Tuning of the Optical, Electronic, and Magnetic Properties of Boron Nitride Nanosheets with Oxygen Doping and Functionalization

Engineering of the optical, electronic, and magnetic properties of hexagonal boron nitride (h-BN) nanomaterials via oxygen doping and functionalization has been envisaged in theory. However, it is still unclear as to what extent these properties can be altered using such methodology because of the lack of significant experimental progress and systematic theoretical investigations. Therefore, here, comprehensive theoretical predictions verified by solid experimental confirmations are provided, which unambiguously answer this long-standing question. Narrowing of the optical bandgap in h-BN nanosheets (from ≈5.5 eV down to 2.1 eV) and the appearance of paramagnetism and photoluminescence (of both Stokes and anti-Stokes types) in them after oxygen doping and functionalization are discussed. These results are highly valuable for further advances in semiconducting nanoscale electronics, optoelectronics, and spintronics.

Intense oxygen doping and functionalization of hexagonal boron nitride (h-BN) nanosheets narrow the bandgap of the material from ≈5.5 to 2.1 eV in experiments, and lead to the appearance of paramagnetism and photoluminescence properties, which are not seen in h-BN. These findings pave a new way for the engineering of the optical, electronic, and magnetic properties of BN nanosheets.

http://ift.tt/2qYxFQJ

Bioinspired Composite Microfibers for Skin Adhesion and Signal Amplification of Wearable Sensors

A facile approach is proposed for superior conformation and adhesion of wearable sensors to dry and wet skin. Bioinspired skin-adhesive films are composed of elastomeric microfibers decorated with conformal and mushroom-shaped vinylsiloxane tips. Strong skin adhesion is achieved by crosslinking the viscous vinylsiloxane tips directly on the skin surface. Furthermore, composite microfibrillar adhesive films possess a high adhesion strength of 18 kPa due to the excellent shape adaptation of the vinylsiloxane tips to the multiscale roughness of the skin. As a utility of the skin-adhesive films in wearable-device applications, they are integrated with wearable strain sensors for respiratory and heart-rate monitoring. The signal-to-noise ratio of the strain sensor is significantly improved to 59.7 because of the considerable signal amplification of microfibrillar skin-adhesive films.

Strong adhesion of wearable sensors to dry and wet skin is proposed by a novel approach. Micropatterned adhesive films are composed of microfibers decorated with mushroom-shaped vinylsiloxane tips. Crosslinking the viscous tips directly on the skin significantly enhances the adhesion performance due to their great shape adaptation, which in turn highly increases the output signal quality of wearable strain sensors.

http://ift.tt/2rxKwXb

Biphasic Supramolecular Self-Assembly of Ferric Ions and Tannic Acid across Interfaces for Nanofilm Formation

Cell nanoencapsulation provides a chemical tool for the isolation and protection of living cells from harmful, and often lethal, external environments. Although several strategies are available to form nanometric films, most methods heavily rely on time-consuming multistep processes and are not biocompatible. Here, the interfacial supramolecular self-assembly and film formation of ferric ions (Fe^III) and tannic acid (TA) in biphasic systems is reported, where Fe^III and TA come into contact each other and self-assemble across the interface of two immiscible phases. The interfacial nanofilm formation developed is simple, fast, and cytocompatible. Its versatility is demonstrated with various biphasic systems: hollow microcapsules, encasing microbial or mammalian cells, that are generated at the water–oil interface in a microfluidic device; a cytoprotective Fe^III–TA shell that forms on the surface of the alginate microbead, which then entraps probiotic Lactobacillus acidophilus; and a pericellular Fe^III–TA shell that forms on individual Saccharomyces cerevisiae. This biphasic interfacial reaction system provides a simple but versatile structural motif in materials science, as well as advancing chemical manipulability of living cells.

The biphasic interfacial supramolecular self-assembly of ferric ions (Fe^III) and tannic acid in a heterogeneous system provides a powerful method for the formation of uniform and stable nanofilms in one step. The versatility of the synthetic strategy is demonstrated under various experimental settings (water–oil, hydrogel–water, and cell–water biphasic systems).

http://ift.tt/2qYG1YF

Bioinspired Ultratough Hydrogel with Fast Recovery, Self-Healing, Injectability and Cytocompatibility

Inspired by the mussel byssus adhesiveness, a highly hydrated polymeric structure is designed to combine, for the first time, a set of interesting features for load-bearing purposes. These characteristics include: i) a compressive strength and stiffness in the MPa range, ii) toughness and the ability to recover it upon successive cyclic loading, iii) the ability to quickly self-heal upon rupture, iv) the possibility of administration through minimally invasive techniques, such as by injection, v) the swelling ratio being adjusted to space-filling applications, and vi) cytocompatibility. Owing to these characteristics and the mild conditions employed, the encapsulation of very unstable and sensitive cargoes is possible, highlighting their potential to researchers in the biomedical field for the repair of load-bearing soft tissues, or to be used as an encapsulation platform for a variety of biological applications such as disease models for drug screening and therapies in a more realistic mechanical environment. Moreover, given the simplicity of this methodology and the enhanced mechanical performance, this strategy can be expanded to applications in other fields, such as agriculture and electronics. As such, it is anticipated that the proposed strategy will constitute a new, versatile, and cost-effective tool to produce engineered polymeric structures for both science and technology.

Inspired by the mussel byssus attachment system, a self-healable, ultratough and strong hydrogel is reported. The mild conditions employed during the fabrication process, as well as the use of nature-based materials, make it a prospective candidate for a wide range of applications including in the biomedical field.

http://ift.tt/2rxDEZz

Synergistic Phase and Disorder Engineering in 1T-MoSe2 Nanosheets for Enhanced Hydrogen-Evolution Reaction

MoSe₂ is a promising earth-abundant electrocatalyst for the hydrogen-evolution reaction (HER), even though it has received much less attention among the layered dichalcogenide (MX₂) materials than MoS₂ so far. Here, a novel hydrothermal-synthesis strategy is presented to achieve simultaneous and synergistic modulation of crystal phase and disorder in partially crystallized 1T-MoSe₂ nanosheets to dramatically enhance their HER catalytic activity. Careful structural characterization and defect characterization using positron annihilation lifetime spectroscopy correlated with electrochemical measurements show that the formation of the 1T phase under a large excess of the NaBH₄ reductant during synthesis can effectively improve the intrinsic activity and conductivity, and the disordered structure from a lower reaction temperature can provide abundant unsaturated defects as active sites. Such synergistic effects lead to superior HER catalytic activity with an overpotential of 152 mV versus reversible hydrogen electrode (RHE) for the electrocatalytic current density of j = −10 mA cm⁻², and a Tafel slope of 52 mV dec⁻¹. This work paves a new pathway for improving the catalytic activity of MoSe₂ and generally MX₂-based electrocatalysts via a synergistic modulation strategy.

Synergistic regulation of crystal phase and disorder engineering in partially crystallized 1T phase MoSe₂ nanosheets that are directly hydrothermally synthesized enhances catalytic activity toward the hydrogen-evolution reaction (HER). The optimized MoSe₂ nanosheets exhibit a record-high HER catalytic activity, with η = 152 mV versus RHE for j = −10 mA cm⁻² and a Tafel slope of 52 mV dec⁻¹.

http://ift.tt/2qYIT7D

A prospective study of quality of life in amyotrophic lateral sclerosis patients

Objects

The aim of this prospective and longitudinal study was to describe individual quality of life in patients with amyotrophic lateral sclerosis (ALS) and its correlations with physical function and emotional well-being from diagnosis and over time.

Materials and methods

Thirty-six patients were included in the study. Individual quality of life was measured with the Schedule of Evaluation of Individual Quality of Life-Direct Weighting (SEIQoL-DW), illness severity was assessed using the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALS FRS-R), and emotional distress was measured using the Hospital Anxiety and Depression Scale (HADS). Data were collected from diagnosis and thereafter, every six months for a period of two years. Twelve patients completed the 24-month follow-up.

Results

Family, friends and own physical health were important for overall quality of life, from diagnosis and during the disease progression. Most patients had good quality of life, which remained stable, despite changed physical functions. Several patients scored above the cut-off score for doubtful and clinical anxiety and depression early on after diagnosis, and there was a significant decrease in anxiety over time. Soon after diagnosis, there was a correlation between depression and quality of life.

Conclusion

The family, social relations and own physical health are important for overall quality of life in patients with ALS. Thus, supporting the family and facilitating so that patients can continue to stay in contact with friends are important aspects during the disease. Conducting an early screening for depression can be important for preventing decreased quality of life.

http://ift.tt/2rkhWva

Expression of Coagulation Factor XIII Subunit A Correlates with Outcome in Childhood Acute Lymphoblastic Leukemia

Abstract

Previously we identified B-cell lineage leukemic lymphoblasts as a new expression site for subunit A of blood coagulation factor XIII (FXIII-A). On the basis of FXIII-A expression, various subgroups of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) can be identified. Fifty-five children with BCP-ALL were included in the study. Bone marrow samples were obtained by aspiration and the presence of FXIII-A was detected by flow cytometry. G-banding and fluorescent in situ hybridization was performed according to standard procedures. The 10-year event-free survival (EFS) and overall survival (OS) rate of FXIII-A-positive and FXIII-A-negative patients showed significant differences (EFS: 84% vs. 61%, respectively; p = 0.031; OS: 89% vs. 61%; p = 0.008). Of all the parameters examined, there was correlation only between FXIII-A expression and 'B-other' genetic subgroup. Further multivariate Cox regression analysis of FXIII-subtype and genetic group or 'B-other' subgroup identified the FXIII-A negative characteristic as an independent factor associated with poor outcome in BCP-ALL. We found an excellent correlation between long-term survival and the FXIII-A-positive phenotype of BCP lymphoblasts at presentation. The results presented seem to be convincing enough to suggest a possible role for FXIII-A expression in the prognostic grouping of childhood BCP-ALL patients.

http://ift.tt/2qyqddW

Issue Information

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Scarlet Fever

http://otorhinolaryngology-crete.blogspot.com/2017/05/scarlet-fever.html

A 20-year-old man presented to his primary care physician with a 3-day history of swollen tonsils, sore throat, fevers, chills, and rash. The nonpruritic rash had started on his abdomen, spread to his chest and back, and then appeared on his arms, legs, and face. He had no known allergies or exposures to new medications and had no history of similar rash. Examination revealed exudative tonsillitis (Panel A), strawberry tongue, and cervical adenopathy with tenderness. Skin examination revealed diffuse blanching erythema with punctate papules that caused the skin on his chest, abdomen, back, arms, and legs to have a sandpaper-like quality (Panel B shows the left side of his abdomen). His neck and right flank had linear petechial patches. A rapid test for streptococcal pharyngitis was positive. The finding of acute streptococcal pharyngitis along with the diffuse rash led to a diagnosis of scarlet fever. The rash of scarlet fever is a delayed-type hypersensitivity to an exotoxin and therefore occurs in persons who have had a previous exposure to Streptococcus pyogenes. The rash classically manifests with linear petechial confluences that are known as Pastia's lines, which were seen in this patient. The patient was treated with antibiotic agents and had complete resolution of his symptoms within 3 days.

Alyson Brinker, M.D.

Navy Hospital Guam, Yigo, Guam 

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Dopamine and noradrenaline, but not serotonin, in the human claustrum are greatly reduced in patients with Parkinson's disease: possible functional implications

http://ift.tt/2pZbKoe

Issue Information

http://ift.tt/2rkMywh

Issue Cover (May 2017)

Cover image by Naoki Ihara, Ai Nakashima, Naosuke Hoshina, Yuji Ikegaya and Haruki Takeuchi

http://ift.tt/2pZjAOH

Perilesional Reorganization in a Patient With Brain Tumor.

No abstract available

http://ift.tt/2qCFVCU

Clinical and prognostic significance of HIF-1α overexpression in oral squamous cell carcinoma: a meta-analysis

Abstract

Background

Recent studies have indicated an association between hypoxia inducible factor-1 alpha (HIF-1α) expression and poor prognosis in patients with oral squamous cell carcinoma (OSCC); however, definitive evidence of this association is yet to be obtained. We performed a meta-analysis to evaluate the association of HIF-1α expression with clinicopathological characteristics and overall survival (OS) of patients with OSCC.

Methods

A literature search for relevant studies published in English language as of February 05, 2016, was performed on PubMed, Web of Science, and EMBASE databases. Eighteen studies with a combined study population of 1474 patients with OSCC are included in the meta-analysis. Odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI) was calculated using random-effects model or fixed-effects model.

Results

HIF-1α overexpression was significantly associated with larger tumor size (OR = 2.28, 95% CI = 1.49–3.50, P = 0.017), advanced TNM stage (OR = 2.29, 95% CI = 1.50–3.49, P = 0.158), and lymph node metastasis (OR = 2.05, 95% CI = 1.19–3.53, P < 0.001), but not with poor differentiation (OR = 1.21, 95% CI = 0.55–2.64, P = 0.024). These results demonstrated an association between HIF-1α expression and biological behavior of OSCC. On pooled analyses, high expression of HIF-1α was associated with worse OS (HR = 1.70, 95% CI = 1.10–2.61, P < 0.001). On subgroup analyses, overexpression of HIF-1α was significantly associated with poor prognosis in Asian population (HR = 2.33, 95% CI = 1.72–3.15, P = 0.862).

Conclusions

Our findings demonstrate an association of HIF-1α overexpression with tumor size, tumor stage, lymph node metastasis, and overall survival. HIF-1α could be an independent prognostic marker in patients with OSCC.

http://ift.tt/2rxrPTi

Differential effects of early-life nutrient restriction in long-lived GHR-KO and normal mice

Abstract

There is increasing evidence that growth hormone (GH) and insulin-like growth factor 1 (IGF-1) signaling (collectively referred to as somatotropic signaling) during development has a profound influence on aging and longevity. Moreover, the absence of GH action was shown to modify responses of adult mice to calorie restriction (CR) and other antiaging interventions. It was therefore of interest to determine whether GH resistance in GH receptor knockout (GHR-KO) mice would modify the effects of mild pre-weaning CR imposed by increasing the number of pups in a litter (the so-called litter crowding). In addition to the expected impact on body weight, litter crowding affected glucose homeostasis, hepatic expression of IGF-1 and genes related to lipid metabolism, and expression of inflammatory markers in white adipose tissue, with some of these effects persisting until the age of 2 years. Litter crowding failed to further extend the remarkable longevity of GHR-KO mice and, instead, reduced late life survival of GHR-KO females, an effect opposite to the changes detected in normal animals. We conclude that the absence of GH actions alters the responses to pre-weaning CR and prevents this intervention from extending longevity.

http://ift.tt/2qYeHtz

Proatherogenic Lipid Profile in Early Childhood: Association with Weight Status at 4 Years and Parental Obesity

To determine lipid profiles in early childhood and evaluate their association with weight status at 4 years of age. Additionally, we evaluated whether the risk of overweight or having an altered lipid profile was associated with parental weight status.

http://ift.tt/2pZen9E

Eruptive Xanthomas in Lipoprotein Lipase Deficiency

A 12-year-old-boy was referred by his pediatrician for assessment of eruptive skin lesions (Figure 1). The boy has lipoprotein lipase (LPL) deficiency because of homozygous mutation in the LPL gene diagnosed in neonatal age with acute onset of cardiac failure and bilateral pneumothorax. He was initially treated with plasmapheresis and then with lipid dietary restriction, omega3 oil, and fibrates, but the compliance to dietotherapy prescriptions worsened during time. Blood exams revealed a chylous appearance (Figure 2).

http://ift.tt/2rkh618

SMAD4 loss is associated with cetuximab resistance and induction of MAPK/JNK activation in head and neck cancer cells

Purpose: We previously demonstrated an association between decreased SMAD4 expression and cetuximab resistance in head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to further elucidate the clinical relevance of SMAD4 loss in HNSCC. Experimental Design: SMAD4 expression was assessed by immunohistochemistry in 130 newly diagnosed and 43 recurrent HNSCC patients. Correlative statistical analysis with clinicopathological data was also performed. OncoFinder, a bioinformatics tool, was used to analyze molecular signaling in TCGA tumors with low or high SMAD4 mRNA levels. The role of SMAD4 was investigated by shRNA knockdown and gene reconstitution of HPV-negative HNSCC cell lines in vitro and in vivo. Results: Our analysis revealed that SMAD4 loss was associated with an aggressive, HPV-negative, cetuximab-resistant phenotype. We found a signature of pro-survival and anti-apoptotic pathways that were commonly dysregulated in SMAD4-low cases derived from TCGA-HNSCC dataset and an independent oral cavity squamous cell carcinoma (OSCC) cohort obtained from GEO. We show that SMAD4 depletion in a HNSCC cell line induces cetuximab resistance and results in worse survival in an orthotopic mouse model in vivo. We implicate JNK and MAPK activation as mediators of cetuximab resistance and provide the foundation for the concomitant EGFR and JNK/MAPK inhibition as a potential strategy for overcoming cetuximab resistance in HNSCCs with SMAD4 loss. Conclusions: Our study demonstrates that loss of SMAD4 expression is a signature characterizing the cetuximab-resistant phenotype and suggests that SMAD4 expression may be a determinant of sensitivity/resistance to EGFR/MAPK or EGFR/JNK inhibition in HPV-negative HNSCC tumors.

http://ift.tt/2q20CpO

Can Microsatellite Status of Colorectal Cancer be Reliably Assessed after Neoadjuvant Therapy?

Purpose: Determination of microsatellite instability (MSI) by PCR is the gold standard; however, immunohistochemistry (IHC) of mismatch repair (MMR) proteins is frequently performed instead. The reliability of these methods on post-neoadjuvant-therapy specimens is unknown.  We examined the effect of neoadjuvant therapy on MSI results by PCR and IHC. Experimental design: A total of 239 colorectal cancers resected after neoadjuvant therapy were assessed for MSI with PCR and IHC. PCR and IHC results for matched paired pre- and post-treatment specimens were compared. In parallel, two isogenic cell lines conditioned for MMR functioning and two different patient-derived xenografts (PDX) were exposed to chemotherapy, radiation or both. We also examined whether establishment of PDXs induced MSI changes in five tumors. IHC and MSI were tested after treatment to assess for changes. Results: We identified paired pre- and post-treatment specimens for 37 patients: 2 with PCR only, 34 with IHC only, and 1 with both. All three patients with PCR had microsatellite stable pre- and post-treatment specimens. Of the 35 patients with IHC, 30 had intact MMR proteins in pre- and post-treatment specimens, 1 had equivocal MLH1 staining in the pre-treatment and loss in the post-treatment specimen, and 4 had intact pre-treatment MSH6 but variable post-treatment staining. In the experimental setting, no changes in MSI status were detected after treatment or tumor implantation in animals. Conclusions: Our findings show that expression of MMR proteins, commonly MSH6, can change after neoadjuvant therapy and confirm PCR as the gold-standard test for MSI after neoadjuvant therapy.

http://ift.tt/2qxsmGk

Cyclin D1 restrains oncogene-induced autophagy by regulating the AMPK-LKB1 signaling axis

Autophagy activated after DNA damage or other stresses mitigates cellular damage by removing damaged proteins, lipids and organelles. Activation of the master metabolic kinase AMPK enhances autophagy. Here we report that cyclin D1 restrains autophagy by modulating the activation of AMPK. In cell models of human breast cancer or in a cyclinD1-deficient model, we observed a cyclin D1-mediated reduction in AMPK activation. Mechanistic investigations showed that Cyclin D1 inhibited mitochondrial function, promoted glycolysis and reduced activation of AMPK (pT172), possibly through a mechanism that involves cyclin D1-Cdk4/Cdk6 phosphorylation of LKB1. Our findings suggest how AMPK activation by cyclin D1 may couple cell proliferation to energy homeostasis.

http://ift.tt/2rxqonZ

MET exon 14 mutation encodes an actionable therapeutic target in lung adenocarcinoma

Targeting somatically activated oncogenes has revolutionized the treatment of non-small cell lung cancer (NSCLC). Mutations in the gene mesenchymal-epithelial transition (MET) near the exon 14 splice sites are recurrent in lung adenocarcinoma and cause exon skipping (METΔ14). Here we analyzed 4,422 samples from 12 different malignancies to estimate the rate of said exon skipping. METΔ14 mutation and transcript were most common in lung adenocarcinoma. Endogenously expressed levels of METΔ14 transformed human epithelial lung cells in a Hepatocyte growth factor (HGF)-dependent manner. Additionally, overexpression of the orthologous mouse allele induced lung adenocarcinoma in a novel, immunocompetent mouse model. Met inhibition showed clinical benefit in this model. Additionally, we observed a clinical response to crizotinib in a patient with METΔ14-driven NSCLC, only to observe new missense mutations in the MET activation loop, critical for binding to crizotinib, upon clinical progression. These findings support genomically selected clinical trials directed towards METΔ14 in a fraction of NSCLC patients, confirm second-site mutations for further therapeutic targeting prior to and beyond acquired resistance, and provide an in vivo system for the study of METΔ14 in an immunocompetent host.

http://ift.tt/2qY0BYU

Mismatch Repair Proteins Initiate Epigenetic Alterations During Inflammation-Driven Tumorigenesis

Aberrant silencing of genes by DNA methylation contributes to cancer, yet how this process is initiated remains unclear. Using a murine model of inflammation-induced tumorigenesis, we tested the hypothesis that inflammation promotes recruitment of epigenetic proteins to chromatin, initiating methylation and gene silencing in tumors. Compared to normal epithelium and non-inflammation-induced tumors, inflammation-induced tumors gained DNA methylation at CpG islands, some of which are associated with putative tumor suppressor genes. Hypermethylated genes exhibited enrichment of repressive chromatin marks and reduced expression prior to tumorigenesis, at a time point coinciding with peak levels of inflammation-associated DNA damage. Loss of MutS homolog 2 (MSH2), a mismatch repair (MMR) protein, abrogated early inflammation-induced epigenetic alterations and DNA hypermethylation alterations observed in inflammation-induced tumors. These results indicate that early epigenetic alterations initiated by inflammation and MMR proteins lead to gene silencing during tumorigenesis, revealing a novel mechanism of epigenetic alterations in inflammation-driven cancer. Understanding such mechanisms will inform development of pharmacotherapies to reduce carcinogenesis.

http://ift.tt/2rxopjC

Targeting FBW7 as a strategy to overcome resistance to targeted therapy in non-small cell lung cancer

Inhibition of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) signaling is highly effective in a subgroup of non-small cell lung cancer (NSCLC) patients with distinct clinicopathological features. However, resistance to EGFR and ALK inhibitors inevitably occurs, and the molecular mechanism underlying resistance is not fully understood. In this study, we report a PI3K/Akt- and MEK/Erk-independent resistance mechanism by which loss of the E3 ubiquitin ligase F-box and WD repeat domain containing 7 (FBW7α) leads to targeted therapy resistance via stabilization of anti-apoptotic protein MCL-1. Using a panel of in vitro and in vivo studies, we showed that the regulatory machinery responsible for MCL-1 protein degradation was a step-wise event involving phosphorylation and nucleus translocation. Erk cooperated with GSKβ to phosphorylate MCL-1 Ser159 residue, which enabled MCL-1 to translocate into the nucleus and bind FBW7. Defects in this sequence impaired MCL-1 degradation and cell apoptosis, recapitulating phenotypes observed in FBW7 deficiency. Downregulation of FBW7 was found in EGFR inhibitor-resistant human NSCLC specimens and correlated with increased MCL-1 protein expression. Reactivation of FBW7 sensitized resistant cells to targeted therapy and facilitated MCL-1 degradation. Overall, our study provides proof-of-principle insight into a PI3K/Akt- and MEK/Erk-independent resistant model and suggests that targeting FBW7 can overcome resistance to targeted therapy.

http://ift.tt/2qYaCoS

Inhibition of mitochondrial matrix chaperones and anti-apoptotic Bcl-2 family proteins empower antitumor therapeutic responses

Rational therapeutic approaches based on synthetic lethality may improve cancer management. Based on a high-throughput drug screen, we provide preclinical proof of concept that targeting the mitochondrial Hsp90 chaperone network (mtHsp90) and inhibition of Bcl-2, Bcl-xL and Mcl-1 is sufficient to elicit synthetic lethality in tumors recalcitrant to therapy. Our analyses focused on BH3 mimetics that are broad acting (ABT263 and Obatoclax) or selective (ABT199, WEHI-539 and A1210477), along with the established mitochondrial matrix chaperone inhibitor Gamitrinib-TPP. Drug combinations were tested in various therapy-resistant tumors in vitro and in vivo in murine model systems of melanoma, triple-negative breast cancer and patient-derived orthotopic xenografts of human glioblastoma (PDX). We found that combining BH3-mimetics and Gamitrinib-TPP blunted cellular proliferation in a synergistic manner by massive activation of intrinsic apoptosis. In like manner, suppressing either Bcl-2, Bcl-xL or Mcl-1 recapitulated the effects of BH3-mimetics and enhanced the effects of Gamitrinib-TPP. Mechanistic investigations revealed that Gamitrinib-TPP activated a PERK-dependent integrated stress response which activated the pro-apoptotic BH3 protein Noxa and its downstream targets Usp9X and Mcl-1. Notably, in the PDX glioblastoma and BRAFi-resistant melanoma models, this drug combination safely and significantly extended host survival. Our results show how combining mitochondrial chaperone and Bcl-2 family inhibitors can synergize to safely degrade the growth of tumors recalcitrant to other treatments.

http://ift.tt/2rxjxea

Expansion of tumor-infiltrating CD8+ T cells expressing PD-1 improves the efficacy of adoptive T cell therapy

Recent studies have found that tumor-infiltrating lymphocytes (TIL) expressing PD-1 can recognize autologous tumor cells, suggesting that cells derived from PD-1+ TIL can be used in adoptive T cell therapy (ACT). However, no study thus far has evaluated the antitumor activity of PD-1-selected TIL in vivo. In two mouse models of solid tumors, we show that PD-1 allows identification and isolation of tumor-specific TIL without previous knowledge of their antigen specificities. Importantly, despite the high proportion of tumor-reactive T cells present in bulk CD8 TIL before expansion, only T cell products derived from sorted PD-1+, but not from PD-1- or bulk CD8 TIL, specifically recognized tumor cells. The fold-expansion of PD-1+ CD8 TIL was 10 times lower than that of PD-1- cells, suggesting that outgrowth of PD-1- cells was the limiting factor in the tumor specificity of cells derived from bulk CD8 TIL. The highly differentiated state of PD-1+ cells was likely the main cause hampering ex vivo expansion of this subset. Moreover, PD-1 precisely identified marrow-infiltrating, myeloma-specific T cells in a mouse model of multiple myeloma. In vivo, only cells expanded from PD-1+ CD8 TIL contained tumor progression, and their efficacy was enhanced by PDL-1 blockade. Overall, our data provide a rationale for the use of PD-1-selected TIL in ACT.

http://ift.tt/2qY5TUw

Educating student midwives around dignity and respect

Publication date: Available online 18 May 2017
Source:Women and Birth
Author(s): Jenny S. Hall, Mary Mitchell
FocusThere is currently limited information available on how midwifery students learn to provide care that promotes dignity and respect.BackgroundIn recent years the importance of dignity in healthcare and treating people with respect has received considerable emphasis in both a national and international context.AimThe aim of this discussion paper is to describe an educational workshop that enables learning to promote dignity and respect in maternity care.DiscussionAn interactive workshop, using different creative methods as triggers for learning will be described. Provision of learning opportunities for students around dignity and respect is important to ensure appropriate care is provided in practice. The use of creative methods to inspire has contributed to deep learning within participants. An evaluation of the workshop illustrated how learning impacted on participants practice. Data to support this is presented in this paper.ConclusionThe use of creative teaching approaches in a workshop setting appears to provide an effective learning opportunity around dignified and respectful care. These workshops have evoked a deep emotional response for some participants, and facilitators must be prepared for this outcome to ensure a safe space for learning.



http://ift.tt/2qzcnYZ

Pilot test of a home-based program to prevent perceived insufficient milk

Publication date: Available online 18 May 2017
Source:Women and Birth
Author(s): Natsuko K. Wood, Elizabeth A. Sanders, Frances M. Lewis, Nancy F. Woods, Susan T. Blackburn
ProblemAlthough the World Health Organization and American Academy of Pediatrics recommend exclusive breastfeeding for the first six months, only 22% of U.S. mothers do so. Mothers' perceived insufficient milk (PIM) is the primary reason for breastfeeding discontinuation globally. There are two changeable causes of PIM: (1) mothers' misinterpretation of their infant's behavior, and (2) mothers' lack of confidence in their ability to breastfeed.AimThe purpose of this study was to evaluate the short-term effect of a home-based intervention designed to prevent and/or reduce PIM.MethodsA mixed-methods, single-group, pretest-midtest-posttest design was used for evaluating a home-based breastfeeding program. The program was implemented during three 1.0- to 1.5-h home intervention sessions at 6, 13, and 27 days postpartum, delivered to 14 dyads of breastfeeding mothers and their full-term singleton infants.FindingsWe found significant increases over time in mothers' sensitivity to infant behavior and breastfeeding self-efficacy as well as significant decreased attribution of infant crying to PIM. Exit interviews indicated that the program was accepted by participating mothers.DiscussionThis is the first intervention study that has directly targeted the causes of PIM. The home-based intervention has the potential to add to maternal competencies both in correctly assessing their infants' behavior, thereby preventing erroneous attribution of infant behavior to PIM, as well as simultaneously bolstering maternal confidence in breastfeeding skills.ConclusionBy building maternal competencies, the home-based intervention has a longer-range potential to prevent breastfeeding discontinuation. Further evaluation is warranted.



http://ift.tt/2rxvdwv

A critical analysis of Australian policies and guidelines for water immersion during labour and birth

Publication date: Available online 18 May 2017
Source:Women and Birth
Author(s): Megan Cooper, Helen McCutcheon, Jane Warland
BackgroundAccessibility of water immersion for labour and/or birth is often dependent on the care provider and also the policies/guidelines that underpin practice. With little high quality research about the safety and practicality of water immersion, particularly for birth, policies/guidelines informing the practice may lack the evidence necessary to ensure practitioner confidence surrounding the option thereby limiting accessibility and women's autonomy.AimThe aims of the study were to determine how water immersion policies and/or guidelines are informed, who interprets the evidence to inform policies/guidelines and to what extent the policy/guideline facilitates the option for labour and birth.MethodPhase one of a three-phase mixed-methods study critically analysed 25 Australian water immersion policies/guidelines using critical discourse analysis.FindingsPolicies/guidelines pertaining to the practice of water immersion reflect subjective opinions and views of the current literature base in favour of the risk-focused obstetric and biomedical discursive practices. Written with hegemonic influence, policies and guidelines impact on the autonomy of both women and practitioners.ConclusionPolicies and guidelines pertaining to water immersion, particularly for birth reflect opinion and varied interpretations of the current literature base. A degree of hegemonic influence was noted prompting recommendations for future maternity care policy and guidelines'.Ethical considerationsThe Human Research Ethics Committee of the University of South Australia approved the research.



http://ift.tt/2qzeWKq

The potential role of infectious agents and pelvic inflammatory disease in ovarian carcinogenesis

Abstract

Background

The etiological cause of ovarian cancer is poorly understood. It has been theorized that bacterial or viral infection as well as pelvic inflammatory disease could play a role in ovarian carcinogenesis.

Aim

To review the literature on studies examining the association between ovarian cancer and bacterial or viral infection or pelvic inflammatory disease.

Methods

Database search through MEDLINE, applying the medical subject headings: "Ovarian neoplasms", AND "Chlamydia infections", "Neisseria gonorrhoeae", "Mycoplasma genitalium", "Papillomaviridae", or "pelvic inflammatory disease". Corresponding searches were performed in EMBASE, and Web of Science. The literature search identified 935 articles of which 40 were eligible for inclusion in this review.

Results

Seven studies examined the association between bacterial infection and ovarian cancer. A single study found a significant association between chlamydial infection and ovarian cancer, while another study identified Mycoplasma genitalium in a large proportion of ovarian cancer cases. The remaining studies found no association. Human papillomavirus detection rates varied from 0 to 67% and were generally higher in the Asian studies than in studies from Western countries. Cytomegalovirus was the only other virus to be detected and was found in 50% of cases in a case-control study. The association between ovarian cancer and pelvic inflammatory disease was examined in seven epidemiological studies, two of which, reported a statistically significant association.

Conclusions

Data indicate a potential association between pelvic inflammatory disease and ovarian cancer. An association between ovarian cancer and high-risk human papillomavirus genotypes may exist in Asia, whereas an association in Western countries seems unlikely due to the low reported prevalence. Potential carcinogenic bacteria were found, but results were inconsistent, and further research is warranted.

http://ift.tt/2rxvYFU

Differences in age-specific HPV prevalence between self-collected and health personnel collected specimen in a cross-sectional study in Ghana

Abstract

Background

HPV infections are ubiquitous and particularly common among sexually active young women. However, there are regional and national variations in age-specific HPV prevalence, which have implications for cervical cancer control. Data on age-specific HPV prevalences for Ghana and most sub-Saharan countries are scanty. Therefore, this study primarily sought to determine the age-specific HPV prevalence among women in a Ghanaian community and to determine whether these prevalences determined with health-personnel and self-collected specimens were comparable.

Methods

In this cross-sectional study, conducted between March 2012 and March 2013, cervical specimens were collected by self- and health-personnel collection from 251 women who were between the ages of 15 and 65 years. HPV present in these specimens were genotyped by a nested-multiplex PCR and Luminex fluoro-microspheres based method. Information on the demographic, sexual and reproductive characteristics of the women were also obtained. A Chi-square test of association was employed to determine the association of the distribution of age groups with each categorised sexual and reproductive characteristic and HPV risk type's status.

Results

The age group distribution of the participants was significantly associated with overall (χ ² = 36.1; p = 0.001), high risk (χ ² = 26.09; p = 0.002) and low risk (χ ² = 21.49; p = 0.011) HPV prevalences. The age-specific HPV prevalence pattern for each of the HPV risk types, determined with self-collected specimen, showed three peaks (at 20–24 years; 40–44 years and ≥ 55 years), while those determined with health-personnel collected specimen, showed two peaks (at 20–24 years and ≥ 55 years) for each HPV risk type's prevalence pattern. The high risk HPV prevalences determined with self-collected specimen were often higher than those determined with health-personnel specimen for the age groups between 25 and 45 years, who are mostly targeted for screening by HPV testing. Additionally, there were interesting variations in patterns of age-specific HPV genotype-specific prevalence between the two specimen collection methods.

Conclusions

The usefulness of self-collected specimen for high risk HPV burden determination and the existence of a two peaked and three peaked age-specific HPV prevalences in Ghana have been clearly indicated.

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Definition of a RACK1 Interaction Network in Drosophila melanogaster Using SWATH-MS

Receptor for Activated C kinase 1 (RACK1) is a scaffold protein that has been found in association with several signaling complexes, and with the 40S subunit of the ribosome. Using the model organism Drosophila melanogaster, we recently showed that RACK1 is required at the ribosome for IRES-mediated translation of viruses. Here, we report a proteomic characterization of the interactome of RACK1 in Drosophila S2 cells. We carried out Label-Free quantitation using both Data-Dependent and Data-Independent Acquisition and observed a significant advantage for the Sequential Window Acquisition of all THeoretical fragment-ion spectra (SWATH) method both in terms of identification of interactants and quantification of low abundance proteins. These data represent the first SWATH spectral library available for Drosophila and will be a useful resource for the community. A total of 52 interacting proteins were identified, including several molecules involved in translation such as structural components of the ribosome, factors regulating translation initiation or elongation and RNA binding proteins. Among these 52 proteins, 15 were identified as partners by the SWATH strategy only. Interestingly, these 15 proteins are significantly enriched for the functions translation and nucleic acid binding. This enrichment reflects the engagement of RACK1 at the ribosome and highlights the added value of SWATH analysis. A functional screen did not reveal any protein sharing the interesting properties of RACK1, which is required for IRES-dependent translation and not essential for cell viability. Intriguingly however, 10 of the RACK1 partners identified restrict replication of Cricket paralysis virus, an IRES-containing virus.

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Mechanisms of Resistance to FLT3 Inhibitors and the Role of the Bone Marrow Microenvironment

The presence of FLT3 mutations in acute myeloid leukemia (AML) carries a particularly poor prognosis, making the development of FLT3 inhibitors an imperative goal. The last decade has seen an abundance of clinical trials using these drugs alone or in combination with chemotherapy. This culminated with the recent approval by the US Food and Drug Administration of Midostaurin for the treatment of FLT3-mutated AML. Initial success has been followed by the emergence of clinical resistance. Although novel FLT3 inhibitors are being developed, studies into mechanisms of resistance raise hope of new strategies to prevent emergence of resistance and eliminate minimal residual disease.

http://ift.tt/2qY2qVF

Association of post-treatment hypoalbuminemia and survival in Chinese patients with metastatic renal cell carcinoma

Hypoalbuminemia adversely affects the clinical outcomes of various cancers. The purpose of this study was to estimate the prognostic value of hypoalbuminemia 3–5 weeks after treatment in patients with metastat...

http://ift.tt/2pZlajC

The Prediction of Viscous Losses and Pressure Drop in Models of the Human Airways

Abstract

This paper examines the viscous flow resistance in branching tubes as applied to simplified models of the lungs, and compares the results of Computational Fluid Dynamics (CFD) simulations for a range of conditions with measurement data. The results are in good agreement with the available measurement data for both inspiration and expiration. A detailed sensitivity analysis of the dissipation and viscous resistance in a branch then examines the ratio of the viscous resistance to that for a fully developed Poiseuille flow, Z. As other researchers have noted, the calculated resistances give lower values than those from the standard correlation of Pedley et al. The results demonstrate that the resistance is sensitive to the velocity profile upstream of the bifurcations, and explain from fluid dynamical considerations the apparent sensitivity of the resistance to the generation number of the branch. The paper also suggests a revised value for the calibration constant in the expression for Z. Finally, a limited set of results are presented for junction losses, and for expiration.

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Analysis of Tenodesis Techiques for treatment of Scapholunate Instability using the Finite Element method

Chronic Scapholunate ligament (SL) injuries are difficult to treat and can lead to wrist dysfunction. Whilst several tendon reconstruction techniques have been employed in the management of SL instability, SL gap reappearance after surgery has been reported. Using finite element model and cadaveric study data we investigated the performance of the Corella, schapolunate axis (SLAM) and modified Brunelli tenodesis (MBT) techniques. Virtual tenodesis surgery was undertaken in 3D finite element (FE) models to obtain the scapholunate (SL) gap and angle resulting from the three reconstruction techniques. The Corella technique was found to achieve the SL gap and angle closest to the intact, restoring SL gap and angle to within 5.6% and 0.6% respectively. The MBT method resulted in an SL gap least close to the intact. The results of our study indicate that the contribution of volar SLIL to scapholunate stability could be important.

http://ift.tt/2q1X1rO

Attenuated Error-Related Potentials in Amyotrophic Lateral Sclerosis with Executive Dysfunctions

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron diseases. It is characterized by progressive degeneration of the upper and lower motor neuron, resulting in muscle paralysis and atrophy. Despite intensive research, curative therapy is still not available. The prognosis is fatal, with a median survival of 2-5 years after disease onset. The incidence in Europe is 2.16 per 100,000 (Logroscino et al., 2010). Different genetic mutations have been associated with the familial form of disease (Robberecht and Philips, 2013), but the etiology of the more common sporadic ALS (90% of cases) remains largely unknown.

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Phase-locked and non-phase-locked EEG responses to pinprick stimulation before and after experimentally-induced secondary hyperalgesia

Intense or sustained nociceptor activation, induced for example by capsaicin or high frequency electrical stimulation (HFS), triggers an activity-dependent long-lasting, but reversible, long-term potentiation (LTP) in spinal nociceptive pathways (Sandkühler, 2007). In humans, topical capsaicin or HFS of the skin induces hyperalgesia in the treated area ("primary" hyperalgesia, LaMotte et al., 1991; Klein et al., 2004; Henrich et al., 2015). This primary hyperalgesia is thought to result from both a peripheral sensitization of nociceptors and LTP in spinal nociceptive pathways (Sandkühler and Gruber-Schoffnegger, 2012).

http://ift.tt/2qCEfJL

Influence of transcutaneous spinal stimulation on human LTP-like pain amplification. A randomized, double-blind study in volunteers

Non-invasive transcutaneous spinal direct current stimulation (tsDCS) has been proven to affect nociceptive circuits in healthy individuals and might be promising in pain treatment (Priori et al. 2014).

http://ift.tt/2pQMtRf

Methanol extract of Dicranopteris linearis L. leaves impedes acetaminophen-induced liver intoxication partly by enhancing the endogenous antioxidant system

The present study investigated the potential of methanolic extract of Dicranopteris linearis (MEDL) leaves to attenuate liver intoxication induced by acetaminophen (APAP) in rats.

http://ift.tt/2rxboXb

Practitioners’ perspectives on evaluating treatment outcomes in traditional Chinese medicine

There are no generally accepted standards for evaluation of treatment outcomes in traditional Chinese medicine (TCM). Pattern differentiation and individual treatments are recognized as the most distinguishing...

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Targeting T cell metabolism to regulate T cell activation, differentiation and function in disease

Chirag H Patel | Jonathan D Powell

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Respiratory support after extubation: noninvasive ventilation or high-flow nasal cannula, as appropriate

http://ift.tt/2qXKavJ

External validation of SAPS 3 and MPM0-III scores in 48,816 patients from 72 Brazilian ICUs

The performance of severity-of-illness scores varies in different scenarios and must be validated prior of being used in a specific settings and geographic regions. Moreover, models' calibration may deteriorat...

http://ift.tt/2rxicnR

Increasing utilization of intensity modulated radiation therapy in vulvar cancer: National Practice Patterns 2004–2012

Abstract

Objective

The aim of this study is to evaluate utilization of intensity modulated radiation therapy (IMRT) for vulvar cancer between 2004 and 2012, and determine the survival impact of IMRT and 2D/3D radiation therapy (RT) for women treated with postoperative, preoperative, or primary radiation.

Methods

Women with vulvar carcinoma who received IMRT or 2D/3D RT were identified in the National Cancer Data Base (NCDB) between 2004 and 2012. Patient characteristics were compared between those that received IMRT and 2D/3D RT using chi-square, Fisher's exact, and Mann-Whitney tests. Women were stratified by treatment approach, and overall survival (OS) was estimated via the Kaplan-Meier method and compared using the log-rank test. Factors associated with OS were determined using univariate and multivariate Cox proportional hazards regression models.

Results

A total of 6027 women were included (median age 67 years). Women received either 2D/3D RT (n = 4723) or IMRT (n = 1304). A total of 3.3% of women received IMRT in 2004, compared to 19.3% in 2008 and 43.0% in 2012. More women in the IMRT cohort received radiation doses >55 Gy compared to the 2D/3D RT cohort (47.5 vs. 40.3%, p < 0.001). Women received postoperative radiation (n = 3395), preoperative radiation (n = 478), or primary radiation (n = 1852). On multivariate analyses, the effect of radiation technique (IMRT vs. 2D/3D RT) on OS among women receiving post-operative, pre-operative, or primary radiation was not significant (p > 0.05).

Conclusions

IMRT utilization for vulvar cancer increased between the years 2004 and 2012. Survival was not significantly compromised with the use of IMRT compared to conventional 2D/3D RT techniques and may have allowed for dose escalation in some situations.

http://ift.tt/2rwJM4z

Patient and physician views on the quality of care for inflammatory bowel disease after one-year follow-up: Results from SOLUTION-2, a prospective IG-IBD study

Perception of quality of care is important in the management of patients with chronic diseases, particularly inflammatory bowel disease.

http://ift.tt/2rx7Pzk

Cytology Brushing of a Pancreas Cyst Wall for the Diagnosis of Cystic Neuroendocrine Tumor: When FNA Fails

http://ift.tt/2qyEBCY

Duodenal Gangliocytic Paraganglioma: Endoscopy, Sonography and F-18 FDG PET/CT imaging

We report a case of duodenal gangliocytic paraganglioma (GP). Duodenal GP is a rare subepithelial lesion that typically arises from the region of the major duodenal papilla. It is the third most common duodenal neuroendocrine tumor (NET), after gastrinoma and somatostatinoma. According to the World Health Organization classification, duodenal GP is considered a benign lesion, even though occasionally it may exhibit regional lymph node metastasis. Its clinical manifestations include gastrointestinal bleeding, abdominal pain and anemia.

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Reactive versus proactive therapeutic drug monitoring in IBD patients treated with infliximab: A self-fulfilling prophecy

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10-Year Retained Video Capsule with Crohn’s-Associated Small Bowel Adenocarcinoma

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Cirrhosis presenting as cutaneous calciphylaxis

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Treatment of Crohn’s Disease Anastomotic Stricture with a Lumen-Apposing Metal Stent

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Opioids in Gastroenterology: Treating Adverse Effects and Creating Therapeutic Benefits

The use of opioid medications on both an acute and chronic basis is ubiquitous in the U.S. As opioid receptors densely populate the gastrointestinal tract, symptoms and side effects can be expected in these patients. In the esophagus, dysmotility may result manifesting with dysphagia and a syndrome indistinguishable from primary achalasia. In the stomach, a marked delay in gastric emptying may ensue with postprandial nausea and early satiety. Postoperatively, particularly with abdominal surgery, opioid induced ileus may ensue.

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White Paper AGA: Functional Dyspepsia

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Should Nivolumab-induced colitis be treated by Infliximab?

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A rare hepatic tumor

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Caregiver Burden in Adults with Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic condition which has a relapsing and remitting disease course. There is high degree of inpatient and outpatient health care utilization by IBD patients along with a great deal of psychosocial stress associated with the condition. Patients frequently rely on family, friends and other informal caregivers to provide medical, instrumental and emotional support. The role of caregiving for adult IBD patients can lead to significant caregiver burden. At present, there are limited data on the existence of caregiver burden in adult IBD patients.

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New insights into effective targeted therapy for the treatment of adult acute lymphoblastic leukemia

International Journal of Hematologic Oncology May 2017, Vol. 5, No. 4, Pages 127-131.


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A look back at 2016 in International Journal of Hematologic Oncology

International Journal of Hematologic Oncology May 2017, Vol. 5, No. 4, Pages 119-121.


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Sequencing of DICER1 in sarcomas identifies biallelic somatic DICER1 mutations in an adult-onset embryonal rhabdomyosarcoma

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Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases

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Hallmarks of response to immune checkpoint blockade

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GP participation in increasing uptake in a national bowel cancer screening programme: the PEARL project

http://ift.tt/2qyISqc

Statin use, candidate mevalonate pathway biomarkers, and colon cancer survival in a population-based cohort study

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Frozen shoulder and risk of cancer: a population-based cohort study

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Stroma-regulated HMGA2 is an independent prognostic marker in PDAC and AAC

http://ift.tt/2rwYlUV

Targeted sequencing-based analyses of candidate gene variants in ulcerative colitis-associated colorectal neoplasia

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CIP2A mediates fibronectin-induced bladder cancer cell proliferation by stabilizing β-catenin

Abstract

Background

Fibronectin (FN) is associated with tumorigenesis and progression in bladder cancer, however, the underlying mechanisms causing this remain largely unknown. Furthermore, cancerous inhibitor of protein phosphatase 2A (CIP2A) has been shown to play important regulatory roles in cancer proliferation. Here, we investigated whether FN regulates CIP2A expression to promote bladder cancer cell proliferation.

Methods

The correlations of stromal FN with CIP2A and proliferating cell nuclear antigen (PCNA) expression were analyzed in a cohort bladder cancer patients. The roles of FN and CIP2A in regulating bladder cancer cell proliferation were evaluated in cell and animal models. Cycloheximide treatment was used to determine the effects of CIP2A on β-catenin stabilization. The CIP2A-β-catenin interaction was confirmed by immunofluorescence staining and co-immunoprcipitation.

Results

In this study, we found that stromal FN expression correlated positively with the levels of CIP2A and PCNA in bladder cancer tissues. Meanwhile, in human bladder cancer cell lines (T24 and J82), exogenous FN significantly promoted cell proliferation, however, CIP2A depletion inhibited this process. Furthermore, the interaction between CIP2A and β-catenin enhanced the stabilization of β-catenin, which was involved in FN-induced cell proliferation. In vivo, CIP2A depletion repressed FN-accelerated subcutaneous xenograft growth rates.

Conclusions

These data reveal that CIP2A is a crucial mediator of FN-induced bladder cancer cell proliferation via enhancing the stabilization of β-catenin. Promisingly, FN and CIP2A could serve as potential therapeutic targets for bladder cancer treatment.

http://ift.tt/2qyKXSZ

CC Nerd-The Case of the Anatomic Inaccuracy

A recent publication in Chest by Semler et al examined the utility of the ramped position for the emergent intubation of patients in the ICU (1). The results not only call into question our use of this technique, but more importantly the outcomes we use to evaluate the efficacy of airway interventions outside the pristine […]

EMCrit by Rory Spiegel.

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THE USE OF AN ACELLULAR OXYGEN CARRIER IN A HUMAN LIVER MODEL OF NORMOTHERMIC MACHINE PERFUSION.

Background: Normothermic machine perfusion of the liver (NMP-L) is a novel technique that preserves liver grafts under near-physiological conditions whilst maintaining their normal metabolic activity. This process requires an adequate oxygen supply, typically delivered by packed red blood cells (RBC). We present the first experience using an acellular hemoglobin-based oxygen carrier (HBOC) Hemopure in a human model of NMP-L. Methods: Five discarded high-risk human livers were perfused with HBOC-based perfusion fluid and matched to 5 RBC-perfused livers. Perfusion parameters, oxygen extraction, metabolic activity and histological features were compared during 6 hours of NMP-L. The cytotoxicity of Hemopure was also tested on human hepatic primary cell line cultures using an in vitro model of ischemia reperfusion injury. Results: The vascular flow parameters and the perfusate lactate clearance were similar in both groups. The HBOC-perfused livers extracted more oxygen than those perfused with RBCs (O2ER 13.75 vs 9.43 % x105 per gram of tissue, p=0.001). In vitro exposure to Hemopure did not alter intracellular levels of reactive oxygen species and there was no increase in apoptosis or necrosis observed in any of the tested cell lines. Histological findings were comparable between groups. There was no evidence of histological damage caused by Hemopure. Conclusion: Hemopure can be used as an alternative oxygen carrier to packed red cells in NMP-L perfusion fluid. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Clinical experience with transcutaneous supraorbital nerve stimulation in patients with refractory migraine or with migraine and intolerance to topiramate: a prospective exploratory clinical study

Migraine is included in the top-ten disabling diseases and conditions among the Western populations. Non-invasive neurostimulation, including the Cefaly® device, for the treatment of various types of pain is a...

http://ift.tt/2qXrv31

Case report: a novel frameshift mutation in the mitochondrial cytochrome c oxidase II gene causing mitochondrial disorder

Mitochondrial cytochrome c oxidase 2, MT-CO2, encodes one of the three subunits, which form the catalytic core of cytochrome c oxidase (COX), complex IV. Mutations in MT-CO2 are rare a...

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Key performance indicators' assessment to develop best practices in an Emergency Medical Communication Centre.

Introduction: Emergency Medical Communication Centre (EMCC) represents a pivotal link in the chain of survival for those requiring rapid response for out-of-hospital medical emergencies. Assessing and grading the performance of EMCCs are warranted as it can affect the health and safety of the served population. Objective: The aim of our work was to describe the activity on an EMCC and to explore the associations between different key performance indicators. Methods: We carried out our prospective observational study in the EMCC of Nantes, France, from 6 June 2011 to 6 June 2015. The EMCC performance was assessed with the following key performance indicators: answered calls, Quality of Service 20 s (QS20), occupation rate and average call duration. Results: A total of 35 073 h of dispatch activity were analysed. 1 488 998 emergency calls were answered. The emergency call incidence varied slightly from 274 to 284 calls/1000 citizens/year between 2011 and 2015. The median occupation rate was 35% (25-44). QS20 was correlated negatively with the occupation rate (Spearman's [rho]: -0.78). The structural equation model confirmed that the occupation rate was highly correlated with the QS20 (standardized coefficient: -0.89). For an occupation rate of 26%, the target value estimated by our polynomial model, the probability of achieving a QS20 superior or equal to 95% varied between 56 and 84%. Conclusion: The occupation rate appeared to be the most important factor contributing towards the QS20. Our data will be useful to develop best practices and guidelines in the field of emergency medicine communication centres. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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First in-human radiation dosimetry of 68 Ga-NODAGA-RGDyK

Abstract

Background

Integrin-targeting radiopharmaceuticals have potential broad applications, spanning from cancer theranostics to cardiovascular diseases. We have previously reported preclinical dosimetry results of ⁶⁸Ga-NODAGA-RGDyK in mice. This study presents the first human dosimetry of ⁶⁸Ga-NODAGA-RGDyK in the five consecutive patients included in a clinical imaging protocol of carotid atherosclerotic plaques. Five male patients underwent whole-body time-of-flight (TOF) PET/CT scans 10, 60 and 120 min after tracer injection (200 MBq). Quantification of ⁶⁸Ga activity concentration was first validated by a phantom study. To be used as input in OLINDA/EXM, time-activity curves were derived from manually drawn regions of interest over the following organs: brain, thyroid, lungs, heart, liver, spleen, stomach, kidneys, red marrow, pancreas, small intestine, colon, urinary bladder and whole body. A separate dosimetric analysis was performed for the choroid plexuses. Female dosimetry was extrapolated from male data. Effective doses (EDs) were estimated according to both ICRP60 and ICRP103 assuming 30-min and 1-h voiding cycles.

Results

The body regions receiving the highest dose were urinary bladder, kidneys and choroid plexuses. For a 30-min voiding cycle, the EDs were 15.7 and 16.5 μSv/MBq according to ICRP60 and ICRP103, respectively. The extrapolation to female dosimetry resulted in organ absorbed doses 17% higher than those of male patients, on average.

The 1-h voiding cycle extrapolation resulted in EDs of 19.3 and 19.8 μSv/MBq according to ICRP60 and ICRP103, respectively. A comparison is made with previous mouse dosimetry and with other human studies employing different RGD-based radiopharmaceuticals.

Conclusions

According to ICRP60/ICRP103 recommendations, an injection of 200 MBq ⁶⁸Ga-NODAGA-RGDyK leads to an ED in man of 3.86/3.92 mSv. For future therapeutic applications, specific attention should be directed to delivered dose to kidneys and potentially also to the choroid plexuses.

Trial registration

Clinical trial.gov, NCT01608516

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Erratum to: Evaluation of the Short-Term Cost-Effectiveness of IDegLira Versus Continued Up-Titration of Insulin Glargine U100 in Patients with Type 2 Diabetes in the USA

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EMS Week 2017: What it means to be 'Always in Service'

"Always in Service" is the 2017 EMS Week theme. Like the themes from previous years – "Called to Care" and "Everyday Heroes" – this year's theme of "Always in Service" is not explicitly defined and it is under the umbrella of EMS Strong. EMS Week is an annual celebration and recognition of EMS providers. The American College of Emergency Physicians ...

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Characterization of the novel In1059 harbouring VIM gene cassette

VIM-type enzyme encodes the most widely acquired metallo-β-lactamases in Gram- negative bacteria. To obtain current epidemiological data for integrons from enterobacteriae in hospital, the study characterizes ...

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Regorafenib Approved for Liver Cancer [News in Brief]

FDA nod marks first new treatment in a decade for patients with disease progression on standard of care.

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Congress OKs $2 Billion Boost for the NIH [News in Brief]

Researchers' fears of immediate funding cuts allayed, but many concerned about proposed cuts for FY 2018.

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Preparation of Plasma Membrane Vesicles from Bone Marrow Mesenchymal Stem Cells for Potential Cytoplasm Replacement Therapy

Age-related diseases are associated with multiple defects in components of the cytoplasm. Here, we present a protocol to prepare plasma membrane vesicles from bone marrow mesenchymal stem cells. This technique could potentially be used as a means of cytoplasm replacement therapy to ameliorate or even reverse age-associated phenotypes.

http://ift.tt/2pQ9Om8

Pharmacokinetics and safety of vismodegib in patients with advanced solid malignancies and hepatic impairment

Abstract

Purpose

Vismodegib is a Hedgehog pathway inhibitor approved for the treatment of advanced basal cell carcinoma. Currently, the pharmacokinetics (PK) and safety of vismodegib in patients with hepatic dysfunction are unknown and are the objective of this study.

Methods

Patients with advanced solid malignancies and hepatic impairment were enrolled into one of four cohorts: normal [bilirubin (bili) < upper limit of normal (ULN)], mild (ULN < bili ≤ 1.5 × ULN), moderate (1.5 × ULN < bili ≤ 3×ULN), and severe (3 × ULN < bili < 10 × ULN) dysfunction. Patients received oral vismodegib 150 mg daily. Plasma PK samples on days 1, 3, 5, and 8 were collected. Vismodegib therapy was continued until disease progression, intolerable toxicity, or withdrawal of consent.

Results

Thirty-one patients were accrued: nine normal, eight mild, eight moderate, and six severe. Four patients experienced dose-limiting toxicity of hyperbilirubinemia on study: one in the moderate cohort and three in the severe cohort. Six patients died within 30 days after the last dose of vismodegib. All deaths were attributed to disease progression. Observed maximal and average steady-state concentrations and AUC of vismodegib at steady state (day 8) were similar across cohorts. Average AAG concentrations in patients with hepatic impairment were comparable to those of patients with normal hepatic function.

Conclusions

Hepatic impairment does not appear to impact vismodegib PK, and therefore, dose adjustment is not necessary in this special population. The study was influenced by the high number of patients with hepatocellular carcinoma with advanced cirrhosis; rendering it difficult to draw any causal relationships between vismodegib exposure and the serious adverse events.

http://ift.tt/2pYpS12

Decreased human leukocyte antigen A*02:01 frequency is associated with risk of glioma and existence of human cytomegalovirus: a case–control study in Northern China

Abstract

Background

Human leukocyte antigens (HLAs) play an important role in host defense against viral infection and tumorigenesis. Human cytomegalovirus (HCMV) has been linked to glioma development. This study investigated the relationship between HLA distribution, presence of HCMV, and glioma development in a Han Chinese population.

Methods

The study population included 150 glioma patients and 150 tumor-free brain injury control subjects (control-A) matched according to geography, ethnicity, age, and gender. HLA allele frequency was compared between the two groups using peripheral blood samples by PCR sequence-based typing. These data were also compared with HLA frequencies obtained from a Northern Chinese Han population database (control-B). HCMV DNA was detected in the peripheral blood of glioma patients and control group-A by nested PCR. The expression of HCMV proteins IE1-72 and pp65 in tumor tissues was evaluated by immunohistochemistry.

Results

The frequency of HLA-A*02:01 was decreased in glioma patients as compared to control group-A and -B (P < 0.001 and P = 0.001, respectively). The age/sex-adjusted odds ratio for HLA-A*02:01 positivity vs. negativity was 0.392 (95% confidence interval 0.225–0.683). HCMV was more frequently detected in the peripheral blood and tumor tissue of HLA-A*02:01-negative glioma patients. HLA-A*02:01 and HCMV were not associated with overall survival.

Conclusion

There is a correlation between decreased HLA-A*0201 allele frequency and glioma susceptibility.

http://ift.tt/2rvXJiq

Oligopeptide Competition Assay for Phosphorylation Site Determination

Peptide competition assays are widely used in a variety of molecular and immunological experiments. This paper describes a detailed method for an in vitro oligopeptide-competing kinase assay and the associated validation procedures, which may be useful to find specific phosphorylation sites.

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Isolation of Intermediate Filament Proteins from Multiple Mouse Tissues to Study Aging-associated Post-translational Modifications

In this method, we present biochemical procedures for rapid and efficient isolation of intermediate filament (IF) proteins from multiple mouse tissues. Isolated IFs can be used to study changes in post-translational modifications by mass spectrometry and other biochemical assays.

http://ift.tt/2rvxyZP

Measuring Protein Binding to F-actin by Co-sedimentation

This protocol describes a method to test the ability of a protein to co-sediment with filamentous actin (F-actin) and, if binding is observed, to measure the affinity of the interaction.

http://ift.tt/2rvQcAD

Risk factors for paraaortic lymph node metastasis in endometrial cancer

Abstract

Objective

The purpose of this study was to determine the risk factors for paraaortic lymph node (LN) metastasis in endometrial cancer (EC) patients who underwent comprehensive surgical staging.

Methods

A total of 641 women with EC (endometrioid, non-endometrioid, or mixed histology) who underwent comprehensive surgical staging including pelvic and paraaortic LN dissection between 2008 and 2016 were included in this retrospective study. Patient data were analyzed with respect to paraaortic LN involvement, and predictive factors for paraaortic LN metastasis were investigated.

Results

Lymph node metastasis was detected in 90 (14%) patients, isolated pelvic LN metastasis in 28 (4.3%), isolated paraaortic LN metastasis in 15 (2.3%), and both pelvic and paraaortic LN metastasis in 47 (7.3%) women, respectively. Univariate analysis showed that the risk of paraaortic LN metastasis significantly increased in patients with non-endometrioid histology, age greater than 60 years, grade 3 tumor, deep myometrial invasion, lymphovascular space invasion (LVSI), primary tumor diameter (≥2 cm), cervical stromal invasion, adnexal involvement, serosal invasion, pelvic LN involvement, two or more positive pelvic LNs, and positive peritoneal cytology (p < 0.05). At the end of multivariate analysis, the presence of LVSI [odds ratio (OR), 4.8; 95% confidence interval (CI), 1.25–18.2; p = 0.022] and pelvic LN metastasis (OR, 18.8; 95% CI, 5.7–61.6; p < 0.001) remained as independent risk factors for paraaortic LN involvement in women with EC.

Conclusion

The presence of LVSI and pelvic LN involvement appear to be independent risk factors for paraaortic LN metastasis in patients with EC. LVSI may be considered as a routine pathological parameter during frozen section analysis in women with EC undergoing surgery.

http://ift.tt/2pXMA9q

A 21st-Century Health IT System — Creating a Real-World Information Economy

Data generated as a by-product of the day-to-day work of delivery systems are a fundamental currency of the 21st Century Cures Act. How efficiently and effectively we use this "real-world" evidence will shape the way medicine is practiced and the way drugs are approved. In 2009, the Health…

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The Committed Perspective — Policy Principles for Regional Health Plans

At a recent Washington gathering, a bipartisan contingent of health policy wonks compared the Affordable Care Act (ACA) to the Beatles. Take away the individual mandate and purchasing subsidies, and you're left with George and Ringo. Wipe out the Medicaid expansion and you're down to just Ringo — a…

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Fatty acid metabolism and prospects for targeted therapy of cancer

Abstract

Fatty acids are fundamental substrates required for energy storage, synthesis of membranes, generation of signaling molecules and lipid droplet formation in cancer cells. High levels of fatty acid metabolic activity are one of the most aberrant metabolic alterations in cancer cells. The de novo fatty acid synthesis pathway is the primary source of fatty acids in cancer cells, but cancer cells can also acquire fatty acids through the lipolytic pathway, which helps cells survive and maintain their invasiveness. Key enzymes, including ATP-citrate lyase (ACLY), fatty acid synthase (FASN), acetyl-coenzyme A (CoA) carboxylase (ACC), stearoyl-CoA desaturase 1(SCD1) and monoacylglycerol lipase (MAGL), which are involved in fatty acid synthesis and degradation, are overexpressed in cancer cells. The alterations in fatty acid metabolomics in different cancers, at different stages of cancer, and in different tissues are clinically significant. This review focuses on current research into fatty acid metabolism to explore new targets against the fatty acid metabolic pathways for anticancer therapy.

Practical applications: High levels of fatty acid metabolic activity are one of the most aberrant metabolic alterations in cancer cells. Reprogramming in fatty acid metabolism plays an important role in energy storage, membrane proliferation, the generation of signaling molecules and lipid droplet formation in cancer cells. Understanding the mechanism of regulated the fatty acid metabolic pathways in cancer would reveal novel targeted therapy of cancer.

http://ift.tt/2qAMfKY

Improving oxidative stability of liquid fish oil supplements for pets

Abstract

Omega-3 polyunsaturated fatty acids have produced beneficial health effects in animals and are recommended by veterinaries to pet patients suffering from osteoarthritis. However, these oils are highly susceptible to lipid oxidation. The objectives of this study were to improve oxidative stability of fish oil by adding vegetable oils, mixed tocopherols and rosemary extract and to formulate a commercial product according to the results obtained. The formulated product was evaluated against commercial fish oil products.

An initial screening for antioxidative effect was performed by using Oxipres equipment. The effect of antioxidant and vegetable oil blends was examined in oils stored at 30 and 40°C by measuring peroxide value, volatile compounds with GC-MS and tocopherol content.

Addition of vegetable oil and rosemary extract at high level (4000 to 6000 ppm) plus 600 ppm of mixed tocopherols increased oxidative stability to the same extent as 2000 ppm mixed tocopherols in Oxipres. Overall, oxidative stability of fish oil or fish oil + vegetable oil blends was improved the most by addition of 5000 ppm rosemary extract and 500 ppm mixed tocopherols. A commercial oil blend with composition optimized based on the results of this study performed better than other commercial marine oils tested.

Practical applications: In some commercial oil blends for pets, a high level of vegetable oils is included in order to increase oxidative stability. In this study, vegetable oils are included at 30% level. At this level of vegetable oil inclusion, the omega-3 EPA and DHA content of the blends is at least 21% of total fatty acids for both fish and tuna oil based blends. In this study we wanted to examine, whether we could reduce the level of vegetable oil inclusion without compromising oxidative stability. This study demonstrates how the oxidative stability of omega-3 PUFA formulations for pets can be improved by combining fish oil with vegetable oils and by adding an antioxidant blend consisting of high concentrations of rosemary extract and tocopherol. The results are also of relevance to the manufacturers of dietary supplements.

http://ift.tt/2pPFwjo

SYNTHESIS AND THERMAL STUDY OF POLYMERS FROM SOYBEAN, SUNFLOWER, AND GRAPE SEED MALEINATED OIL

Abstract

Biodegradable polymers and polymers synthesized from industrial wastes (glycerol) currently have a great appeal due to factors such as sustainability, economic viability, and environmental preservation. The aim of this study was to synthesize some polymers from different maleinated vegetable oils with glycerol. Simultaneous thermogravimetric analysis – differential thermal analysis (TGA-DTA) and differential scanning calorimetry (DSC) were employed to evaluate the thermal decomposition, thermal stability, dehydration, oxidation, glass transition, and crystallization processes. Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (¹H-NMR) were employed to elucidate reaction sites and polymeric structure.

Practical applications: The polymer synthesis of each vegetable oil was similar in time and process; however, the final product presented different physical characteristics. The results obtained by TGA-DTA and DSC data showed that these polymers had different thermal behaviors, which is related by different quantity of unsaturated fatty acids in each oil structure. Finally, the FTIR and ¹H-NMR analysis help to clarify the polymers structure and the reaction sites: hence, it was possible propose a reaction mechanism and the structure. The results indicate that the synthesis was effortless and use inexpensive reagents, such as vegetable oils, maleic anhydride, and glycerol. These polymers could be applied in the area of adhesives and waterproofing materials.

http://ift.tt/2qAPVfT

Comparison and optimization of in silico algorithms for predicting the pathogenicity of sodium channel variants in epilepsy

Summary

Objective

Variants in neuronal voltage-gated sodium channel α-subunits genes SCN1A, SCN2A, and SCN8A are common in early onset epileptic encephalopathies and other autosomal dominant childhood epilepsy syndromes. However, in clinical practice, missense variants are often classified as variants of uncertain significance when missense variants are identified but heritability cannot be determined. Genetic testing reports often include results of computational tests to estimate pathogenicity and the frequency of that variant in population-based databases. The objective of this work was to enhance clinicians' understanding of results by (1) determining how effectively computational algorithms predict epileptogenicity of sodium channel (SCN) missense variants; (2) optimizing their predictive capabilities; and (3) determining if epilepsy-associated SCN variants are present in population-based databases. This will help clinicians better understand the results of indeterminate SCN test results in people with epilepsy.

Methods

Pathogenic, likely pathogenic, and benign variants in SCNs were identified using databases of sodium channel variants. Benign variants were also identified from population-based databases. Eight algorithms commonly used to predict pathogenicity were compared. In addition, logistic regression was used to determine if a combination of algorithms could better predict pathogenicity.

Results

Based on American College of Medical Genetic Criteria, 440 variants were classified as pathogenic or likely pathogenic and 84 were classified as benign or likely benign. Twenty-eight variants previously associated with epilepsy were present in population-based gene databases. The output provided by most computational algorithms had a high sensitivity but low specificity with an accuracy of 0.52–0.77. Accuracy could be improved by adjusting the threshold for pathogenicity. Using this adjustment, the Mendelian Clinically Applicable Pathogenicity (M-CAP) algorithm had an accuracy of 0.90 and a combination of algorithms increased the accuracy to 0.92.

Significance

Potentially pathogenic variants are present in population-based sources. Most computational algorithms overestimate pathogenicity; however, a weighted combination of several algorithms increased classification accuracy to >0.90.

http://ift.tt/2qvqCNI

Diffuse Parenchymal Lung Disease on Chest Radiographs and CT

Background

We prospectively identified B-lines in patients undergoing ultrasound examinations following liver transplants who also had a chest x-ray (CXR) and/or chest CT scan on the same day to determine if an association between the presence of B-lines s from the thorax on ultrasound images correlates with the presence of pulmonary abnormalities on chest radiographs.

Materials and Methods

Following IRB approval, patients undergoing routine postoperative liver transplant ultrasound examinations and a CXR and/or CT scan on the same day between 1/1/2015 through 7/1/2016 were prospectively identified.Two readers blinded to CXR and CT images and reports independently reviewed the US. Inter-reader agreement for presence/absence of the B-lines was evaluated for the presence or absence of diffuse parenchymal lung disease on CXR and CT, as well as on clinical evaluation. Receiver operating characteristic (ROC) curves were constructed.

Results

There was good agreement between the two readers on the presence/absence of B-lines (kappa: 0.94) The area under the ROC curve (AUC) for discriminating between DPLD+ and DPLD- for both readers was 0.79 (95% CI: 0.71-0.87.

Conclusion

There is an association between the presence of extensive B-lines to the point of confluence and "dirty shadowing" on ultrasound examinations of the chest and associated findings on chest radiographs and CT scans of diffuse parenchymal lung disease. Conversely, isolated B-lines do not always correlate with abnormalities on chest X-ray or and in fact appear sometimes to be a normal variant.

http://ift.tt/2q0c6dC

Clinical and Genetic Associations of Objectively Identified Interstitial Changes in Smokers

Background

Smoking related lung injury may manifest on computed tomography (CT) as both emphysema and interstitial changes. We have developed an automated method to quantify interstitial changes and hypothesized that this measurement would be associated with lung function, quality of life, mortality, and a MUC5B polymorphism.

Methods

Using CT scans from the COPDGene study, lung parenchyma was objectively labeled as a tissue subtype and the percentage of the lung occupied by interstitial subtypes was calculated.

Findings

8345 participants had clinical and CT data available. A 5% absolute increase in interstitial changes was associated with an absolute increase in percent predicted forced vital capacity of 2.47% (pConclusions

http://ift.tt/2qvIJ6m

Clinical characteristics of pertussis-associated cough in adults and children: a diagnostic systematic review and meta-analysis

Background

Pertussis (whooping cough) is a highly infective cause of cough that causes significant morbidity and mortality. Existing case definitions include paroxysmal cough, whooping and post-tussive vomiting but diagnosis can be difficult. We determined the diagnostic accuracy of clinical characteristics of pertussis-associated cough.

Methods

We systematically searched CINAHL, Embase, Medline and SCI-EXPANDED/CPCI-S up to June 2016. Eligible studies compared clinical characteristics in those positive and negative for Bordetella pertussis infection, confirmed by laboratory investigations. Two authors independently completed screening, data extraction and quality and bias assessments. For each characteristic RevMan was used to produce descriptive forest plots. We used the bivariate meta-analysis method to generate pooled estimates of sensitivity and specificity.

Results

Of 1969 identified papers, 53 were included. Forty-one clinical characteristics were assessed for diagnostic accuracy. In adult patients, paroxysmal cough and absence of fever had a high sensitivity (93.2%, CI 83.2-97.4 and 81.8%, CI 72.2-88.7 respectively) and low specificity (20.6%, CI 14.7-28.1 and 18.8%, CI 8.1-37.9 respectively), whereas post-tussive vomiting and whooping had low sensitivity (32.5%, CI 24.5-41.6 and 29.8%, CI 8.0-45.2 respectively) and high specificity (77.7%, CI 73.1-81.7 and 79.5%, CI 69.4-86.9 respectively). Post-tussive vomiting in children is moderately sensitive (60.0%, CI 40.3-77.0) and specific 66.0%, CI 52.5-77.3).

Conclusions

In adult patients the presence of whooping or post-tussive vomiting should rule in a possible diagnosis of pertussis, whereas the lack of a paroxysmal cough or the presence of fever should rule it out. In children, post-tussive vomiting is much less helpful as a clinical diagnostic test.

http://ift.tt/2q0whb9

Decreased serum sirtuin-1 in chronic obstructive pulmonary disease

Background

The protein deacetylase sirtuin-1 (SIRT1) is an anti-aging molecule that is decreased in the lung from patients with chronic obstructive pulmonary disease (COPD). Recently, SIRT1 was reported to be detectable in serum, but serum SIRT1 levels have not yet been reported in patients with COPD.

Methods

Serum SIRT1 was measured by Western blotting, and relative ratio of band density in samples against that of a positive control were calculated.

Results

Several molecular sizes of SIRT1, including 120kDa (actual size) and fragments (102, 75kDa) were quantified by Western blotting. Among them, only the 120kDa serum SIRT1 (s120S) was significantly decreased in the patients with COPD compared to the control subjects without COPD (s120S ratio in healthy: 0.90±0.34, vs COPD: 0.68±0.24; p=0.014), and was positively correlated with airway obstruction (FEV1/ FVC; r=0.31; p=0.020) and its severity measured by FEV1 % predicted (r=0.29; p=0.029). Serum s120S also showed a positive correlation with body mass index (BMI; r=0.36; p=0.0077) and diffusing capacity of the lung per unit volume (KCO%; r=0.32; p=0.025). It was also significantly decreased with increasing severity of lung emphysema (r=-0.40, p=0.027) and with a clinical history of frequent COPD exacerbations (infrequent: 0.76±0.20 vs frequent: 0.56±0.26; p=0.027). SIRT1 was not detected in supernatant of A549 and primary epithelial cells in normal culture condition.

Conclusions

Serum SIRT1 (s120S) was decreased in the patients with COPD, potentially as reflected by the reduced SIRT1 within cells as a result of oxidative stress, and might be a potential biomarkers for certain disease characteristics of COPD.

http://ift.tt/2qvFD2p

Identification of Pulmonary Hypertension Caused by Left Heart Disease (World Health Organization Group 2) Based on Cardiac Chamber Volumes Derived from Chest CT

Background

Evaluations of patients with pulmonary hypertension (PH) commonly include chest computed tomography (CT). We hypothesized that cardiac chamber volumes calculated from the same CT scans can yield additional information to distinguish left heart disease-related PH (WHO Group 2) from other PH subtypes.

Methods

Patients with right heart catheterization (RHC)-confirmed PH and contrast-enhanced chest CT studies were enrolled in this retrospective multicenter study. Cardiac chamber volumes were calculated using automated segmentation software and compared between Group 2 and non-Group 2 PH patients.

Results

This study included 114 PH patients, of whom 27 (24%) were classified as Group 2 based on their pulmonary capillary wedge pressure. Group 2 PH patients exhibited significantly larger median left atrial (LA) volumes (118 vs. 63 mL, P Conclusions

http://ift.tt/2q0iqBU

The global burden of diagnostic errors in primary care

Diagnosis is one of the most important tasks performed by primary care physicians. The World Health Organization (WHO) recently prioritized patient safety areas in primary care, and included diagnostic errors as a high-priority problem. In addition, a recent report from the Institute of Medicine in the USA, 'Improving Diagnosis in Health Care', concluded that most people will likely experience a diagnostic error in their lifetime. In this narrative review, we discuss the global significance, burden and contributory factors related to diagnostic errors in primary care. We synthesize available literature to discuss the types of presenting symptoms and conditions most commonly affected. We then summarize interventions based on available data and suggest next steps to reduce the global burden of diagnostic errors. Research suggests that we are unlikely to find a 'magic bullet' and confirms the need for a multifaceted approach to understand and address the many systems and cognitive issues involved in diagnostic error. Because errors involve many common conditions and are prevalent across all countries, the WHO's leadership at a global level will be instrumental to address the problem. Based on our review, we recommend that the WHO consider bringing together primary care leaders, practicing frontline clinicians, safety experts, policymakers, the health IT community, medical education and accreditation organizations, researchers from multiple disciplines, patient advocates, and funding bodies among others, to address the many common challenges and opportunities to reduce diagnostic error. This could lead to prioritization of practice changes needed to improve primary care as well as setting research priorities for intervention development to reduce diagnostic error.

http://ift.tt/2qwYaM7

Incident reporting: rare incidents may benefit from national problem solving

We would like to congratulate the authors on the pragmatic nationwide approach that they have adopted in Denmark to address the key issues around incident reporting. Rabol and colleagues1 highlight again the challenges of collecting and meaningfully using such data.

Though experts in Denmark have drawn many of the same conclusions reached in our Delphi exercise,2 it is interesting that our findings differed on the usefulness of incident reports to detect rare events. The Danish Society concluded that rare events are difficult to detect due to deficiencies in data mining and that efforts are better spent solving known safety problems at a local level. Undoubtedly, the management of 'big data' is challenging, and one must consider carefully resource allocation at national and local levels. One of the initial 'burning platforms' driving the creation of the National Reporting and Learning System (NRLS) in England, however,...

http://ift.tt/2rvhGpw

Incident reporting must result in local action

It was with great interest that we read the study of Howell and colleagues.1

In 2003, Denmark was the first country in the world to adopt a law on patient safety that obligated hospital staff to report, the hospitals to react and the National Board of Health to communicate the learning from patient safety incidents. The national reporting system was made strictly confidential, with a clear division between disciplinary and learning functions. Local data are transmitted anonymously to the national level. In 2010 and 2011, the law was expanded to cover all of healthcare, including primary care, and allowing incident reporting from patients and families.

However, recently, the Danish incident reporting system has received criticism for being too bureaucratic, and with too little learning and too few actions resulting from the more than 180 000 annual reports. Reporting in itself is time-consuming (20–30 min per report) and analysis of...

http://ift.tt/2qx4oeZ

High Reliability and 'Cargo Cult QI: response to Sutcliffe et al. BMJ Qual Saf 2017;26:248-51

In their article regarding high-reliability organisations, Sutcliffe et al1 argue that healthcare's failure to understand the fundamental concepts that underlie high reliability has limited their impact on patient safety and healthcare quality. In considering their claims, an important issue arises that extends beyond the pursuit of high reliability: the failure within healthcare to develop a nuanced understanding of the theoretical basis for improvement methodologies. More specifically, the pressure to pursue quality improvement (QI) initiatives may presently exceed our expertise for achieving them successfully. This is an issue that, if not addressed, may compromise future attempts to improve the quality of healthcare.

The authors are not the first to suggest that efforts to import methods from other industries have failed due to a limited understanding of their fundamental mechanisms.2 Recognising that this is a recurrent concern provides an opportunity for reflection on how improvement efforts have evolved...

http://ift.tt/2rveeuO

Patient and family empowerment as agents of ambulatory care safety and quality

Introduction

Since publication of To Err is Human: Building a Safer Health System,1 consideration of medical errors and injuries has broadened beyond hospital-based harms to patient experiences of harm in primary care.23 The National Patient Safety Foundation (NPSF)4 has concluded that progress towards a healthcare culture of safety depends on the establishment of a systems approach that extends beyond hospitals to care settings in the community and patients' homes, herein referred to as ambulatory care settings. Included in NPSF's recommendations for such an approach is partnering with patients and families at all levels of care. Less well articulated is how this partnering may be achieved in the settings highlighted by NPSF.

The objectives of this viewpoint are twofold. The first is to hypothesise pathways through which an empowered patient–family partnership may effectively advance healthcare safety and quality in ambulatory...

http://ift.tt/2qx7SOk

Can we use patient-reported feedback to drive change? The challenges of using patient-reported feedback and how they might be addressed

Introduction

The resolve to put patients at the heart of the National Health Service (NHS) has been ubiquitous in the aftermath of the Francis Report, and the policy agenda is beginning to reflect attempts to deliver that promise. The introduction of new care models at NHS 'vanguard' sites, the 3-year target to give all patients access to their electronic care records, and the expansion of integrated care services all exemplify the salience of patient-centricity at the national level.1 This pattern has been witnessed across many developed health systems.2

The ideals of this paradigm have also captured the attention of local commissioners and providers, offering an evolved concept of service design that resonates with patients' needs. As a result, providers are increasingly turning to patient-reported feedback to drive local improvement. This trend is indicative of progress in the field of patient experience: policy discourse has...

http://ift.tt/2rvbZrs

Learning from near misses in aviation: so much more to it than you thought

Since its inception, the patient safety movement has been obsessed with reporting systems; roughly 20% of the To Err Is Human report1 dealt with some aspect of reporting; similarly, about 10% of the articles in BMJ Quality & Safety (and its predecessors) mention 'reporting' in their title, abstract or keywords. This interest sprang from an unholy trinity—an infortuitous combination of the epidemiological bent of many health professionals interested in safety, the epistemological blinders that a medical education produces2 and a kind of 'aviation envy'—a fascination with aviation safety as an exemplar which healthcare would do well to emulate.3 But, in an all-too-common pattern in patient safety, fundamental aspects of successful safety practices in other domains were misunderstood, misapplied, mistranslated or missed altogether as health professionals encountered work whose basic assumptions are far removed from the realism and positivism of biomedicine.2

http://ift.tt/2qxbzn4

Implementation and de-implementation: two sides of the same coin?

Avoiding low value care received increasing attention in many countries, as with the Choosing Wisely campaign and other initiatives to abandon care that wastes resources or delivers no benefit to patients. While an extensive literature characterises approaches to implementing evidence-based care, we have limited understanding of the process of de-implementation, such as abandoning existing low value practices. To learn more about the differences between implementation and de-implementation, we explored the literature and analysed data from two published studies (one implementation and one de-implementation) by the same orthopaedic surgeons. We defined 'leaders' as those orthopaedic surgeons who implemented, or de-implemented, the target processes of care and laggards as those who did not. Our findings suggest that leaders in implementation share some characteristics with leaders in de-implementation when comparing them with laggards, such as more open to new evidence, younger and less time in clinical practice. However, leaders in de-implementation and implementation differed in some other characteristics and were not the same persons. Thus, leading in implementation or de-implementation may depend to some degree on the type of intervention rather than entirely reflecting personal characteristics. De-implementation seemed to be hampered by motivational factors such as department priorities, and economic and political factors such as cost-benefit considerations in care delivery, whereas organisational factors were associated only with implementation. The only barrier or facilitator common to both implementation and de-implementation consisted of outcome expectancy (ie, the perceived net benefit to patients). Future studies need to test the hypotheses generated from this study and improve our understanding of differences between the processes of implementation and de-implementation in the people who are most likely to lead (or resist) these efforts.

http://ift.tt/2rvkgMh

A work observation study of nuclear medicine technologists: interruptions, resilience and implications for patient safety

Background

Errors by nuclear medicine technologists during the preparation of radiopharmaceuticals or at other times can cause patient harm and may reflect the impact of interruptions, busy work environments and deficient systems or processes. We aimed to: (a) characterise the rate and nature of interruptions technologists experience and (b) identify strategies that support safety.

Methods

We performed 100 hours of observation of 11 technologists at a major public hospital and measured the proportions of time spent in eight categories of work tasks, location of task, interruption rate and type and multitasking (tasks conducted in parallel). We catalogued specific safety-oriented strategies used by technologists.

Results

Technologists completed 5227 tasks and experienced 569 interruptions (mean, 4.5 times per hour; 95% CI 4.1 to 4.9). The highest interruption rate occurred when technologists were in transit between rooms (10.3 per hour (95% CI 8.3 to 12.5)). Interruptions during radiopharmaceutical preparation occurred a mean of 4.4 times per hour (95% CI 3.3 to 5.6). Most (n=426) tasks were interrupted once only and all tasks were resumed after interruption. Multitasking occurred 16.6% of the time. At least some interruptions were initiated by other technologists to convey important information and/or to render assistance. Technologists employed a variety of verbal and non-verbal strategies in all work areas (notably in the hot-lab) to minimise the impact of interruptions and optimise the safe conduct of procedures. Although most were due to individual choices, some strategies reflected overt or subliminal departmental policy.

Conclusions

Some interruptions appear beneficial. Technologists' self-initiated strategies to support safe work practices appear to be an important element in supporting a resilient work environment in nuclear medicine.

http://ift.tt/2qx30ZG

Implementation of a structured hospital-wide morbidity and mortality rounds model

Importance

There is a paucity of literature on the quality and effectiveness of institutional morbidity & mortality (M&M) rounds processes.

Objective

We sought to implement and evaluate the effectiveness of a hospital-wide structured M&M rounds model at improving the quality of M&M rounds across multiple specialties.

Design, setting, participants

We conducted a prospective interventional study involving 24 clinical groups (1584 physicians) at a tertiary care teaching hospital from January 2013 to June 2015.

Intervention

We implemented the published Ottowa M&M Model (OM3): appropriate case selection, cognitive/system issues analyses, interprofessional participation, dissemination of lessons and effector mechanisms.

Main outcomes and measures

We created an OM3 scoring index reflecting these elements to measure the quality of M&M rounds. Secondary outcomes include explicit discussions of cognitive/system issues and resultant action items.

Results

OM3 scores for all participating groups improved significantly from a median of 12.0/24 (95% CI 10 to 14) to 20.0/24 (95% CI 18 to 21). An increased frequency of in-rounds discussion around cognitive biases (pre 154/417 (37%), post 256/466 (55%); p<0.05) and system issues (pre 175/417 (42%), post 259/466 (62%); p<0.05) were reported by participants via online surveys postintervention, while in-person surveys throughout the intervention period demonstrated even higher frequencies (cognitive biases 1222/1437 (85%); system issues 1250/1437 (87%)). We found 45 action items resulting directly from M&M rounds postintervention, compared with none preintervention.

Conclusions and relevance

Implementation of a structured model enhanced the quality of M&M rounds with demonstrable policy improvements hospital wide. The OM3 can be feasibly implemented at other hospitals to effectively improve quality of M&M rounds across different specialties.

http://ift.tt/2rvlJlC