans, ~70-80 hours in mice). Given these characteristics, it is likely that the shape of the CD101 exposure (i.e. the time course of CD101 concentrations) influences efficacy. To test this hypothesis, the same total area under the concentration-time curve (AUC) was administered to groups of neutropenic ICR mice infected with Candida albicans R303 using three different schedules. A total CD101 dose of 2 mg/kg was administered as a single IV dose or in equal divided doses of either 1 mg/kg twice weekly or 0.29 mg/kg/day over seven days. The studies were performed using a murine disseminated candidiasis model. Animals were euthanized at 168 hours following the start of treatment. Fungi grew well in the no-treatment control group with variable activity in treatment groups. When the CD101 AUC_0-168 was administered as a single dose, a >2-log₁₀ CFU reduction from baseline at 168 hours was observed. When twice weekly and daily regimens with similar AUC values were administered, net fungal stasis and a >1-log₁₀ CFU increase from baseline were observed, respectively. These data support the hypothesis that the shape of the CD101 AUC influences efficacy. Thus, CD101 demonstrated a greater degree of fungal killing when administered once per week relative to when the same dose was divided into twice weekly or daily regimens.

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In Vitro Interactions of Echinocandins with Triazoles Against Multidrug-Resistant Candida auris [PublishAheadOfPrint]

The in vitro interactions between echinocandins and azoles were determined against ten multidrug-resistant Candida auris strains by using a microdilution checkerboard technique. Our results suggest synergistic interactions between micafungin and voriconazole with FICI range values of 0.15 to 0.5, and indifferent interactions were observed when micafungin was combined with fluconazole (FICI range: 0.62-1.5). Combinations of caspofungin with fluconazole or voriconazole exhibit indifferent interactions. No antagonism was observed for any combination.

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Evaluation of Urinary KIM-1 for Prediction of Polymyxin B-Induced Nephrotoxicity [PublishAheadOfPrint]

Nephrotoxicity associated with the polymyxins has been a significant barrier to their use....

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Amino acid substitution in the major multi-drug efflux transporter protein AcrB contributes to azithromycin low-susceptibility in Haemophilus influenzae [PublishAheadOfPrint]

Generally, clarithromycin-resistant Haemophilus influenzae with a nonsense mutation in acrR exhibited susceptibility to azithromycin, although one strain was found to be nonsusceptible. We aimed to clarify the differences. This strain had an amino acid substitution, Arg327Ser, in AcrB. Introduction of this substitution into H. influenzae Rd caused an increase in the MIC of azithromycin, suggesting that this substitution contributed to nonsusceptibility. These findings indicate that azithromycin-nonsusceptible isolates could occur by stepwise mutation in acr region.

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Translational Efficacy of Humanized Exposures of Cefepime, Ertapenem, and Levofloxacin against Extended Spectrum {beta}-lactamase (ESBL) producing E. coli in a Murine Complicated Urinary Tract Infection Model [PublishAheadOfPrint]

Validated animal models are required as bridging tools to assess the utility of novel therapies and potential microbiologic outcomes. Herein, we utilized uropathogenic ESBL/non-ESBL E. coli in the neutropenic murine cUTI model with humanized exposures of cefepime, ertapenem, and levofloxacin to assess its translation value to human outcomes. Our data support the translational utility of this murine model to cUTI in man as humanized exposures produced microbiologic outcomes consistent with phenotypic profiles of the organisms.

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Development of methionyl-tRNA synthetase inhibitors as antibiotics for Gram-positive bacterial infections [PublishAheadOfPrint]

Antibiotic resistant bacteria are widespread and pose a growing threat to human health. New antibiotics acting by novel mechanisms of action are needed to combat this threat. The bacterial methionyl-tRNA synthetase (MetRS) enzyme is essential for protein synthesis and the type found in Gram-positive bacteria is substantially different from its counterpart found in the mammalian cytoplasm. Selective inhibitors, both previously published and new, were shown to be highly active on Gram positive bacteria with minimum inhibitory concentrations (MICs) ≤ 1.3 μg/mL against Staphylococcus, Enterococcus, and Streptococcus strains. Incorporation of radioactive precursors demonstrated the mechanism of activity was due to inhibition of protein synthesis. Little activity was observed against Gram-negative bacteria, consistent with Gram-negative species containing a different type of MetRS enzyme. The ratio of MIC to minimum bactericidal concentrations (MBC) was consistent with a bacteriostatic mechanism. Protein binding was high (>95%) for the compounds and this translated to a substantial increase in MICs when tested in the presence of plasma. Despite this, the compounds were very active when tested in the Staphylococcus aureus murine thigh infection model. Compounds 1717 and 2144 given by oral gavage resulted in 3-4-log decreases in bacterial load compared to vehicle-treated mice which was comparable to results observed with the comparator drugs, vancomycin and linezolid. In summary, the research describes MetRS inhibitors with oral bioavailability that represent a class of compounds acting by a novel mechanism with excellent potential for clinical development.

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Intracavitary and systemic daptomycin for successful treatment of a postpneumonectomy intrathoracic infection. [PublishAheadOfPrint]

Treatment of an infected postneumonectomy cavity is very difficult. We present a patient with an infection of a postneumonectomy cavity by Staphylococcus epidermidis treated with local daptomycin for different dwell times, maintaining high antibiotic levels over minimum inhibitory concentration. Clinical and microbiological cure were achieved successfully.

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Population pharmacokinetics of posaconazole tablets and Monte-Carlo simulations: should all the patients receive the same dose? [PublishAheadOfPrint]

Background

Posaconazole is extensively used for invasive fungal infection prophylaxis. The gastro-resistant tablet formulation has allowed overcoming bioavailability issues encountered with the oral suspension. However, now overexposure is frequent. This study aimed at (i) describing posaconazole tablets pharmacokinetics in a real-life cohort of patients with haematological malignancies, and (ii) performing Monte-Carlo simulations to assess the possibility to reduce the daily dose while keeping sufficient exposure.

Patients and methods

Forty-nine consecutive inpatients were prospectively included. Posaconazole trough concentrations (TC) were measured once a week and biological and demographic data were collected. Concentrations were analysed by compartment modelling, and Monte-Carlo simulations were performed using estimated parameters to assess the rate of attainment of target TC after dose reduction.

Results

Posaconazole pharmacokinetics was well described using a one-compartment model with first-order absorption and elimination. The values of the parameters (interindividual variabilities) were: absorption constant k_a=0.588h^-1 (fixed), distribution volume V/F=420L (28.2%), clearance CL/F=7.3L/h (24.2%) with 31.9% interoccasion variability. Forty-nine percent of the simulated patients had TC at steady-state ≥1.5μg/mL and maintained TC above 1μg/mL after dose reduction to 200mg daily. A third of these patients eligible to dose reduction had TC ≥1.5μg/mL as soon as 48h of treatment.

Conclusion

Though less impacted by bioavailability issues than the oral suspension, posaconazole tablets pharmacokinetics remains highly variable. Simulations showed that approximately half of the patients would beneficiate from a dose reduction from 300mg to 200mg while keeping TC above the minimal recommended target of 0.7μg/mL, resulting in a 33% cost saving of this very expensive drug.

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Potentiation of Tobramycin by Silver Nanoparticles Against Pseudomonas aeruginosa Biofilms [PublishAheadOfPrint]

Increasing antibiotic resistance among pathogenic bacterial species is a serious public health problem and has prompted research examining the antibacterial effects of alternative compounds and novel treatment strategies. Compounding this problem is the ability of many pathogenic bacteria to form biofilms during chronic infections. Importantly, these communities are often recalcitrant to antibiotics treatments that show effectiveness against acute infection. The antimicrobial properties of silver have been known for decades, but recently silver and silver-containing compounds have seen renewed interest as antimicrobial agents for treating bacterial infections. The goal of this study was to assess the ability of citrate-capped silver nanoparticles (AgNPs) of various sizes, alone and in combination with the aminoglycoside antibiotic tobramycin, to inhibit established Pseudomonas aeruginosa biofilms. Our results demonstrate that smaller 10-nm and 20-nm AgNPs were more effective at synergistically potentiating the activity of tobramycin. Visualization of biofilms treated with combinations of 10-nm AgNPs and tobramycin reveals the synergistic bactericidal effect may be caused by disrupting cellular membranes. MBEC assays using clinical P. aeruginosa isolates shows that small AgNPs are more effective than larger AgNPs at inhibiting biofilms, but that the synergy effect is likely a strain-dependent phenomenon. These data suggest that small AgNPs synergistically potentiate the activity of tobramycin against P. aeruginosa in vitro and may reveal a potential role for AgNP/antibiotic combinations in treating patients with chronic infections in a strain-specific manner.

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Potent {beta}-Lactam Enhancer Activity of Zidebactam and WCK 5153 against Acinetobacter baumannii, Including Carbapenemase-Producing Clinical Isolates [PublishAheadOfPrint]

Multidrug-resistant Acinetobacter baumannii has rapidly spread worldwide resulting in a serious threat to hospitalized patients. Zidebactam and WCK 5153 are novel non-β-lactam bicyclo-acyl hydrazide β-lactam enhancer antibiotics being developed to target multidrug-resistant A. baumannii. The objectives of this work were to determine the penicillin-binding protein (PBP) IC₅₀s, OXA-23 inhibition profiles, and antimicrobial activities of zidebactam and WCK 5153, alone and in combination with β-lactams, against multidrug-resistant A. baumannii. MICs and time kill kinetics were performed against an A. baumannii clinical strain producing the carbapenemase OXA-23 and belonging to the widespread European clone II, sequence type 2 (ST2). Inhibition of OXA-23 purified enzyme by zidebactam, WCK 5153, and comparators was assessed. All of the compounds tested displayed K_{i app} values >100 μM indicating poor OXA-23 β-lactamase inhibition. The PBP IC₅₀ values of zidebactam, WCK 5153, cefepime, ceftazidime, meropenem and sulbactam (range of concentrations tested 0.02 - 2 μg/mL) were also determined. Zidebactam and WCK 5153 demonstrated specific high-affinity PBP2 binding in A. baumannii (0.01 μg/mL for both of the compounds). MICs of zidebactam and WCK 5153 were >1024 μg/mL for wild-type and multidrug-resistant Acinetobacter spp. strains. Importantly, combinations of cefepime or sulbactam with 8 μg/mL of zidebactam or WCK 5153 led to a 4- and 8-fold MIC reduction, respectively and showed enhanced killing. Notably, several of the combinations resulted in full bacterial eradication at 24h. We conclude that zidebactam and WCK 5153 are PBP2 inhibitors that show potent β-lactam enhancer effect against A. baumannii, including a multidrug-resistant OXA-23-producing ST2 international clone.

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Efficacy of Humanized Exposures of Cefiderocol (S-649266) against a Diverse Population of Gram-negative Bacteria in the Murine Thigh Infection Model [PublishAheadOfPrint]

Cefiderocol (S-649266) is a novel siderophore cephalosporin with potent in vitro activity against clinically encountered multi-drug resistant (MDR) Gram-negative isolates; however, its spectrum of antibacterial activity against these difficult-to-treat isolates remains to be fully explored in vivo. Herein, we evaluated the efficacy of cefiderocol humanized exposures in a neutropenic murine thigh model to support a suitable MIC breakpoint. Furthermore, we compared cefiderocol's efficacy with humanized exposures of meropenem and cefepime against a subset of these phenotypically diverse isolates. Ninety-five Gram-negative isolates were studied. Efficacy was determined as the change in log₁₀CFU at 24h compared with 0h controls. Bacterial stasis or ≥ 1 log reduction in 67 isolates with MICs ≤ 4 μg/mL was noted in 77, 88, and 85% of Enterobacteriaceae, A. baumannii (AB), and P. aeruginosa (PSA), respectively. For isolates with MICs ≥ 8 μg/mL, bacterial stasis or ≥ 1 log₁₀ reduction was observed in only 2 of 28 strains (8 Enterobacteriaceae, 19 AB, and 1 PSA). Against highly resistant meropenem and cefepime organisms, cefiderocol maintained its in vivo efficacy. Overall, humanized exposures of cefiderocol produced similar reductions in bacterial density for organisms with MICs ≤ 4 μg/mL, whereas isolates with MICs of ≥ 8 μg/mL generally displayed bacterial growth in the presence of the compound. Data derived in the current study assists with the delineation of MIC susceptibility breakpoints for cefiderocol against these important nosocomial Gram-negative pathogens; however, additional clinical data are required to substantiate these observations.

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Differential Influence of Antiretroviral PK Enhancers, Ritonavir and Cobicistat, on Intestinal P-Glycoprotein Transport and the PK/PD Disposition of Dabigatran [PublishAheadOfPrint]

Dabigatran etexilate (DE) is a P-gp probe substrate and its active anticoagulant moiety, dabigatran, is a substrate of the MATE-1 transporter. The antiretroviral pharmacokinetic enhancers, ritonavir and cobicistat, inhibit both these transporters. Healthy volunteers received single doses of DE 150mg alone, followed by ritonavir 100mg or cobicistat 150mg daily for two weeks. DE was then given two hours before ritonavir or cobicistat. One week later, DE was given simultaneously with ritonavir or cobicistat. No significant increases in dabigatran PK exposure or thrombin time (TT) measures were observed with simultaneous administration of ritonavir. Separated administration of ritonavir resulted in a mean (90% Confidence Interval [CI]) 29% [18-40%] decrease in dabigatran PK exposure, but did not significantly change TT measures. However, cobicistat increased dabigatran PK exposure (AUC_0- and C_max by 127% each [90% CI: 81-173% and 59-196%, respectively]) and increased TT measures (AUEC_0-24 and TT₂₄ by 33% [22-44%] and 51% [22-78%], respectively) when given simultaneously with dabigatran. Similar increases were observed when cobicistat was administered separately by two hours from dabigatran. In all comparisons, there was no significant change observed in dabigatran elimination half-life. Therefore, ritonavir is likely safe to coadminister with DE, while there is a potential need for reduced dosing and prudent clinical monitoring with co-administration of cobicistat due to greater net inhibition of intestinal P-gp transport and increased bioavailability.

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Induction of mitochondrial ROS production by itraconazole, terbinafine and amphotericin B as a mode of action against Aspergillus fumigatus [PublishAheadOfPrint]

Drug resistance in fungal pathogens is of incredible importance to global health, yet the mechanisms of drug action remain only loosely defined. Antifungal compounds have been shown to trigger the intracellular accumulation of reactive oxygen species (ROS) in human-pathogenic yeasts, but the source of those ROS remained unknown. In the present study, we examined the role of endogenous ROS for the antifungal activity of the three different antifungal substances itraconazole, terbinafine, and amphotericin B, which all target the fungal cell membrane. All three antifungals showed to have an impact on fungal redox homeostasis by causing increased intracellular ROS production. Interestingly, the elevated ROS levels induced by antifungals were abolished by inhibition of the mitochondrial respiratory complex I with rotenone. Further, evaluation of lipid peroxidation using the thiobarbituric acid assay revealed that rotenone pretreatment decreased ROS-induced lipid peroxidation during incubation of A. fumigatus with itraconazole and terbinafine. By applying the mitochondria specific lipid peroxidation probe MitoPerOx we also confirmed that ROS are induced in mitochondria and subsequently cause significant oxidation of mitochondrial membrane in the presence of terbinafine and amphotericin B. To summarize, our study suggests that the induction of ROS production contributes to the ability of antifungal compounds to inhibit fungal growth. Moreover, mitochondrial complex I is the main source of deleterious ROS production in A. fumigatus challenged with antifungal compounds.

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Heterogeneous Genetic Location of mcr-1 in Colistin-Resistant Escherichia coli Isolated from Humans and Retail Chicken Meat in Switzerland: Emergence of mcr-1-Carrying IncK2 Plasmids [PublishAheadOfPrint]

We characterized the genetic environment of mcr-1 in colistin-resistant Escherichia coli strains isolated in Switzerland during 2014-2016 from humans (n=3) and chicken meat (n=6). Whole genome and plasmid sequencing identified mcr-1 integrated in IncX4 (of which, one carrying the mcr-1.2 variant), IncI2, IncHI2 and novel IncK2 plasmids (overall, n=7), as well as in the bacterial chromosome (n=2) in single or duplicate copies. Our study supports the easy mobilization of mcr-1 across diverse genetic locations.

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In Vitro Activity of Luliconazole, Lanoconazole, and Efinaconazole Compared with Five Antifungal Drugs Against Melanized Fungi and Relatives [PublishAheadOfPrint]

The in vitro activities of novel imidazoles in comparison with five antifungal drugs against clinical (n = 28) and environmental (n = 102) isolates of black mold and melanized yeast were determined. Luliconazole and lanoconazole had the lowest geometric mean MICs, followed by efinaconazole against tested isolates in comparison with other drugs. Therefore, it appears that these new imidazoles drugs are promising candidates for treatment of infections due to melanized fungi and relatives.

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Albumin Counteracts Immune-suppressive Effects of Lipid Mediators in Patients With Advanced Liver Disease

Patients with acute decompensation and acute on chronic liver failure (AD/ACLF) have immune dysfunction, which increases their risk for infections; however there are no effective treatments to restore their immune function. We investigated whether the potentially immune-restorative effects of albumin are mediated by its effects on prostaglandin E2 (PGE2) and other lipids.

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MITF-high and MITF-low cells and a novel subpopulation expressing genes of both cell states contribute to intra and inter-tumoral heterogeneity of primary melanoma.

Purpose. Understanding tumour heterogeneity is an important challenge in current cancer research. Transcription and epigenetic profiling of cultured melanoma cells have defined at least two distinct cell phenotypes characterised by distinctive gene expression signatures associated with high or low/absent expression of Microphthalmia-associated transcription factor (MITF). Nevertheless, heterogeneity of cell populations and gene expression in primary human tumours is much less well characterised. Experimental design. We performed single cell gene expression analyses on 472 cells isolated from needle biopsies of 5 primary human melanomas, 4 superficial spreading and one acral melanoma. The expression of MITF-high and MITF-low signature genes was assessed and compared to investigate intra and inter-tumoural heterogeneity and correlated gene expression profiles. Results. Single cell gene expression analyses revealed varying degrees of intra and inter-tumour heterogeneity conferred by the variable expression of distinct sets of genes in different tumours. Expression of MITF partially correlated with that of its known target genes while SOX10 expression correlated best with PAX3 and ZEB2. Nevertheless, cells simultaneously expressing MITF-high and MITF-low signature genes were observed both by single cell analyses and RNAscope. Conclusions. Single cell analyses can be performed on limiting numbers of cells from primary human melanomas revealing their heterogeneity. While tumours comprised variable proportions of cells with the MITF-high and MITF-low gene expression signatures characteristic of melanoma cultures, primary tumours also comprised cells expressing markers of both signatures defining a novel cell state in tumours in vivo.

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Timing of PD-1 Blockade Is Critical to Effective Combination Immunotherapy with Anti-OX40

Purpose: Antibodies specific for inhibitory checkpoints PD-1 and CTLA-4 have shown impressive results against solid tumors. This has fueled interest in novel immunotherapy combinations to affect patients who remain refractory to checkpoint blockade monotherapy. However, how to optimally combine checkpoint blockade with agents targeting T-cell costimulatory receptors, such as OX40, remains a critical question.

Experimental Design: We utilized an anti-PD-1–refractory, orthotopically transplanted MMTV-PyMT mammary cancer model to investigate the antitumor effect of an agonist anti-OX40 antibody combined with anti-PD-1. As PD-1 naturally aids in immune contraction after T-cell activation, we treated mice with concurrent combination treatment versus sequentially administering anti-OX40 followed by anti-PD-1.

Results: The concurrent addition of anti-PD-1 significantly attenuated the therapeutic effect of anti-OX40 alone. Combination-treated mice had considerable increases in type I and type II serum cytokines and significantly augmented expression of inhibitory receptors or exhaustion markers CTLA-4 and TIM-3 on T cells. Combination treatment increased intratumoral CD4⁺ T-cell proliferation at day 13, but at day 19, both CD4⁺ and CD8⁺ T-cell proliferation was significantly reduced compared with untreated mice. In two tumor models, sequential combination of anti-OX40 followed by anti-PD-1 (but not the reverse order) resulted in significant increases in therapeutic efficacy. Against MMTV-PyMT tumors, sequential combination was dependent on both CD4⁺ and CD8⁺ T cells and completely regressed tumors in approximately 30% of treated animals.

Conclusions: These results highlight the importance of timing for optimized therapeutic effect with combination immunotherapies and suggest the testing of sequencing in combination immunotherapy clinical trials. Clin Cancer Res; 1–13. ©2017 AACR.

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Predictors of post-colonoscopy emergency department use

Unplanned hospital visits within 7 days of colonoscopy was recently proposed as a quality measure. It is unknown if patient, procedure, or endoscopist characteristics predict post-colonoscopy emergency department (ED) visits. Our aim was to determine the incidence and relatedness of ED visits within 7 days of colonoscopy, and to identify predictors of post-colonoscopy ED use.

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A Prospective Comparison of Live and Video-Based Assessments of Colonoscopy Performance

Colonoscopy performance is typically assessed by a supervisor in the clinical setting. There are limitations of this approach, however, as it allows for rater bias and increases supervisor workload demand during the procedure. Video-based assessment of recorded procedures has been proposed as a complementary means by which to assess colonoscopy performance. This study sought to investigate the reliability, validity and feasibility of video-based assessments of competence in performing colonoscopy, compared with live assessment.

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Term Neonate with Atypical Hypoxic-Ischemic Encephalopathy Presentation: A Case Report

AJP Rep 2017; 07: e171-e173
DOI: 10.1055/s-0037-1605372

We describe a case of atypical hypoxic-ischemic encephalopathy (HIE) in a neonate following a normal pregnancy and delivery who was found to have an umbilical vein thrombosis. The infant arrived to our center with continuous bicycling movement of her lower extremities. She had a continuous electroencephalogram that showed burst suppression and magnetic resonance imaging of the brain showed diffusely abnormal cerebral cortical/subcortical diffusion restriction which may be secondary hypoxic-ischemic injury. Interestingly, a pathology report noted a focal umbilical vein thrombosis appearing to have compressed an umbilical artery with associated arterial dissection and hematoma. Our case illustrates how umbilical venous or arterial thrombosis may be associated with HIE and refractory seizures.
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Article in Thieme eJournals:
Table of contents  |  Abstract  |  open access Full text

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Editors, Issue sections

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Contents, Cover details

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Editorial Overview: Antigen Processing and Presentation; many fingers in many pies

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Editorial overview: Metabolism of T cells: integrating nutrients, signals, and cell fate

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Editors, Issue sections

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Contents, Cover details

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Editorial overview: Germinal centers and memory B-cells: from here to eternity

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Editorial overview: Many shades of grey: how immune response is regulated by tumors

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Neutrophil-to-Lymphocyte Ratio Predicts Prognosis in Castration-Resistant Prostate Cancer Patients Who Received Cabazitaxel Chemotherapy

Introduction and Objectives. An elevated neutrophil-to-lymphocyte ratio (NLR) has been suggested to be associated with a poor prognosis in several cancers. We evaluated the utility of an elevated NLR as a biomarker to predict the prognosis of metastatic castration-resistant prostate cancer (mCRPC) patients treated with cabazitaxel (CBZ). Methods. We analyzed 47 patients who received CBZ chemotherapy for mCRPC in our institutions. The NLR was calculated using the neutrophil and lymphocyte counts before CBZ chemotherapy. We determined the NLR cut-off value based on the sensitivity and specificity levels derived from area under the receiver operator characteristic curves for death. A multivariate analysis was performed to investigate the association between the NLR and the prognosis. Results. The median overall survival (OS) after CBZ was 10.0 months (range: 6.3–13.2). The median OS was shorter in patients with a high NLR (≥3.83) than in those with a low NLR (

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Predictability of Urinary CD80 in the Relapse of Primary Nephrotic Syndrome

Purpose. The current study is aimed at investigating whether urinary CD80 is reliable to predict the recurrence of pediatric PNS. Materials and Methods. A total of 128 children, 105 males and 23 females, were enrolled in this study. Urinary samples were collected from SSNS and SRNS patients and 25 healthy children as controls. Urinary CD80 was measured by ELISA and adjusted for urinary creatinine excretion. Results. Urinary CD80 in relapse stage of SSNS was significantly higher, and the urinary CD80 of paired relapse and remission stages of each SSNS patient were also significantly different. No significant difference was found between the urinary CD80 in SRNS relapse group, SRNS remission group, and the control group. Similarly, there was no significant difference between frequent SSNS and not frequent SSNS in remission group, as well as the relapse group. There is no correlation between urinary CD80 and 24-hour urinary protein. Conclusion. The increase of urinary CD80 was closely associated with the relapse of SSNS but was not related to the frequency of relapse. The urinary CD80 changes of concentration were reliable to predict the recurrence of SSNS. However, it cannot be used to predicate the frequent recurrence of PNS.

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Intracellular Recordings of Spectral Sensitivities in Stomatopods: a Comparison across Species

Abstract

Stomatopods (mantis shrimps) possess one of the most complex eyes in the world with photoreceptors detecting up to 12 different colors. It is not yet understood why stomatopods have almost four times the number of spectral photoreceptors compared with most other animals. It has, however, been suggested that these seemingly redundant photoreceptors could encode color through a new mechanism. Here we compare the spectral sensitivities across five species of stomatopods within the superfamily Gonodactyloidea using intracellular electrophysiological recordings. The results show that the spectral sensitivities across species of stomatopods are remarkably similar apart from some variation in the long-wavelength receptors. We relate these results to spectral sensitivity estimates previously obtained using microspectrophotometry and discuss the variation in the spectral sensitivity maxima (λ_max) of the long-wavelength receptors in regard to the previous findings that stomatopods are able to tune their spectral sensitivities according to their respective light environment. We further discuss the similarities of the spectral sensitivities across species of stomatopods in regard to how color information might be processed by their visual systems.

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How Song Experience Affects Female Mate-Choice, Male Song, and Monoaminergic Activity in the Auditory Telencephalon in Lincoln's Sparrows

Abstract

A sexual signal can indicate not only the signaler's attractiveness as a potential mate but also the signaler's competitiveness relative to rivals. As the attractiveness or competitiveness of the prevailing signaling environment increases, individuals prospecting for mates should change their choice threshold, whereas competing individuals should shift resources toward elevating their own competitiveness. Previous studies show that experimental elevations of song competition increase male competitive behavior in Lincoln's sparrows (Melospiza lincolnii) and European starlings (Sturnus vulgaris). Through a series of experimental manipulations using laboratory-housed Lincoln's sparrows, we have also discovered that females change the strength of their song preferences depending on the attractiveness of the song environment to which they have recently been exposed; compared to a less-attractive environment, a highly-attractive environment elevates the threshold for releasing phonotaxis behavior toward male song. These behavioral adjustments are associated with changes in forebrain monoaminergic activity that are triggered by experimental manipulations of the quality of the song environment. Findings from these studies suggest possible neural mechanisms for the regulation of adaptive behavioral plasticity associated with dynamic sexual signaling environments.

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Sensory Biology of Starfish—With Emphasis on Recent Discoveries in their Visual Ecology

Abstract

Asteroidea, starfish, constitutes a major part of the macrobenthos in most marine environments. Being members of the echinoderms, they have a nervous system with no well-defined central nervous system. Accordingly, starfish are assumed to pick up rather limited information from the surroundings, and it is also often assumed that most of their behaviors are guided by olfaction. Here, the sensory biology of starfish is reviewed in order to evaluate these assumptions. There is a vast amount of behavioral data dealing with mechanoreception, chemoreception, and combinations of the two (chemosensory-mediated rheotaxis), but the receptors have not yet been identified and almost nothing is known about the physiology behind these senses. What can be concluded from the available data is that starfish possess a sense of touch, some are able to sense gravity and many display positive rheotaxis, moving up currents. A number of starfish species use olfaction during foraging and prey localization. Interestingly, eyes are also present in most starfish, and recent studies have documented that in Linckia laevigata and Acanthaster planci vision plays a major role in seeking out their feeding grounds. The physiology and structure of the eyes filter out small moving objects while optimizing the contrast between the large stationary objects (e.g., coral boulders in the habitat) and the surrounding water. These new results demonstrate the importance of controlling the visual environment when conducting experiments on starfish behavior.

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Congruence Between Latent Class and K-modes Analyses in the Identification of Oncology Patients with Distinct Symptom Experiences

Risk profiling of oncology patients based on their symptom experience assists clinicians to provide more personalized symptom management interventions. Recent findings suggest that oncology patients with distinct symptom profiles can be identified using a variety of analytic methods.

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Bringing a 'Yes, and' mindset to EMS

By Eric Chase, EMS1 Contributor It was late in December and I was grinding through the holiday season. I was often assessing failures from the last call that didn't end well, compounded with my own feelings of inadequacy. I'd go over the decision points and questions from Monday morning quarterbacks, saying ,"they just don't know what we do anyhow." I wonder why people complain ...

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Curcumin-supplemented diets improve antioxidant enzymes and alter acetylcholinesterase genes expression level in Drosophila melanogaster model

Abstract

Curcumin, a bioactive polyphenolic compound in turmeric (Curcuma longa) rhizomes has been shown to exert anti-aging properties with limited scientific basis. Hence, this study sought to examine the antioxidant and anti-cholinesterase activities of curcumin-supplemented diets as well as their molecular effect on superoxide dismutase (SOD) and acetylcholinesterase (AChE) genes expression level associated with lifespan extension in Drosophila melanogaster model. In this experiment, D. melanogaster (both genders) of 1 to 3 days old were fed diets either containing no curcumin (control) or supplemented with curcumin at 0.2 and 1.0 mg/g of diet for 7 days. Subsequently, the survival and locomotor activities were determined. In addition, we evaluated RT-PCR expressions of SOD and AChE mRNA genes. Furthermore, catalase, SOD and AChE activities were determined. Curcumin-supplemented diet improves survival ability but did not affect locomotor activity when compared with the control. In addition, there was a significant increase in SOD and catalase with a concomitant decrease of AChE activities when compared with the control. Furthermore, curcumin-supplemented diets suppress AChE mRNA expression but no alteration on SOD gene expression level was observed when compared with control. In conclusion, our present results suggest that a down-regulation of AChE gene expression with a concomitant decrease of AChE activity as well as improving antioxidant status could be some possible mechanism in which curcumin exert anti-aging potential and increases lifespan of D. melanogaster.

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Extrapulmonary Latent Tuberculosis Reactivation After Negative Screening Tests in a Liver Transplant Recipient.

Background: Posttransplant tuberculosis (TB) is an uncommon complication following liver transplantation (LT). Given its high mortality, it is advocated to screen for latent TB with tuberculin skin test (TST), interferon [gamma] release assay and/or chest radiography before LT. Case Report: A 52-year-old Filipino gentleman was admitted with an 8-week history of abdominal pain, hematochezia, and weight loss. His pre-LT screening for latent TB with TST and chest radiography was negative. Colonoscopy revealed an ulcerated polypoid lesion in the terminal ileum. The cause of ulceration was histologically indeterminate. Because a lymphoproliferative disorder was suspected, a right hemicolectomy was done during which hard white studding was noted in the distal small bowel. Induration and a mass formation in the terminal ileum and the cecum were also seen. Histopathology showed necrotizing granulomas. Stain for acid-fast bacilli was negative. The strong suspicion for TB prompted us to obtain a chest computed tomography scan, which showed calcified perivascular and left hilar lymph nodes reflecting prior granulomatous disease. QuantiFERON-TB Gold In-Tube Test was positive. Treatment with standard anti-TB regimen was initiated. Two weeks later, cultures from intestinal tissue grew Mycobacterium tuberculosis. The patient reported a complete resolution of his symptoms at 3-month follow-up. Conclusions: Chest computed tomography scan and interferon [gamma] release assays in conjunction with TST and chest radiograph may improve the detection of latent TB in transplant candidates. Combining these tests to diagnose latent TB is a strategy that needs to be evaluated in future studies. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Herpes Vegetans and Review of Verrucous Lesions of the Anogenital Region.

Herpes vegetans is one of the rare atypical presentations of herpes simplex virus in immunocompromised patients such as those with human immunodeficiency virus (HIV) infection, which presents as an exophytic, proliferative lesion that resembles either a verrucous or a malignant growth. Patients with immunosuppression as in HIV infection may experience more frequent and more severe recurrences of genital herpes. They are also more likely to be resistant to standard antiherpetic agents such as acyclovir. Herpes simplex virus infection in patients with immune suppression such as HIV can also be atypical in morphology and present a diagnostic and therapeutic challenge. The verrucous lesions of the anogenital region can be similar in many causes of, and it is important to look for subtle differences in appearance and use a variety of diagnostic methods to arrive at a correct diagnosis. We performed a literature review of the verrucous lesions in the anogenital region and also report a case of herpes vegetans. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Blastomycosis Masquerading as Severe Community-Acquired Pneumonia in a Nonendemic Region: A Case Report and Literature Review.

A case is presented of an otherwise healthy, middle-aged man who presented in Boston, Mass, with fever and cough and was initially diagnosed as having community-acquired pneumonia. Despite an outpatient course of azithromycin and then levofloxacin, he clinically worsened over 2 weeks, eventually developing acute respiratory distress syndrome. Alternative causes were then considered, with workup revealing severe pulmonary blastomycosis infection. Despite eventual appropriate antifungal therapy, he had advanced disease at the time of his delayed diagnosis and died because of complications of the infection. The patient's presenting chest radiograph, potassium hydroxide preparation of bronchoscopy specimen, and silver stain of lung tissue with massive fungal disease burden are presented as clinical images. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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A Case of Primary Tuberculous Laryngitis in New York City.

Tuberculous laryngitis occurs in less than 1% of all tuberculosis cases. Patients usually present with dysphonia, but the insidious nature of the disease and the broad differential diagnoses often lead to missed or delayed diagnosis. In the United States, it is rare and regrettably requires several patient visits before the correct diagnosis is made. We report a case of primary tuberculous laryngitis from our hospital, which was successfully diagnosed and treated, but after a delay of more than 2 months. We emphasize that in patients presenting with prolonged dysphonia physicians must maintain a high index of suspicion, obtain a thorough epidemiologic history, and liaise with pathologists in order to correctly diagnose this disease. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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A Child With Accidental Overdose and Intramuscular Administration of Bacillus Calmette-Guerin Vaccine: Is Isoniazid Sufficient Alone?.

Inadvertent bacillus Calmette-Guerin can cause complications. This report presents a 17-month-old boy with inadvertent, high-dose intramuscular bacillus Calmette-Guerin vaccination. Uniquely, our patient had abscess despite isoniazid prophylaxis. He had complete recovery with antimycobacterial treatment. Because there is no consensus about the management of these cases, close follow-up and prompt initiation of antimycobacterial treatment is essential in case of development of new symptoms. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Progressive Multifocal Leukoencephalopathy Treated With CMX001 in a Non-Human Immunodeficiency Virus Patient After Rituximab Therapy for Lymphoma: A Case Report.

Progressive multifocal leukoencephalopathy is an opportunistic infection well described in non-human immunodeficiency virus (HIV) patients receiving rituximab in whom it is associated with high mortality. Although immune reconstitution contributes the most to recovery in HIV-positive patients, no viable treatment option exists for non-HIV patients. We describe a case of progressive multifocal leukoencephalopathy in a patient who received rituximab, treated with the investigational agent CMX001. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Zika Virus: A Review and Clinical Updates.

Zika virus is a recent mosquito-borne threat, yet many providers have limited knowledge of the virus and its potential complications. Current research indicates that Zika infection is associated with severe neurological conditions such as Guillain-Barre syndrome and is causative of congenital microcephaly and other birth defects. Given increasing global travel, domestic endemic areas in Florida and Texas, and the virus' diverse transmission routes, medical providers across specialties need basic understanding of the disease and its potential complications, as well as understanding of current Centers for Disease Control and Prevention guidelines. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Clinical Profile of Suspected H1N1 Influenza Patients and Predictor of Mortality in H1N1-Positive Patients.

There were spurts of swine flu cases every year, even though the pandemic was over in August 2010. Most of the studies on swine flu pivoted around pandemic years 2009 to 2010. Here, through this retrospective study conducted at a tertiary care hospital in New Delhi, India, we compared clinical characteristics between H1N1-positive and H1N1-negative patients admitted in years 2015 to 2016. Among H1N1-positive patients, variables were compared among survival and death groups. Among 122 suspected H1N1 patients, 30 were positive for H1N1 reverse transcription-polymerase chain reaction. Symptom of rhinitis and low serum albumin were significantly more in H1N1-positive patients. Applying univariate analysis among H1N1-positive patients, respiratory rate, albumin level, alanine transaminase, aspartate transaminase, and PaO2/fraction of inspired oxygen (FIO2) ratio were statistically different between the survival and death groups. Further using simple logistic regression among H1N1-positive patients, PaO2/FIO2 less than or equal to 200 had an odds ratio of 9.2 (95% confidence interval [CI], 1.6-51.4), alanine transaminase level more than or equal to 40 U/L had an odds ratio of 7.3 (95% CI, 1.4-38.9), and albumin level less than or equal to 3.0 (gm/dl) had an odds ratio of 44.8 (95% CI, 4.0-497.4), and these were independently associated with death. After considering for causality/plausibility aspects, PaO2/FIO2 less than or equal to 200 had significant higher odds ratio of 12.3 (95% CI, 1.7-90.1) for death even if adjusted for age and sex. Hence, the value of PaO2/FIO2 at admission is a good predictor of mortality among H1N1-positive patients. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Propionibacterium acnes Septic Pericarditis in a Patient With Sarcoidosis and Acne.

Propionibacterium acnes has been recently recognized as a common cause of pericarditis in both immunocompetent and immunocompromised hosts. It is frequently missed on routine cultures because of its slow growth. We present the first case of infective pericarditis caused by P. acnes in a man with acne and severe sarcoidosis. This case emphasizes the importance of considering this microorganism as a causative agent of pericarditis in this setting. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Retrospective Evaluation of the Use of Ceftolozane/Tazobactam at a Large Academic Medical Center.

Background: Ceftolozane/tazobactam is currently Food and Drug Administration-approved for the treatment of complicated intra-abdominal and urinary tract infections; however, it is often used in clinical practice for nosocomial pneumonia, particularly due to Pseudomonas aeruginosa. Previous data in this area are limited to small case studies. Methods: This was a retrospective case series of all patients receiving ceftolozane/tazobactam for a variety of infectious indications at a large academic medical center. Results: There were 60 cases included in this evaluation. Most patients were treated for pneumonia (34 [56.7%]), followed by intra-abdominal infection (11 [18.3%]), skin and soft tissue infection (3 [5%]), primary bacteremia (4 [6.7%]), bone and joint infection (2 [3.3%]), and pleural space infection (2 [3.3%]); 12 patient encounters (20%) had a concomitant bacteremia. Most patients had P. aeruginosa isolated (86.7%): 18 (34.6%) of these were non-multidrug resistant (MDR), 21 MDR (40.4%), and 13 extensively drug resistant (25%). The overall ceftolozane/tazobactam susceptibility rate was 83% with rates of 94.1%, 94.7%, and 45.5%, respectively, for non-MDR, MDR, and extensively drug-resistant isolates. Clinical cure was achieved in 25 (64.1%), clinical failure occurred in 10 (25.6%), and clinical status was unable to be determined in 4 cases (10.3%). Ten patients died in the hospital while on ceftolozane/tazobactam. Conclusions: It seems that ceftolozane/tazobactam is a reasonable option for P. aeruginosa infections, yet prospective analyses are needed to further guide dosing recommendations and provide additional insight into patient outcomes associated with the use of this agent. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Angioinvasion by Cunninghamella as a Cause of Anterior Spinal Artery Syndrome in an Immunocompromised Patient.

Cunninghamella bertholletiae is an opportunistic fungi species in the order Mucorales that almost exclusively affects immunocompromised hosts. It is highly invasive and is well known for angioinvasion of surrounding vasculature. We describe a case of pulmonary Cunninghamella infection with dissemination and invasion of the anterior spinal artery causing anterior spinal artery syndrome. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Extensively Drug-Resistant Pseudomonas aeruginosa Sternal Osteomyelitis: Suggested Reconstructive Approach and Novel Optimization of Antimicrobial Therapeutics.

Background: Sternal wound infection continues to be the leading complication after median sternotomy. With the growing concern of multidrug-resistant and extensively drug-resistant (XDR) bacterial infections, sternal wound reconstruction is a critical step in successfully healing these patients. The use of a rectus abdominis muscle flap for coverage of the lower one third of sternal wounds as well as objectively optimizing antimicrobial therapy has revolutionized the field of sternal wound reconstruction, yet both practices are not well documented within the literature. Clinical Scenario: A 72-year-old man developed an XDR Pseudomonas aeruginosa infection of his sternum after median sternotomy. The sternal wound was successfully reconstructed using a dual flap approach of bilateral pectoralis major myocutaneous flaps and a rectus abdominis muscle flap. Because of the antibiotic susceptibility profile and patient allergy profile, parental tobramycin and high-dose continuous-infusion meropenem were used to treat the osteomyelitis; meropenem serum concentrations were obtained via mass spectroscopy to optimize bactericidal activity. Conclusions: Osteomyelitis secondary to XDR P. aeruginosa is exceedingly rare in the literature. Individuals with this type of infection can be successfully treated with aggressive surgical debridement, subsequent reconstruction using bilateral pectoralis major myocutaneous flaps and a rectus abdominis muscle flap for coverage of the sternal wound, and both guided and targeted parental antibiotics. Lastly, the innovative use of antibiotic concentrations was instrumental in targeting the appropriate dose of antimicrobials in this patient. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Invasive Pulmonary Aspergillosis and Methicillin-Resistant Staphylococcus aureus Associated With Influenza A Infection.

Bacterial superinfection is a known complication of influenza infection, with Streptococcus pneumoniae and Staphylococcus aureus often being the offending pathogens. In recent decades, there has been an increased prevalence of superinfection with Aspergillus in seemingly immunocompetent hosts. We describe a fatal case of influenza complicated by simultaneous methicillin-resistant S. aureus pneumonia and invasive pulmonary aspergillosis. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Direct-Acting Antiviral Therapy and Improvement in Graft Survival of Hepatitis C Liver Transplant Recipients.

No abstract available

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Cytomegalovirus Viral Load in Bronchoalveolar Lavage to Diagnose Lung Transplant Associated CMV Pneumonia.

Background: The diagnostic yield for cytomegalovirus (CMV) PCR viral load in Bronchoalveolar Lavage (BAL) or in plasma to diagnose CMV pneumonia in lung transplant recipients remains uncertain, and was investigated in a large cohort of consecutive lung transplant recipients. Methods: Bronchoscopies within the first year of lung transplantation with CMV detectable in BAL by PCR (ie, viral load >=273 IU/mL) were included (66 recipients; 145 bronchoscopies); at each bronchoscopy episode 2 independent experts reviewed clinical and laboratory information to determine whether the patient at that time fulfilled the criteria for CMV pneumonia per current international recommendations. Corresponding plasma CMV PCR viral load determined at time of the bronchoscopy (n=126) was also studied. Optimal CMV PCR viral load cut off for CMV pneumonia diagnosis was determined using receiver operating characteristics (ROC). Results: CMV was detected in BAL with CMV PCR in 145 episodes, and 34 (23%) of these episodes fulfilled the criteria for CMV pneumonia. The AUC-ROC for CMV in BAL was 90% at the optimum cut off (4545 IU/mL) with a corresponding sensitivity of 91% and specificity of 77% (in plasma the corresponding values were 274 IU/mL, 63% and 76%, respectively). Conclusions: CMV PCR viral load in BAL had a high performance to diagnose CMV pneumonia in lung transplant recipients; plasma CMV viral load did not reliably aid as a diagnostic tool. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Improved Outcomes of Kidney Transplantation in Infants (Age < 2 years): A Single Center Experience.

Background: Infants (age

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Sofosbuvir-based Regimens in HIV/HCV Coinfected Patients after Liver Transplantation: Results from the ANRS CO23 CUPILT Study.

Background: A recurrence of hepatitis C virus after liver transplantation affects survival in HIV/HCV coinfected patients. This study assessed the efficacy and safety of sofosbuvir-based regimens in HIV/HCV coinfected patients following liver transplantation. Methods: 29 HIV/HCV coinfected transplanted patients receiving tacrolimus, cyclosporine or everolimus-based immunosuppressive therapy were enrolled in the CUPILT cohort. Their antiviral treatment combined sofosbuvir, daclatasvir with or without ribavirin (n=10/n=6), or sofosbuvir, ledipasvir with or without ribavirin (n=2/n=11). Results: The median delay between liver transplantation and treatment initiation was 37.5 months (IQR 14.4-99.2). The breakdown of HCV genotypes was: G1: 22 patients (75.9%), G3: 3 patients (10.3%) and G4: 4 patients (13.8%). The treatment indications were HCV recurrence (>= F1 n=23) or fibrosing cholestatic hepatitis (n=6). Before starting sofosbuvir, the HCV viral load and CD4 count were 6.7 log10 IU/mL (IQR 5.9-7.2), and 342 cells/mm3 (IQR 172-483), respectively. At W4, the HCV viral load was

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Swine Leukocyte Antigen (SLA) Class II is a Xenoantigen.

Background: Over 130 000 patients in the United States alone need a life-saving organ transplant. Genetically modified porcine organs could resolve the donor organ shortage, but human xenoreactive antibodies destroy pig cells and are the major barrier to clinical application of xenotransplantation. The objective of this study was to determine whether waitlisted patients possess preformed antibodies to swine leukocyte antigen (SLA) class II, homologs of the class II human leukocyte antigens (HLA). Methods: Sera from people currently awaiting solid organ transplant were tested for IgG binding to class II SLA proteins when expressed on mammalian cells. Pig fibroblasts were made positive by transfection with the class II transactivator (CIITA). As a second expression system, transgenes encoding the alpha and beta chains of class II SLA were transfected into Human embryonic kidney (HEK293) cells. Results: Human sera containing IgG specific for class II HLA molecules exhibited greater binding to class II SLA positive cells than to SLA negative cells. Sera lacking antibodies against class II HLA showed no change in binding regardless of the presence of class II SLA. These antibodies could recognize either SLA-DR or SLA-DQ complexes. Conclusions: Class II SLA proteins may behave as xenoantigens for people with humoral immunity towards class II HLA molecules. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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A Misleading Pattern of Serologic Findings During Hepatitis B Virus Infection

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Population Health Science and the Challenges of Prediction

In their current Annals report, Dalton and colleagues show that a neighborhood disadvantage index outperformed the American College of Cardiology/American Heart Association Pooled Cohort Equations Risk Model by a factor of 3. The editorialists discuss the article and see it as a sobering reminder of the limitations of predictive models that fail to consider base prevalence and co-occurring factors.

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A Call for Open-Source Cost-Effectiveness Analysis

Some observers claim that many published research findings in the biomedical literature are false. Simulation models seem to be especially vulnerable to this claim, because they require so many assumptions and predict future outcomes. The authors of this commentary propose one way to manage this problem.

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Accuracy of Cardiovascular Risk Prediction Varies by Neighborhood Socioeconomic Position A Retrospective Cohort Study

Background:

Inequality in health outcomes in relation to Americans' socioeconomic position is rising.

Objective:

First, to evaluate the spatial relationship between neighborhood disadvantage and major atherosclerotic cardiovascular disease (ASCVD)–related events; second, to evaluate the relative extent to which neighborhood disadvantage and physiologic risk account for neighborhood-level variation in ASCVD event rates.

Design:

Observational cohort analysis of geocoded longitudinal electronic health records.

Setting:

A single academic health center and surrounding neighborhoods in northeastern Ohio.

Patients:

109 793 patients from the Cleveland Clinic Health System (CCHS) who had an outpatient lipid panel drawn between 2007 and 2010. The date of the first qualifying lipid panel served as the study baseline.

Measurements:

Time from baseline to the first occurrence of a major ASCVD event (myocardial infarction, stroke, or cardiovascular death) within 5 years, modeled as a function of a locally derived neighborhood disadvantage index (NDI) and the predicted 5-year ASCVD event rate from the Pooled Cohort Equations Risk Model (PCERM) of the American College of Cardiology and American Heart Association. Outcome data were censored if no CCHS encounters occurred for 2 consecutive years or when state death data were no longer available (that is, from 2014 onward).

Results:

The PCERM systematically underpredicted ASCVD event risk among patients from disadvantaged communities. Model discrimination was poorer among these patients (concordance index [C], 0.70 [95% CI, 0.67 to 0.74]) than those from the most affluent communities (C, 0.80 [CI, 0.78 to 0.81]). The NDI alone accounted for 32.0% of census tract–level variation in ASCVD event rates, compared with 10.0% accounted for by the PCERM.

Limitations:

Patients from affluent communities were overrepresented. Outcomes of patients who received treatment for cardiovascular disease at Cleveland Clinic were assumed to be independent of whether the patients came from a disadvantaged or an affluent neighborhood.

Conclusion:

Neighborhood disadvantage may be a powerful regulator of ASCVD event risk. In addition to supplemental risk models and clinical screening criteria, population-based solutions are needed to ameliorate the deleterious effects of neighborhood disadvantage on health outcomes.

Primary Funding Source:

The Clinical and Translational Science Collaborative of Cleveland and National Institutes of Health.

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Do Less Harm: Evaluating HIV Programmatic Alternatives in Response to Cutbacks in Foreign Aid

Background:

Resource-limited nations must consider their response to potential contractions in international support for HIV programs.

Objective:

To evaluate the clinical, epidemiologic, and budgetary consequences of alternative HIV program scale-back strategies in 2 recipient nations, the Republic of South Africa (RSA) and Côte d'Ivoire (CI).

Design:

Model-based comparison between current standard (CD4 count at presentation of 0.260 × 10⁹ cells/L, universal antiretroviral therapy [ART] eligibility, and 5-year retention rate of 84%) and scale-back alternatives, including reduced HIV detection, no ART or delayed initiation (when CD4 count is <0.350 × 10⁹ cells/L), reduced investment in retention, and no viral load monitoring or second-line ART.

Data Sources:

Published RSA- and CI-specific estimates of the HIV care continuum, ART efficacy, and HIV-related costs.

Target Population:

HIV-infected persons, including future incident cases.

Time Horizon:

5 and 10 years.

Perspective:

Modified societal perspective, excluding time and productivity costs.

Outcome Measures:

HIV transmissions and deaths, years of life, and budgetary outlays (2015 U.S. dollars).

Results of Base-Case Analysis:

At 10 years, scale-back strategies increase projected HIV transmissions by 0.5% to 19.4% and deaths by 0.6% to 39.1%. Strategies can produce budgetary savings of up to 30% but no more. Compared with the current standard, nearly every scale-back strategy produces proportionally more HIV deaths (and transmissions, in RSA) than savings. When applying the least harmful and most efficient alternatives for achieving budget cuts of 10% to 20%, every year of life lost will save roughly $900 in HIV-related outlays in RSA and $600 to $900 in CI.

Results of Sensitivity Analysis:

Scale-back programs, when combined, may result in clinical and budgetary synergies and offsets.

Limitation:

The magnitude and details of budget cuts are not yet known, nor is the degree to which other international partners might step in to restore budget shortfalls.

Conclusion:

Scaling back international aid to HIV programs will have severe adverse clinical consequences; for similar economic savings, certain programmatic scale-back choices result in less harm than others.

Primary Funding Source:

National Institutes of Health and Steve and Deborah Gorlin MGH Research Scholars Award.

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Raising the Bar in Attribution

Payment trends are producing powerful financial incentives that influence how physicians provide patient care. To be effective, these incentives must target the physician responsible for care. The authors of this article consider whether current methods that assign responsibility for a patient's care to a specific physician work well enough.

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The application of information theory for the estimation of old-age multimorbidity

Abstract

Elderly patients are commonly characterized by the presence of several chronic aging-related diseases at once, or old-age "multimorbidity," with critical implications for diagnosis and therapy. However, at the present there is no agreed or formal method to diagnose or even define "multimorbidity." There is also no formal quantitative method to evaluate the effects of individual or combined diagnostic parameters and therapeutic interventions on multimorbidity. The present work outlines a methodology to provide such a measurement and definition, using information theoretical measure of normalized mutual information. A cohort of geriatric patients, suffering from several age-related diseases (multimorbidity), including ischemic heart disease, COPD, and dementia, were evaluated by a variety of diagnostic parameters, including static as well as dynamic biochemical, functional-behavioral, immunological, and hematological parameters. Multimorbidity was formally coded and measured as a composite of several chronic age-related diseases. The normalized mutual information allowed establishing the exact informative value of particular parameters and their combinations about the multimorbidity value. With the currently intensifying attempts to reduce aging-related multimorbidity by therapeutic interventions into its underlying aging processes, the proposed method may outline a valuable direction toward the formal indication and evidence-based evaluation of effectiveness of such interventions.

http://ift.tt/2wcU2TP

S197 Foramen ovale electrodes in epilepsy

Temporal lobe epilepsy is the most prevalent type of epileptic syndrome, and also the most frequent type of surgically treatable epilepsy. But in many cases the laterality is difficult to prove based on non-invasive investigations and scalp EEG. There is broad evidence that suggest that the seizure onset zone may be on the opposite side compared to where the seizure is seen on the scalp EEG due to rapid spread to the contralateral side.Based on these data a technique was developed first by Wieser et al., which allowed direct corticographic recordings from the medial temporal structures without performing invasive surgery.

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O207 Safety and effects on motor cortex excitability of five closely repeated cathodal transcranial direct current stimulations

To assess safety and effects of five cathodal-tDCS (charge density 342,857C/m2) delivered at increasing time intervals in 25h.

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P226 The effect of interstimulus interval between the conditioning and test stimulus on inhibition and fascilitation: A transcranial magnetic stimulation study

Transcranial magnetic stimulation (TMS) technique creates small and temporary electrical current on cerebral cortex via a strong magnetic field. Previous studies investigating the cortical excitability using paired pulse stimulation technique have implemented a suprathreshold test stimulus (TS) conditioned by subthreshold stimulus (CS). If interstimulus interval (ISI) between CS and TS is 1–6ms, motor evoked potential (MEP) amplitude will decrease and it is called short interval intracortical inhibition (SICI).

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P380 Intelligence is predicted by single-vs-double-sensory brain responses

This research investigated the association between intelligence test scores and gamma-range steady-state power-responses (SS-PR) to an auditory, a visual, and a combined audiovisual stimulation. We hypothesized, and established empirically, that the difference in SS-PR from the mono-modal to the bimodal stimulation (P) is associated with intelligence.

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P222 Diagnostic and therapeutic possibilities of transcranial magnetic stimulation in patients after traumatic brain injury

Recovery of both mental and motor functions is one of the key problems of neurorehabilitation of patients with traumatic brain injury (TBI), accompanied by posttraumatic unconsciousness state (PUS). The purpose of pilot study is to clarify the diagnostic and therapeutic potential of TMS in patients after TBI with impaired motor activity and consciousness.

http://ift.tt/2iCLZuB

Electroencephalographic, Heart Rate, and Galvanic Skin Response Assessment for an Advertising Perception Study: Application to Antismoking Public Service Announcements

The following protocol describes a series of operational and computational steps required to properly estimate the emotional and cerebral reaction of a group of subjects towards a selected number of Public Service Announcements (PSAs) against smoking, aired in the USA and Europe during the period between 1998 and 2015.

http://ift.tt/2vyhtUT

Two New Therapies Approved for Acute Myeloid Leukemia

FDA has approved two new treatments for some adult patients with acute myeloid leukemia (AML): enasidenib (Idhifa®), which targets the IDH2 protein; and liposomal cytarabine-daunorubicin CPX-351 (Vyxeos®), a two-drug chemotherapy combination encapsulated in liposomes.

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Endothelial Growth Factor Receptors in Angiogenesis

Abstract

It is hard to underestimate the role of endothelial growth factor receptors in the generation of new blood vessels. This axis is involved in vascular development in embryos and angiogenesis in adults. As the signaling of these tyrosine kinase receptors has been elucidated, we have gained an appreciation of the complex interactions with other receptors, co-receptors, and downstream pathways.

Its involvement in pathology makes it a particularly tempting therapeutic target with its manipulation offering several theoretical benefits. The most intensely studied is the role of anti-VEGFR drugs in cancer chemotherapy. Initial trials were disappointing but a decade ago the first drug targeting the vascular endothelial growth factor (VEGF) axis was approved, providing a vital proof of concept. Therapies specifically targeting the receptor are in early development for prevention of neovascular diseases of the eye. Conversely, promotion of revascularization following vascular occlusion is another possible application being studied.

While these therapies show promise, the manipulation of VEGF receptors themselves remains a relatively small niche in the therapeutic armory. A deeper understanding of the receptor, its co-receptors, and the downstream web of signaling is required to complete the pieces of the puzzle and unlock the potential of this receptor pathway.

http://ift.tt/2iD2d7i

In Vitro Polymerization of F-actin on Early Endosomes

Early endosome functions depend on F-actin polymerization. Here, we describe a microscopy-based in vitro assay that reconstitutes the nucleation and polymerization of F-actin on early endosomal membranes in test tubes, thus rendering this complex series of reactions amenable to biochemical and genetic manipulations.

http://ift.tt/2vxT69V

The HTA Risk Analysis Chart: Visualising the Need for and Potential Value of Managed Entry Agreements in Health Technology Assessment

Abstract

Background

Recent changes to the regulatory landscape of pharmaceuticals may sometimes require reimbursement authorities to issue guidance on technologies that have a less mature evidence base. Decision makers need to be aware of risks associated with such health technology assessment (HTA) decisions and the potential to manage this risk through managed entry agreements (MEAs).

Objective

This work develops methods for quantifying risk associated with specific MEAs and for clearly communicating this to decision makers.

Methods

We develop the 'HTA risk analysis chart', in which we present the payer strategy and uncertainty burden (P-SUB) as a measure of overall risk. The P-SUB consists of the payer uncertainty burden (PUB), the risk stemming from decision uncertainty as to which is the truly optimal technology from the relevant set of technologies, and the payer strategy burden (PSB), the additional risk of approving a technology that is not expected to be optimal. We demonstrate the approach using three recent technology appraisals from the UK National Institute for Health and Clinical Excellence (NICE), each of which considered a price-based MEA.

Results

The HTA risk analysis chart was calculated using results from standard probabilistic sensitivity analyses. In all three HTAs, the new interventions were associated with substantial risk as measured by the P-SUB. For one of these technologies, the P-SUB was reduced to zero with the proposed price reduction, making this intervention cost effective with near complete certainty. For the other two, the risk reduced substantially with a much reduced PSB and a slightly increased PUB.

Conclusions

The HTA risk analysis chart shows the risk that the healthcare payer incurs under unresolved decision uncertainty and when considering recommending a technology that is not expected to be optimal given current evidence. This allows the simultaneous consideration of financial and data-collection MEA schemes in an easily understood format. The use of HTA risk analysis charts will help to ensure that MEAs are considered within a standard utility-maximising health economic decision-making framework.

http://ift.tt/2wCHq9K

Light-Patterned Crystallographic Direction of a Self-Organized 3D Soft Photonic Crystal

Uniform and patterned orientation of a crystallographic direction of ordered materials is of fundamental significance and of great interest for electronic and photonic applications. However, such orientation control is generally complicated and challenging with regard to inorganic and organic crystalline materials due to the occurrence of uncontrollable dislocations or defects. Achieving uniform lattice orientation in frustrated liquid-crystalline phases, like cubic blue phases, is a formidable task. Taming and tailoring the ordering of such soft, cubic lattices along predetermined or desired directions, and even imparting a prescribed pattern on lattice orientation, are more challenging, due to the entropy-domination attribute of soft matter. Herein, we disclose a facile way to realize designed micropatterning of a crystallographic direction of a soft, cubic liquid-crystal superstructure, exhibiting an alternate uniform and random orientation of the lattice crystallographic direction enabled by a photoalignment technique. Because of the rewritable trait of the photoalignment film, the pattern can be erased and rewritten on-demand by light. Such an oriented soft lattice sensitively responds to various external stimuli such as temperature, electric field, and light irradiation. Furthermore, advanced reflective photonic applications are achieved based on the patterned crystallographic orientation of the cubic blue phase, soft lattice.

A facile way to realize designed micropatterning of a crystallographic direction of a soft, cubic liquid-crystal superstructure is disclosed, exhibiting an alternate uniform and random orientation of the lattice crystallographic direction, enabled by a photoalignment technique, which has not been accomplished before.

http://ift.tt/2vxum1n

Graded Heterojunction Engineering for Hole-Conductor-Free Perovskite Solar Cells with High Hole Extraction Efficiency and Conductivity

Despite great progress in the photovoltaic conversion efficiency (PCE) of inorganic–organic hybrid perovskite solar cells (PSCs), the large-scale application of PSCs still faces serious challenges due to the poor-stability and high-cost of the spiro-OMeTAD hole transport layer (HTL). It is of great fundamental importance to rationally address the issues of hole extraction and transfer arising from HTL-free PSCs. Herein, a brand-new PSC architecture is designed by introducing multigraded-heterojunction (GHJ) inorganic perovskite CsPbBr_xI_3−x layers as an efficient HTL. The grade adjustment can be achieved by precisely tuning the halide proportion and distribution in the CsPbBr_xI_3−x film to reach an optimal energy alignment of the valance and conduction band between MAPbI₃ and CsPbBr_xI_3−x. The CsPbBr_xI_3−x GHJ as an efficient HTL can induce an electric field where a valance/conduction band edge is leveraged to bend at the heterojunction interface, boosting the interfacial electron–hole splitting and photoelectron extraction. The GHJ architecture enhances the hole extraction and conduction efficiency from the MAPbI₃ to the counter electrode, decreases the recombination loss during the hole transfer, and benefits in increasing the open-circuit voltage. The optimized HTL-free PCS based on the GHJ architecture demonstrates an outstanding thermal stability and a significantly improved PCE of 11.33%, nearly 40% increase compared with 8.16% for pure HTL-free devices.

Through energy-band engineering, a brand-new perovskite solar cell architecture with multigraded-heterojunction (GHJ) inorganic perovskite CsPbBr_xI_3−x layers as an efficient hole transport layer is designed. The GHJ architecture enhances the hole extraction and conduction efficiency, and decreases the recombination loss during the hole transfer. A certified efficiency of 11.33% is obtained and the high-performing devices show outstanding thermal- and humidity-stability.

http://ift.tt/2wXenND

Locking and Unlocking the Molecular Spin Crossover Transition

The Fe(II) spin crossover complex [Fe{H₂B(pz)₂}₂(bipy)] (pz = pyrazol-1-yl, bipy = 2,2′-bipyridine) can be locked in a largely low-spin-state configuration over a temperature range that includes temperatures well above the thermal spin crossover temperature of 160 K. This locking of the spin state is achieved for nanometer thin films of this complex in two distinct ways: through substrate interactions with dielectric substrates such as SiO₂ and Al₂O₃, or in powder samples by mixing with the strongly dipolar zwitterionic p-benzoquinonemonoimine C₆H₂(—⋯ NH₂)₂(—⋯ O)₂. Remarkably, it is found in both cases that incident X-ray fluences then restore the [Fe{H₂B(pz)₂}₂(bipy)] moiety to an electronic state characteristic of the high spin state at temperatures of 200 K to above room temperature; that is, well above the spin crossover transition temperature for the pristine powder, and well above the temperatures characteristic of light- or X-ray-induced excited-spin-state trapping. Heating slightly above room temperature allows the initial locked state to be restored. These findings, supported by theory, show how the spin crossover transition can be manipulated reversibly around room temperature by appropriate design of the electrostatic and chemical environment.

Locking of the spin state of a molecular spin crossover system has been achieved, and room-temperature optical isothermal switching from a low spin to high spin state is demonstrated. Key ingredients necessary for a room temperature molecular magnetoelectric are now realizable.

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Low-Noise and Large-Linear-Dynamic-Range Photodetectors Based on Hybrid-Perovskite Thin-Single-Crystals

Organic–inorganic halide perovskites are promising photodetector materials due to their strong absorption, large carrier mobility, and easily tunable bandgap. Up to now, perovskite photodetectors are mainly based on polycrystalline thin films, which have some undesired properties such as large defective grain boundaries hindering the further improvement of the detector performance. Here, perovskite thin-single-crystal (TSC) photodetectors are fabricated with a vertical p–i–n structure. Due to the absence of grain-boundaries, the trap densities of TSCs are 10–100 folds lower than that of polycrystalline thin films. The photodetectors based on CH₃NH₃PbBr₃ and CH₃NH₃PbI₃ TSCs show low noise of 1–2 fA Hz^−1/2, yielding a high specific detectivity of 1.5 × 10¹³ cm Hz^1/2 W⁻¹. The absence of grain boundaries reduces charge recombination and enables a linear response under strong light, superior to polycrystalline photodetectors. The CH₃NH₃PbBr₃ photodetectors show a linear response to green light from 0.35 pW cm⁻² to 2.1 W cm⁻², corresponding to a linear dynamic range of 256 dB.

Photodetectors based on organic–inorganic halide perovskite thin-single-crystals (TSC) are fabricated. Due to the absence of grain-boundaries, very low trap densities, and small thickness (≈10 µm) of the TSC, the TSC photodetectors with vertical p–i–n structure show low noise (1–2 fA Hz^−1/2), high specific detectivity (≈1.5 × 10¹³ cm Hz^1/2 W⁻¹), and large linear-dynamic-range (256 dB).

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Two penetrating vessels as a novel indicator of the appropriate distal end of per-oral endoscopic myotomy

Abstract

Objectives

One of the challenges during per-oral endoscopic myotomy (POEM) is ensuring the appropriate length of myotomy on the gastric side. To determine the appropriate distal end of the gastric myotomy, we focused on the two penetrating vessels (TPVs) found in the gastric cardia during POEM. In this study, we evaluated whether the TPVs could serve as an accurate indicator of the appropriate distal end of the gastric myotomy.

Methods

All patients who underwent POEM between March and August 2016 were included for this study. When making the submucosal tunnel in the 5 o'clock direction into the stomach, two vessels penetrating through the circular muscle along the edge of oblique muscle in the cardia can be exposed. We designated these two vessels as TPVs. The myotomy was extended until the second TPV was exposed. The anal end of the submucosal tunnel was confirmed by the double-scope POEM technique, and the length from the gastroesophageal junction to the anal side end of myotomy was measured by the scale on the endoscope.

Results

Among 37 patients who underwent myotomy in the 5 o'clock position, TPVs were found in 34 patients (91.2%). Sufficient submucosal tunneling on the gastric side was confirmed by the double-scope POEM technique in those 34 patients. The median length of the gastric myotomy was 3.0 cm (range 2-4 cm).

Conclusions

The TPVs appears to be a simple and reliable indicator to determine the appropriate distal end of the myotomy.

This article is protected by copyright. All rights reserved.

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Aqueous Droplets Used as Enzymatic Microreactors and Their Electromagnetic Actuation

Lab-in-a-drop reaction systems allow the versatile implementation of complex reactions in a microfluidic scale. An automated actuation platform consisting of a 3 x 3 matrix of electromagnetic coils was developed and successfully used to merge two 10 µL microreactors and thereby initiate an enzymatic reaction in the resulting liquid marbles.

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Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis

Bacterial infection is a frequent trigger of acute-on-chronic liver failure (ACLF), syndrome that could also increase the risk of infection. This investigation evaluated prevalence and characteristics of bacterial and fungal infections causing and complicating ACLF, predictors of follow-up bacterial infections and impact of bacterial infections on survival.

Patients

407 patients with ACLF and 235 patients with acute decompensation (AD).

Results

152 patients (37%) presented bacterial infections at ACLF diagnosis; 46%(n=117) of the remaining 255 patients with ACLF developed bacterial infections during follow-up (4 weeks). The corresponding figures in patients with AD were 25% and 18% (p<0.001). Severe infections (spontaneous bacterial peritonitis, pneumonia, severe sepsis/shock, nosocomial infections and infections caused by multiresistant organisms) were more prevalent in patients with ACLF. Patients with ACLF and bacterial infections (either at diagnosis or during follow-up) showed higher grade of systemic inflammation at diagnosis of the syndrome, worse clinical course (ACLF 2-3 at final assessment: 47% vs 26%; p<0.001) and lower 90-day probability of survival (49% vs 72.5%;p<0.001) than patients with ACLF without infection. Bacterial infections were independently associated with mortality in patients with ACLF-1 and ACLF-2. Fungal infections developed in 9 patients with ACLF (2%) and in none with AD, occurred mainly after ACLF diagnosis (78%) and had high 90-day mortality (71%).

Conclusion

Bacterial infections are extremely frequent in ACLF. They are severe and associated with intense systemic inflammation, poor clinical course and high mortality. Patients with ACLF are highly predisposed to develop bacterial infections within a short follow-up period and could benefit from prophylactic strategies.

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How to Enjoy a Holiday Weekend

With Labor Day right around the corner, many of us may be planning some much-needed time away from the office. Are you able to truly relax and leave work behind when you are on vacation? Not everyone is able to stop thinking about work when they are not in the office. If this sounds like you, you may want to check out Art Markman's Harvard Business Review article titled "How to Forget About Work When You're Not Working."

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