No Pharmacokinetic Interaction Between the Hepatitis C Virus Inhibitors Elbasvir/Grazoprevir and Famotidine or Pantoprazole

Use of agents to suppress gastric acid secretion is common among patients with hepatitis C virus (HCV) infection. The aims of this open-label, three-period, fixed-sequence study were to evaluate the effect of famotidine and pantoprazole on the pharmacokinetics and safety of elbasvir/grazoprevir fixed-dose combination (FDC) in 16 healthy subjects. Elbasvir and grazoprevir each exhibited similar pharmacokinetics following single-dose administration of elbasvir/grazoprevir with or without famotidine or pantoprazole. Geometric mean ratios (GMRs) of grazoprevir AUC(0,∞), C_max, and C₂₄ (elbasvir/grazoprevir + famotidine or elbasvir/grazoprevir + pantoprazole vs. elbasvir/grazoprevir) ranged from 0.89–1.17. Similarly, GMRs of elbasvir AUC(0,∞), C_max, and C₂₄ (elbasvir/grazoprevir + famotidine or elbasvir/grazoprevir + pantoprazole vs. elbasvir/grazoprevir) ranged from 1.02–1.11. These results indicate that gastric acid-reducing agents do not modify the pharmacokinetics of elbasvir or grazoprevir in a clinically relevant manner and may be coadministered with elbasvir/grazoprevir in HCV-infected patients without restriction.

http://ift.tt/2tfEkUy

Cancer Diagnostic and Predictive Biomarkers 2016

http://ift.tt/2snXSpP

Sex and genetic background influence Superoxide dismutase (cSOD) related phenotypic variation in Drosophila melanogaster

Mutations often have drastically different effects in different genetic backgrounds; understanding a gene's biological function then requires an understanding of its interaction with genetic diversity. The antioxidant enzyme cytosolic superoxide dismutase, cSOD, catalyzes the dismutation of the superoxide radical, a molecule that can induce oxidative stress if its concentration exceeds cellular control. Accordingly, Drosophila melanogaster lacking functional cSOD exhibit a suite of phenotypes including decreased longevity, hypersensitivity to oxidative stress, impaired locomotion, and reduced NADP(H) enzyme activity in males. To date, cSOD-null phenotypes have primarily been characterized using males carrying one allele, cSodⁿ¹⁰⁸red, in a single genetic background. We used analysis of variance, and the effect size partial eta squared, to partition the amount of variation attributable to cSOD activity, sex, and genetic background across a series of life history, locomotor, and biochemical phenotypes associated with the cSOD-null condition. Overall, the results demonstrate that the cSOD-null syndrome is largely consistent across sex and genetic background, but also significantly influenced by both. The sex-specific effects are particularly striking and our results support the idea that phenotypes cannot be considered fully defined if they are examined in limited genetic contexts.

http://ift.tt/2rDM9WW

How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms?

Abstract

Cytomegalovirus (CMV) is an important pathogen for both clinical and population settings. There is a growing body of research implicating CMV in multiple health outcomes across the life course. At the same time, there is mounting evidence that individuals living in poverty are more likely to be exposed to CMV and more likely to experience many of the chronic conditions for which CMV has been implicated. Further research on the causal role of CMV for health and well-being is needed. However, the strong evidence implicating CMV in type 2 diabetes, autoimmunity, cancer, cardiovascular disease, vaccination, and age-related alterations in immune function warrants clinical and public health action. This imperative is even higher among individuals living in socioeconomically disadvantaged settings and those exposed to high levels of chronic psychosocial stress.

http://ift.tt/2tAbVYp

Lung Adenocarcinoma Survival in EGFR-Mutated African-Caribbean Patients: A Multicenter Study in the French West Indies

Abstract

Background

Lung cancer is the leading cause of cancer-related death worldwide. Shorter survival has been repeatedly reported for patients of African ancestry. Multivariate analysis demonstrated that this gap could be a consequence of socio-economic disparities instead of genetic specificities. However, those results were obtained in a pre-targeted therapies era and the effect of tyrosine kinase inhibitors targeting EGFR are not known in this population.

Objective

In this French West Indies study, we report overall survival (OS) in a frequently mutated population treated for lung adenocarcinoma within an equal-access healthcare system.

Patients and Methods

Clinical, demographic, survival, and treatment data have been retrospectively assessed for all patients diagnosed with lung adenocarcinoma in the islands of Martinique and Guadeloupe between 2013 and 2015.

Results

Two hundred and forty-one patients (82% African-Caribbean) were included. EGFR mutations were detected in 37% of all tumor specimens and were associated with non-smoker status in multivariate analysis. Median OS was 16.2 months. For patients with advanced disease, median OS was 11.5 months, depending on EGFR mutation (23 vs. 8.3 months for non-mutated patients, p = 0.0012). There was no difference in survival according to ethnicity or island. In multivariate analysis, performance status (PS) and EGFR mutation were the only independent prognostic factors.

Conclusions

Despite a higher frequency of EGFR mutations in African-Caribbean patients, ethnicity was not an independent factor of OS in lung adenocarcinoma. Lower initial PS in this mainly non-smoking African-Caribbean population may explain the absence of a difference in OS.

http://ift.tt/2sFBVp6

Targeting the PD-1/PD-L1 Immune Checkpoint in EGFR- Mutated or ALK- Translocated Non-Small-Cell Lung Cancer

Abstract

Immune checkpoint inhibitors, notably antibodies targeting programmed death–1 (PD-1) and programmed death ligand–1 (PD-L1), have modified the management of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). Several PD-1/PD-L1 inhibitors have been approved by health authorities for this indication and others are in clinical development. However, only a subset of patients truly benefits from these agents. For patients with mutated EGFR or translocated ALK NSCLC, for whom an immune checkpoint inhibitor can be prescribed after progression on tyrosine kinase inhibitors and chemotherapy, information is scarce and sometimes contradictory. Phase III randomized clinical trials have evaluated different immune checkpoint inhibitors (nivolumab, pembrolizumab, atezolizumab) vs. chemotherapy as second- or subsequent-line therapy in NSCLC, but included very few patients with EGFR/ALK-positive disease. Subgroup analyses found that these patients did not benefit from immune checkpoint inhibitors. Retrospective data show progression-free survival lasting only 1.2–2.1 months. Preclinical data suggested a lower expression of PD-L1 in EGFR/ALK-positive patients compared to EGFR/ALK-negative patients. Our objective herein is to provide an up-to-date review of available data from the various publications on the impact of immune checkpoint inhibitors in patients with EGFR/ALK-positive NSCLC.

http://ift.tt/2sFBr2f

LY294002, a PI3K inhibitor, attenuates Tourette syndrome in rats

Abstract

The present study was designed to investigate the effects of LY294002 on Tourette syndrome (TS) in rats. TS model was induced in rats by DOI (the selective 5-HT2A/2C agonist 1- (2, 5- dimethoxy −4 - iodophenyl) -2- aminopropane). Behavior was assessed by stereotypic score and autonomic activity. Inflammatory cytokines such as interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in serum and striatum were detected. The protein levels of PI3K/Akt/NF-B in striatum were detected by Western Blot. LY294002 treatment significantly reduced IL-6, IL-1β and TNF-α in serum and striatum of TS rats, Also, highly expressed P-PI3K, P-Akt, P-NF-κBp65, P-IκBα in TS rats were restored respectively by LY294002 treatment as indicted in western blot analysis and immunohistochemistry analysis. Thus, it was supposed that the protective effect of LY294002 against TS in rat might be associated with the regulation of PI3K/Akt/NF-B pathway.

http://ift.tt/2sFqqOd

Vitrification of bovine ovarian tissue: effect of perforated antral follicles on the structural preservation of follicles

Abstract

Despite all scientific studies, researches are continuing to increase outcomes of freezing ovarian tissue. The objective was to evaluate whether follicular perforation could improve the survival of antral follicles after vitrification. The present study was conducted on 20 bovine ovaries collected at slaughterhouse and a total of 344 antral follicles (less than 4 mm in diameter). For each ovary, three slices (approximately 1 × 1 cm) were separated from the cortex of each ovary and randomly were assigned in three groups, control (without freezing, fixed in 10% buffered formalin), non­perforated vitrified and perforated vitrified (after exposure to equilibration solution, antral follicles were immediately perforated) groups. After thawing, the tissue slices were evaluated histopathologically. Our histological evaluation showed that vitrification in group V1 did not significantly influence the degree of follicle damage compared to the follicles in fresh group as 69.8% of vitrified follicles were appeared as normal. Increasing follicular size had a significant effect on the vulnerability of follicles using different methods (p < 0.05). Therefore, perforation of follicles of bovine ovarian cortical tissue did not improve freezability of antral follicles by vitrification.

http://ift.tt/2snrSSp

Use of the Furosemide Fludrocortisone Test to Clinically Assess Distal Tubular Acidification

Urine acidification is the net effect of bicarbonate reabsorption, H+ secretion, and the presence of buffers. In distal renal tubular acidosis (dRTA), there is a defect in H+ secretion in the collecting duct. dRTA is traditionally diagnosed by an oral ammonium chloride (NH4Cl) loading test. Patients with dRTA are unable to adequately acidify urine after an acid load with NH4Cl.1 However, this test often leads to nausea and vomiting, resulting in early termination of the test and inconclusive results.

http://ift.tt/2sKXKDi

Spatiotemporal propagation patterns of generalized ictal spikes in childhood absence epilepsy

Childhood absence epilepsy (CAE) is the prototype syndrome of genetic (idiopathic) generalized epilepsy (GGE/IGE) characterized by typical absence seizures (TAS) (Gibbs et al., 1935; Penfield and Jasper, 1954; ILAE 1989; Berg et al., 2010). TAS manifest as brief impairment of consciousness of sudden onset and offset, without aura or post-ictal symptoms (Panayiotopoulos et al., 1989), frequently accompanied by spontaneous eye-opening, staring, random eye-blinking and automatisms (Hirsch and Marescaux, 1994; Panayiotopoulos, 1997).

http://ift.tt/2sFdet0

TMS-evoked long-lasting artefacts: a new adaptive algorithm for EEG signal correction

In the last twenty years, the combination of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) has provided new insights into the investigation of brain dynamics (Ilmoniemi and Kičić, 2010). However, besides the potential of combining these two techniques, their simultaneous use produces different EEG artefacts of electrical and physiological nature. Electrical artefacts result from the voltage induced in the electrodes by the TMS pulse, which is several orders of magnitude larger than the physiological responses (Virtanen et al., 1999).

http://ift.tt/2tfjowM

An enhanced vector-free allele exchange (VFAE) mutagenesis protocol for genome editing in a wide range of bacterial species

Vector-free allele exchange (VFAE) is a newly developed protocol for genome editing in Pseudomonas species. Although several parameters have been determined to optimize the procedures for obtaining a stable and h...

http://ift.tt/2sFkjcJ

H2O2 as a candidate bottleneck for MnP activity during cultivation of Agaricus bisporus in compost

Degradation of lignin by fungi enhances availability of cellulose and hemicellulose in plant waste and thereby increases the amount of carbon source available to these microorganisms. The button mushroom Agaricus...

http://ift.tt/2tf7rHh

Refining Patient Selection for Re-Irradiation of Head and Neck Squamous Carcinoma in the IMRT Era: a Multi-Institution Cohort Study by the MIRI Collaborative

Patients with recurrent or second-primary squamous carcinoma of the head and neck have many treatment options in the modern era. Although modern IMRT-based re-irradiation may confer better outcomes than conventional data may suggest, treatment selection remains challenging. This multi-institution study is the largest analysis of squamous carcinoma to-date and informs treatment selection in the modern era including the identification of distinct prognostic subgroups via a recursive partitioning analysis (RPA).

http://ift.tt/2tAbM7n

Diagnosis of Autoimmune Pancreatitis: The Evolution of Diagnostic Criteria for a Rare Disease

http://ift.tt/2sneDBr

Outcomes and role of urgent endoscopy in high-risk patients with acute nonvariceal gastrointestinal bleeding

We investigated clinical outcomes in high-risk patients with acute nonvariceal upper gastrointestinal bleeding (UGIB), and determined if urgent endoscopy is effective.

http://ift.tt/2rD8wvD

Acute Severe Gastrointestinal Tract Bleeding is Associated with an Increased Risk of Thromboembolism and Death

We performed a retrospective cohort study of patients with and without gastrointestinal bleeding (GIB) to determine whether GIB increases the risks of thromboembolism and death.

http://ift.tt/2sn8jK4

Tongxie Formula Reduces Symptoms of Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is the most common chronic gastrointestinal disorder, yet few drugs are effective in reducing symptoms. Approximately 50% of patients with IBS attempt herbal therapy at least once. We performed a randomized controlled trial to compare the efficacy of the herb formulation tongxie vs placebo or pinaverium (an antispasmodic agent) in reducing symptoms of IBS.

http://ift.tt/2rDtFpp

A terminal rectal mass ultimately identified by histopathology examination

http://ift.tt/2sn8jty

Cost-Effectiveness of Pre versus Post Liver Transplant Hepatitis C Treatment with Direct-Acting Antivirals

Oral direct-acting antivirals (DAAs) for hepatitis C virus (HCV) treatment offer new hope to both pre- and post-liver transplant (LT) patients. However, whether to treat HCV patients pre- versus post-LT is not clear, as treatment can improve liver function but could reduce the chance of receiving a LT while on the waiting list. Our objective was to evaluate the cost-effectiveness of pre-LT versus post-LT HCV treatment with oral DAAs in decompensated cirrhotic patients on the LT waiting list.

http://ift.tt/2rDerRu

Comparison of Patterns and Outcomes of Liver Resection for Hepatocellular Carcinoma: East versus West

http://ift.tt/2sni5f7

Preoperative Predictors of Extraprostatic Extension of Prostate Cancer (pT3a) in a Contemporary Indian Cohort

Abstract

We present our experience with robotic radical prostatectomy and analyse the predictors for extracapsular extension (EPE) in a cohort of Indian patients. Four hundred fifty-three patients underwent robotic radical prostatectomy from May 2010 to October 2015. Post hoc analysis of prospectively maintained data was done. Multivariable regression analysis was used on variables which had significant association with EPE on univariable analysis. Receiver operating characteristic (ROC) curves were plotted for the independent predictors of EPE. Mean age was 64.62 ± 6.44 years. Mean BMI 26.03 ± 4.01 kg/m². Median prostate-specific antigen (PSA) was 13.38 ng/ml (IQR 8.1–23.5). Seventy-seven (16.99%) patients had Gleason >7. Mean core positivity (percentage of cores positive) was 48,93 ± 27.29% and mean maximum percentage of tumour in a core was 33,04 ± 31.16%. Positive surgical margins were present in 141/453 (31.15%). Lymph nodes were positive in 21.2% of those who had nodes removed (77/364). Maximum cancer in a core (p < 0.001), core positivity (p = 0.002) and Gleason score ≥4 + 3 (p = 0.028) were significant predictors of EPE, independent of BMI, PSA, PNI and clinical stage. Receiver operating characteristic (ROC) analysis for core positivity showed an area under the curve (AUC) of 0.775, and a 76% core positivity predicted EPE with a sensitivity of 65% and a specificity of 87.1%, respectively. ROC curve for maximum cancer in a core showed an area under the curve of 0.898. Seventy per cent cancer in a single core predicted EPE with a sensitivity of 80.6% and a specificity of 85.9% Indian patients present with more advanced disease, higher PSA and have higher incidence of EPE. Maximum cancer in a core, ratio of positive cores and Gleason score ≥4 + 3 are predictors of EPE independent of PSA and clinical stage.

http://ift.tt/2teTsS8

Identification of Sentinel Lymph Nodes Using Contrast-Enhanced Ultrasound in Breast Cancer

Abstract

Sentinel lymph node (SLN) biopsy has become the standard of care in axillary staging of breast cancer patients who are clinically node negative as it reduces the morbidity of axillary nodal dissection. SLN biopsy using blue dye and radioisotopes have high identification rates but its limitations include anaphylaxis, disposal of radioactive waste, and potential second surgery in up to 35% of patients who show nodal metastases on SLN biopsy. Contrast-enhanced ultrasound (CEUS) has the potential for SLNs to be identified without the aforementioned risks. CEUS involves the administration of intravenous contrast agents containing microbubbles of perfluorocarbon or nitrogen gas. The bubbles greatly affect ultrasound backscatter and increase vascular contrast in a similar manner to intravenous contrast agents used in CT and MRI. It is safe and easily performed with no requirement for ionizing radiation and no risk of nephrotoxicity. Microbubbles are taken up by lymph nodes when injected directly into tissues, including sub-areolar injection in the breast cancer patient. This method may prove valuable in patients with ductal carcinoma in situ, where operative SLN biopsy remains controversial, and in women undergoing prophylactic mastectomies for high risk. This technique may also have a role after neoadjuvant chemotherapy where frequently there is fibrosis in the treated SLNs.

http://ift.tt/2sF9Pdu

The Origin of Novelty Through the Evolution of Scaling Relationships

Abstract

Morphological novelty is often thought of as the evolution of an entirely new body plan or the addition of new structures to existing body plans. However, novel morphologies may also arise through modification of organ systems within an existing body plan. The evolution of novel scaling relationships between body size and organ size constitutes such a novel morphological feature. Experimental studies have demonstrated that there is genetic variation for allometries and that scaling relationships can evolve under artificial selection. We show that an allometry equation derived from Gompertz growth kinetics can accurately reconstruct complex non-linear allometries, and can be used to deduce the growth kinetics of the parts being compared. The equation also shows the relationship between ontogenetic and static allometries. We discuss how changes in the non-linear kinetics of growth can give rise to novel allometric relationships. Using parameters for wing and body growth of Manduca sexta, and a population simulation of the allometry equation, we show that selection on wing-body scaling can dramatically alter wing size without changing body size.

http://ift.tt/2rCZv5S

Aggressive natural killer cell leukemia or extranodal NK/T cell lymphoma? a case with nasal involvement

Aggressive natural killer cell leukemia/lymphoma (ANKL) is a rare and highly aggressive NK cell neoplasm with a short clinical course and poor prognosis and is often misdiagnosed and confused with NK/T cell ly...

http://ift.tt/2sKAAgr

Programmed death-ligand 1 (PD-L1) is expressed in a significant number of the uterine cervical carcinomas

The programmed death-1/programmed death-ligand-1 (PD-1/PD-L1) immune regulatory axis has emerged as a promising new target for cancer therapeutics, with lasting responses seen in the treatment of metastatic re...

http://ift.tt/2rrDq5M

Chromatin Immunoprecipitation (ChIP) in Mouse T-cell Lines

This work describes a protocol for chromatin immunoprecipitation (ChIP) using a mature mouse T-cell line. This protocol is suitable to investigate the distribution of specific histone marks at specific promoter sites or genome-wide.

http://ift.tt/2scTz1T

A new global and comprehensive model for ICU ventilator performances evaluation

This study aimed to provide a new global and comprehensive evaluation of recent ICU ventilators taking into account both technical performances and ergonomics.

http://ift.tt/2sK9Zjg

Fabrication of 3D Carbon Microelectromechanical Systems (C-MEMS)

Long and hollow glassy carbon microfibers were fabricated based on the pyrolysis of a natural product, human hair. The two fabrication steps of carbon microelectromechanical and carbon nanoelectromechanical systems, or C-MEMS and C-NEMS, are: (i) photolithography of a carbon-rich polymer precursor and (ii) pyrolysis of the patterned polymer precursor.

http://ift.tt/2sErRwG

Cytomegalovirus (CMV) research in immune senescence comes of age: overview of the 6th International Workshop on CMV and Immunosenescence

Abstract

Cytomegalovirus (CMV) is one of the most complex and most ubiquitous latent persistent viruses, with a considerable ability to evade and manipulate the immune system. Following an early-life infection, most immunocompetent humans spend several decades living with CMV, and, because the virus in these hosts does not cause manifest disease, CMV can be considered part of normal aging for more than half of humanity. However, there is accumulating evidence that CMV carriage is not a null event and that both potentially harmful and potentially beneficial outcomes emanate from the interaction of CMV with its mammalian hosts. This article provides an overview of the 6th International Workshop on CMV and Immunosenescence, highlighting the advances in the field made in the past two years, as related to CMV epidemiology/geroscience, CMV virology with an accent on latency, and CMV immune evasion and immune recognition of the virus and its antigens.

http://ift.tt/2tyE820

Cardiovascular implantable electronic devices: a review of the dangers and difficulties in MR scanning and attempts to improve safety

Abstract

An increasing number of patients are being treated with cardiovascular implantable electronic devices (CIEDs), many of which are MR conditional. There is a lack of literature on the safe scanning of MR conditional CIEDs. This review article discusses MR imaging safety in patients with implanted CIEDs. Guidelines on safe use and indications of imaging patients with MR conditional CIEDs are described, followed by a pictorial essay of the radiographic features of these devices. We also discuss the challenges of monitoring the patient in the MR environment, advances in MRI conditional imaging of devices, availability, limitations and workflow including vendor-specific and other collaborative efforts to simplify the scanning process. Radiologists must be able to facilitate the safe utilization of MR imaging in patients who have CIEDs. A thorough knowledge of the hazards of imaging non-MR compatible devices is required as well as knowing how to correctly identify and manage the imaging of patients with MR conditional CIEDs. Finally, we propose steps required to facilitate the safe scanning of patients with MR conditional CIEDs adopted in our institution and a contingency plan in the event that an inadvertent MR scan of a patient with a MRI unsafe CIED should occur.

Main Messages

• Risks of MR imaging in patients who have CIEDs have been worked around.

• There are many technical limitations in enabling safe MR scanning of CIEDs.

• Radiological identification of MRI-conditional status of CIEDs is useful.

• Standardizing conditions for safe MRI scanning is important.

• We offer example algorithms for facilitating safe MRI scanning of CIEDs.

http://ift.tt/2rqTHYL

Martini Coarse-Grained Force Field: Extension to RNA

RNA has an important role not only as the messenger of genetic information but also as a regulator of gene expression. Given its central role in cell biology, there is significant interest in studying the structural and dynamic behavior of RNA in relation to other biomolecules. Coarse-grain molecular dynamics simulations are a key tool to that end. Here, we have extended the coarse-grain Martini force field to include RNA after our recent extension to DNA. In the same way DNA was modeled, the tertiary structure of RNA is constrained using an elastic network.

http://ift.tt/2sAYkmz

Effects of herbal medicine for dysmenorrhea treatment on accompanied acne vulgaris: a study protocol for a randomized controlled trial

The incidence of preadolescent acne among women is increasing. Acne deteriorates the quality of life; conventional treatment options are limited and have not been effective against acne, particularly acne asso...

http://ift.tt/2sE1lmQ

Caffeoylquinic acid derivatives rich extract from Gnaphalium pensylvanicum willd. Ameliorates hyperuricemia and acute gouty arthritis in animal model

The Gnaphalium pensylvanicum willd. is used in China as a folk medicine to treat anti-inflammatory, cough and rheumatism arthritis. The aim of this study was to evaluate the potential of the extract of G. pensylv...

http://ift.tt/2tdNjpb

Effects of Karela (Bitter Melon; Momordica charantia) on genes of lipids and carbohydrates metabolism in experimental hypercholesterolemia: biochemical, molecular and histopathological study

Hypercholesterolemia is a serious diseases associated with type-2 diabetes, atherosclerosis, cardiovascular disorders and liver diseases. Humans seek for safe herbal medication such as karela (Momordica charan...

http://ift.tt/2sEfbFY

Martini Coarse-Grained Force Field: Extension to RNA

RNA has an important role not only as the messenger of genetic information but also as a regulator of gene expression. Given its central role in cell biology, there is significant interest in studying the structural and dynamic behavior of RNA in relation to other biomolecules. Coarse-grain molecular dynamics simulations are a key tool to that end. Here, we have extended the coarse-grain Martini force field to include RNA after our recent extension to DNA. In the same way DNA was modeled, the tertiary structure of RNA is constrained using an elastic network.

http://ift.tt/2sAYkmz

Peripheral venous catheter-related bloodstream infection is associated with severe complications and potential death: a retrospective observational study

The purpose of this study was to identify the clinical characteristics and outcomes of peripheral vascular catheter-related bloodstream infections (PVC-BSIs) and determine the risk of severe complications or d...

http://ift.tt/2rCgx3R

A systematic review and narrative synthesis of group self-management interventions for adults with epilepsy

Epilepsy is a serious and costly long-term condition that negatively affects quality of life, especially if seizures persist on medication. Studies show that people with epilepsy (PWE) want to learn more about...

http://ift.tt/2td6ejR

Improving transitions in acute stroke patients discharged to home: the Michigan stroke transitions trial (MISTT) protocol

For some stroke patients and caregivers, navigating the transition between hospital discharge and returning home is associated with substantial psychosocial and health-related challenges. Currently, no evidenc...

http://ift.tt/2sDFonW

Matched-pair analysis of patients with advanced hypopharyngeal cancer: surgery versus concomitant chemoradiotherapy

Abstract

Background

The aim of this study was to compare the therapeutic outcomes of total pharyngolaryngectomy with those of concomitant chemoradiotherapy in advanced hypopharyngeal cancer.

Methods

This is a retrospective multi-institutional study. The medical records of 979 patients with hypopharyngeal cancer, who were initially treated between 2006 and 2008, were reviewed. In this study, we matched a group of total pharyngolaryngectomy patients with a second group of chemoradiotherapy patients, according to age, gender, subsite, arytenoid fixation, cartilage invasion, and N classification, and analyzed overall survival, disease-specific survival, and locoregional control rates.

Results

The matched-pair analysis included 254 patients. The 5-year overall survival, disease-specific survival, and locoregional control rates were 58.5% and 53.5% (P = 0.30), 68.9% and 68.0% (P = 0.80), and 82.2% and 63.6% (P < 0.01), respectively, for patients in the total pharyngolaryngectomy and chemoradiotherapy groups. For T4a patients with cartilage invasion, the matched-pair analysis included 46 patients. The 5-year overall survival, disease-specific, and locoregional control rates were 56.5% and 26.0% (P = 0.092), 56.5% and 41.3% (P = 0.629), and 43.0% and 42.5% (P = 0.779), respectively, for patients in the total pharyngolaryngectomy and chemoradiotherapy groups.

Conclusions

The data from this large-scale multi-institutional joint research program of hypopharyngeal cancer in Japan suggest that chemoradiotherapy may provide adequate survival benefit for hypopharyngeal cancer patients with the distinct advantage of larynx preservation. Our data also suggest that chemoradiotherapy is as beneficial as total pharyngolaryngectomy for the local control of locally advanced hypopharyngeal cancer.

http://ift.tt/2rBVXRc

Clindamycin Injection ADD-Vantage Vials by Alvogen: Recall - Lack of Sterility Assurance

[Posted 06/16/2017] AUDIENCE: Pharmacy, Health Professional, Infectious Disease ISSUE: Alvogen is voluntarily recalling seven lots of Clindamycin Injection USP ADD-Vantage Vials to the hospital/retail level due to microbial growth detected during a...

http://ift.tt/2sbZ0hv

miR-337 can be a key negative regulator in melanoma

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http://ift.tt/2rC29bM

The screening of the functional microRNA binding site SNPs in sporadic colorectal cancer genes

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http://ift.tt/2smagq3

Current status of research and treatment for non-small cell lung cancer in never-smoking females

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http://ift.tt/2rBhBFn

Factors influencing psychological, social and health outcomes after major burn injuries in adults: cohort study protocol

Introduction

The goal of burn care is that 'the quality of the outcome must be worth the pain of survival'. More research is needed to understand how best to deliver care for patients with burns to achieve this aim. Loss of independence, function as well as loss of income for patients with burns and carers cause a significant burden at both individual and societal levels. Much is being done to advance knowledge in the clinical care field; however, there has been a paucity of research exploring psychosocial outcomes. This paper describes the study background and methods, as implemented in an Australian cohort study of psychosocial outcomes after major burn injuries.

Methods and analysis

In this inception cohort study, a target sample of 230 participants, aged 18 years or over, admitted to a single statewide burns centre with a burn injury are identified by hospital staff for inclusion. Baseline survey data are collected either in person or by telephone within 28 days of the injury and participants then followed up with telephone interviews at 3, 6 and 12 months postburn. Injury and burns treatment information is collected from medical records. Social support is measured as a predictor variable using the Multidimensional Scale of Perceived Social Support. Outcome data are collected via standardised measures in the domains of Quality of Life (SF-12, EQ-5D, BSHS-B), depression (PHQ-9), post-traumatic stress disorder (PCL-C, PAS), community integration (CIQ-R) and Quality-Adjusted Life Years (EQ-5D). Additional survey questions measure life satisfaction, return to work and public services utilisation at 12 months postinjury. Data analysis methods will include analysis of variance, Pearson correlation and hierarchical multiple regression analyses.

Ethics and dissemination

Hospital-based and University of Queensland Human Research Ethics Committees have approved the protocol. Results from the study will be disseminated at national and international conferences, in peer-reviewed journals and in a doctoral thesis.

Trial registration number

Australia New Zealand Clinical Trials Registry (ACTRN12616000828426). Retrospectively registered on 23 June 2016; pre-results.

http://ift.tt/2sDvxhW

GPs' attitudes, beliefs and behaviours regarding exercise for chronic knee pain: a questionnaire survey

Objectives

The aim of this study was to investigate general practitioners' (GPs) attitudes, beliefs and behaviours regarding the use of exercise for patients with chronic knee pain (CKP) attributable to osteoarthritis.

Setting

Primary care GPs in the UK.

Participants

5000 GPs, randomly selected from Binley's database, were mailed a cross-sectional questionnaire survey.

Outcome measures

GPs' attitudes and beliefs were investigated using attitude statements, and reported behaviours were identified using vignette-based questions. GPs were invited to report barriers experienced when initiating exercise with patients with CKP

Results

835 (17%) GPs responded. Overall, GPs were positive about general exercise for CKP. 729 (87%) reported using exercise, of which, 538 (74%) reported that they would use both general and local (lower limb) exercises. However, only 92 (11% of all responding) GPs reported initiating exercise in ways aligning with best-evidence recommendations. 815 (98%) GPs reported barriers in using exercise for patients with CKP, most commonly, insufficient time in consultations (n=419; 51%) and insufficient expertise (n=337; 41%).

Conclusions

While GPs' attitudes and beliefs regarding exercise for CKP were generally positive, initiation of exercise was often poorly aligned with current recommendations, and barriers and uncertainties were reported. GPs' use of exercise may be improved by addressing the key barriers of time and expertise, by developing a pragmatic approach that supports GPs to initiate individualised exercise, and/or by other professionals taking on this role.

http://ift.tt/2sDL4yu

Implementation of a disability management policy in a large healthcare employer: a quasi-experimental, mixed-methods evaluation

Objective

This study describes the process and outcomes of the implementation of a strengthened disability management policy in a large Canadian healthcare employer. Key elements of the strengthened policy included an emphasis on early contact, the training of supervisors and the integration of union representatives in return-to-work (RTW) planning.

Design

The study applied mixed methods, combining a process evaluation within the employer and a quasi-experimental outcome evaluation between employers for a 3-year period prior to and following policy implementation in January 2012.

Participants

Staff in the implementation organisation (n=4000) and staff in a peer group of 29 large hospitals (n=1 19 000).

Outcomes

Work disability episode incidence and duration.

Results

Both qualitative and quantitative measures of the implementation process were predominantly positive. Over the 6-year observation period, there were 624 work disability episodes in the organisation and 8604 in the comparison group of 29 large hospitals. The annual per cent change in episode incidence in the organisation was –5.6 (95% CI –9.9 to –1.1) comparable to the annual per cent change in the comparison group: –6.2 (-7.2 to –5.3). Disability episode durations also declined in the organisation, from a mean of 19.4 days (16.5, 22.3) in the preintervention period to 10.9 days (8.7, 13.2) in the postintervention period. Reductions in disability durations were also observed in the comparison group: from a mean of 13.5 days (12.9, 14.1) in the 2009–2011 period to 10.5 days (9.9, 11.1) in the 2012–2014 period.

Conclusion

The incidence of work disability episodes and the durations of work disability declined strongly in this hospital sector over the 6-year observation period. The implementation of the organisation's RTW policy was associated with larger reductions in disability durations than observed in the comparison group.

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How do smoking cessation medicines compare with respect to their neuropsychiatric safety? A protocol for a systematic review, network meta-analysis and cost-effectiveness analysis

Introduction

Cigarette smoking is one of the leading causes of early death in the UK and worldwide. Public health guidance recommends the use of varenicline, bupropion and nicotine replacement therapy (NRT) as smoking cessation aids in the UK. Additionally, the first electronic cigarette has been licensed for use as a smoking cessation medicine. However, there are ongoing concerns about the safety of these medicines. We present a protocol for a systematic review and network meta-analysis (NMA) to determine how these smoking cessation medicines compare to each other with respect to their neuropsychiatric safety in adult smokers. Secondary aims include updating the evidence regarding the effectiveness and cardiovascular safety of these medicines for use in a cost-effectiveness analysis.

Methods and analysis

We will include randomised controlled trials and observational studies with control groups comparing monotherapy with varenicline, bupropion, NRT or electronic cigarette and combination therapies to each other, placebo or usual care. The primary composite safety outcome will be serious adverse events, defined as events that resulted in death, were life threatening, required hospitalisation or resulted in significant disability or congenital/birth defect. The preferred effectiveness outcome will be sustained smoking cessation defined as abstinence for a minimum of 6 months as determined by biochemical validation. We will include trials identified by previous reviews and search relevant databases for newly published trials as well as contacting study authors to identify unpublished information. We will conduct fixed-effect and random-effect meta-analyses for each pairwise comparison of treatments and outcome; where these estimates differ, we will consider reasons for heterogeneity, quantified using the between-study variance (²). For each outcome, we will construct a NMA in a Bayesian framework which will be compared with the pair-wise results, allowing us to rank treatments. The effectiveness estimates from the NMA will be entered into a probabilistic economic model.

Ethics and dissemination

Ethics approval is not required for this evidence synthesis study as it involves analysis of secondary data from randomised controlled trials and observational studies. The review will make an important contribution to the knowledge base around the effectiveness, safety and cost-effectiveness of smoking cessation medicines. Results will be disseminated to the general public, healthcare practitioners and clinicians, academics, industry and policy makers.

PROSPERO registration number

CRD42016041302.

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Age at menarche and lung function: a Mendelian randomization study

Abstract

A trend towards earlier menarche in women has been associated with childhood factors (e.g. obesity) and hypothesised environmental exposures (e.g. endocrine disruptors present in household products). Observational evidence has shown detrimental effects of early menarche on various health outcomes including adult lung function, but these might represent spurious associations due to confounding. To address this we used Mendelian randomization where genetic variants are used as proxies for age at menarche, since genetic associations are not affected by classical confounding. We estimated the effects of age at menarche on forced vital capacity (FVC), a proxy for restrictive lung impairment, and ratio of forced expiratory volume in one second to FVC (FEV1/FVC), a measure of airway obstruction, in both adulthood and adolescence. We derived SNP-age at menarche association estimates for 122 variants from a published genome-wide meta-analysis (N = 182,416), with SNP-lung function estimates obtained by meta-analysing three studies of adult women (N = 46,944) and two of adolescent girls (N = 3025). We investigated the impact of departures from the assumption of no pleiotropy through sensitivity analyses. In adult women, in line with previous evidence, we found an effect on restrictive lung impairment with a 24.8 mL increase in FVC per year increase in age at menarche (95% CI 1.8–47.9; p = 0.035); evidence was stronger after excluding potential pleiotropic variants (43.6 mL; 17.2–69.9; p = 0.001). In adolescent girls we found an opposite effect (−56.5 mL; −108.3 to −4.7; p = 0.033), suggesting that the detrimental effect in adulthood may be preceded by a short-term post-pubertal benefit. Our secondary analyses showing results in the same direction in men and boys, in whom age at menarche SNPs have also shown association with sexual development, suggest a role for pubertal timing in general rather than menarche specifically. We found no effect on airway obstruction (FEV1/FVC).

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How does it feel to be a pathology resident? Results of a survey on experiences and job satisfaction during pathology residency

Abstract

Residents' career choices and professional motivation can be affected from perception of their role and recognition within a medical team as well as their educational and workplace experiences. To evaluate pathology trainees' perceptions of their pathology residency, we conducted a 42-item survey via a web-based link questioning respondents' personal and institutional background, workplace, training conditions, and job satisfaction level. For the 208 residents from different European countries who responded, personal expectations in terms of quality of life (53%) and scientific excitement (52%) were the most common reasons why they chose and enjoy pathology. Sixty-six percent were satisfied about their relationship with other people working in their department, although excessive time spent on gross examination appeared less satisfactory. A set residency training program (core curriculum), a set annual scientific curriculum, and a residency program director existed in the program of 58, 60, and 69% respondents, respectively. Most respondents (76%) considered that pathologists have a direct and high impact on patient management, but only 32% agreed that pathologists cooperate with clinicians/surgeons adequately. Most (95%) found that patients barely know what pathologists do. Only 22% considered pathology and pathologists to be adequately positioned in their country's health care system. Almost 84% were happy to have chosen pathology, describing it as "puzzle solving," "a different fascinating world," and "challenging while being crucial for patient management." More than two thirds (72%) considered pathology and pathologists to face a bright future. However, a noticeable number of respondents commented on the need for better physical working conditions, a better organized training program, more interaction with experienced pathologists, and deeper knowledge on molecular pathology.

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Characterization of MicroRNA-200 pathway in ovarian cancer and serous intraepithelial carcinoma of fallopian tube

Abstract

Background

Ovarian cancer is the leading cause of death among gynecologic diseases in Western countries. We have previously identified a miR-200-E-cadherin axis that plays an important role in ovarian inclusion cyst formation and tumor invasion. The purpose of this study was to determine if the miR-200 pathway is involved in the early stages of ovarian cancer pathogenesis by studying the expression levels of the pathway components in a panel of clinical ovarian tissues, and fallopian tube tissues harboring serous tubal intraepithelial carcinomas (STICs), a suggested precursor lesion for high-grade serous tumors.

Methods

RNA prepared from ovarian and fallopian tube epithelial and stromal fibroblasts was subjected to quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) to determine the expression of miR-200 families, target and effector genes and analyzed for clinical association. The effects of exogenous miR-200 on marker expression in normal cells were determined by qRT-PCR and fluorescence imaging after transfection of miR-200 precursors.

Results

Ovarian epithelial tumor cells showed concurrent up-regulation of miR-200, down-regulation of the four target genes (ZEB1, ZEB2, TGFβ1 and TGFβ2), and up-regulation of effector genes that were negatively regulated by the target genes. STIC tumor cells showed a similar trend of expression patterns, although the effects did not reach significance because of small sample sizes. Transfection of synthetic miR-200 precursors into normal ovarian surface epithelial (OSE) and fallopian tube epithelial (FTE) cells confirmed reduced expression of the target genes and elevated levels of the effector genes CDH1, CRB3 and EpCAM in both normal OSE and FTE cells. However, only FTE cells had a specific induction of CA125 after miR-200 precursor transfection.

Conclusions

The activation of the miR-200 pathway may be an early event that renders the OSE and FTE cells more susceptible to oncogenic mutations and histologic differentiation. As high-grade serous ovarian carcinomas (HGSOC) usually express high levels of CA125, the induction of CA125 expression in FTE cells by miR-200 precursor transfection is consistent with the notion that HGSOC has an origin in the distal fallopian tube.

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Clindamycin Injection ADD-Vantage Vials by Alvogen: Recall - Lack of Sterility Assurance

[Posted 06/16/2017] AUDIENCE: Pharmacy, Health Professional, Infectious Disease ISSUE: Alvogen is voluntarily recalling seven lots of Clindamycin Injection USP ADD-Vantage Vials to the hospital/retail level due to microbial growth detected during a...

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Editorial Board

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Comparative and analytical study on active toxoplasmosis to assess the IgG avidity in correlation to serological profile in a cohort of Egyptian patients

Abstract

Proper diagnosis of toxoplasmosis is very important for proper treatment in manifested cases and to prevent congenital toxoplasmosis in case of pregnancy. Screening of 180 pregnant females by automated immune assay for Toxoplasma IgG and IgM Abs was done first then positive cases and some of negative cases were evaluated for the Toxoplasma IgG avidity test versus Toxoplasma IgM and IgA Abs using ELISA technique for the detection of active toxoplasmosis during gestation using IHA rising titer as reference test. Assessment of Toxoplasma IgM by ELISA compared with rising titer of IHA as a reference test revealed that the sensitivity, specificity, PPV, and NPP of IgM by ELISA were 66.67, 88.73, 42.86, and 95.45%, respectively. Assessment of Toxoplasma IgA Abs by ELISA compared with rising titer IHA as a reference test showed that the sensitivity, specificity, PPV, and NPP of IgA Abs by ELISA were 44.4, 92.96, 44.4, and 92.96%, respectively. Additionally, by assessment of Toxoplasma IgG avidity compared with rising titer of IHA as a reference test, the sensitivity, specificity, PPV, and NPP of Toxoplasma IgG avidity were 100, 98.59, 90%, and 100%, respectively. Detection of specific Toxoplasma IgM antibodies by ELISA is not always sufficient in the diagnosis of early and late Toxoplasma gondii infection during pregnancy, because Toxoplasma-specific IgM antibodies may persist as long as 18 months after acute acquired infection. Thus, the specific IgG avidity test should be used as more or less low cost tool to detect acute toxoplasmosis.

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A Technique for Extraction of the Distal Segment of a Broken Femoral Nail Using a Flexible Reamer

Publication date: Available online 16 June 2017
Source:Injury
Author(s): C. Zhao, G.J.R. Slater
IntroductionExtraction of broken femoral nails in peri-implant fractures is becoming an increasingly common problem faced by orthopaedic surgeons. Different closed and open techniques for removal of broken nails have been previously described but due to variations in equipment and fracture configurations these methods are not always easily reproducible. We describe an open surgical technique using simple equipment that can be utilised when other methods of extraction have failed.Case Presentation and Surgical TechniqueWe present a case of a peri-implant fracture secondary to non-union involving a short cephalomedullary nail where the broken distal segment of nail was significantly more distal to the femoral fracture site. After multiple failed attempts at extraction with previously described closed techniques a rectangular cortical window was created 2cm distal to the tip of the broken nail using a saw. An antegrade guide wire was passed through the nail and pulled out of the bony window. A flexible intramedullary reamer was subsequently passed in retrograde fashion over the guide wire and a simple pushout technique was used to push both segments of the broken nail through the original insertion site. An exchange nailing was performed and the cortical window was reattached using a cable.DiscussionThis is a simple technique that does not require any specialist equipment and does not require the fracture site to be disturbed. The use of a flexible reamer as a pushout device is ideal as there are multiple size options allowing the surgeon to match the size of the medullary canal with the reamer. Furthermore, the flexibility of the reamer allows easy access through a lateral bone window.ConclusionBroken femoral nail extraction can be technically challenging and when other closed methods have failed we believe our technique offers a simple alternative that can be added to the armamentarium of solutions.



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Does Memory Consolidation by Anesthetics Relate to a Time Window of Age?.

No abstract available

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In Response.

No abstract available

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Insufficient Astrocyte-Derived Brain-Derived Neurotrophic Factor Contributes to Propofol-Induced Neuron Death Through Akt/Glycogen Synthase Kinase 3[beta]/Mitochondrial Fission Pathway.

BACKGROUND: Growing animal evidence demonstrates that prolonged exposure to propofol during brain development induces widespread neuronal cell death, but there is little information on the role of astrocytes. Astrocytes can release neurotrophic growth factors such as brain-derived neurotrophic factor (BDNF), which can exert the protective effect on neurons in paracrine fashion. We hypothesize that during propofol anesthesia, BDNF released from developing astrocytes may not be sufficient to prevent propofol-induced neurotoxicity. METHODS: Hippocampal astrocytes and neurons isolated from neonatal Sprague Dawley rats were exposed to propofol at a clinically relevant dose of 30 [mu]M or dimethyl sulfoxide as control for 6 hours. Propofol-induced cell death was determined by propidium iodide (PI) staining in astrocyte-alone cultures, neuron-alone cultures, or cocultures containing either low or high density of astrocytes (1:9 or 1:1 ratio of astrocytes to neurons ratio [ANR], respectively). The astrocyte-conditioned medium was collected 12 hours after propofol exposure and measured by protein array assay. BDNF concentration in astrocyte-conditioned medium was quantified using enzyme-linked immunosorbent assay. Neuron-alone cultures were treated with BDNF, tyrosine receptor kinase B inhibitor cyclotraxin-B, glycogen synthase kinase 3[beta] (GSK3[beta]) inhibitor CHIR99021, or mitochondrial fission inhibitor Mdivi-1 before propofol exposure. Western blot was performed for quantification of the level of protein kinase B and GSK3[beta]. Mitochondrial shape was visualized through translocase of the outer membrane 20 staining. RESULTS: Propofol increased cell death in neurons by 1.8-fold (% of PI-positive cells [PI%] = 18.6; 95% confidence interval [CI], 15.2-21.9, P .05]). Astrocytes secreted BDNF in a cell density-dependent way and propofol decreased BDNF secretion from astrocytes. Administration of BDNF, CHIR99021, or Mdivi-1 significantly attenuated the propofol-induced neuronal death and aberrant mitochondria in neuron-alone cultures (FC = 0.8, 95% CI, 0.62-0.98; FC = 1.22, 95% CI, 1.11-1.32; FC = 1.35, 95% CI, 1.16-1.54, respectively, P

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Predictors, Prognosis, and Management of New Clinically Important Atrial Fibrillation After Noncardiac Surgery: A Prospective Cohort Study.

BACKGROUND: Despite the frequency of new clinically important atrial fibrillation (AF) after noncardiac surgery and its increased association with the risk of stroke at 30 days, there are limited data informing their prediction, association with outcomes, and management. METHODS: We used the data from the PeriOperative ISchemic Evaluation trial to determine, in patients undergoing noncardiac surgery, the association of new clinically important AF with 30-day outcomes, and to assess management of these patients. We also aimed to derive a clinical prediction rule for new clinically important AF in this population. We defined new clinically important AF as new AF that resulted in symptoms or required treatment. We recorded an electrocardiogram 6 to 12 hours postoperatively and on the 1st, 2nd, and 30th days after surgery. RESULTS: A total of 211 (2.5% [8351 patients]; 95% confidence interval, 2.2%-2.9%) patients developed new clinically important AF within 30 days of randomization (8140 did not develop new AF). AF was independently associated with an increased length of hospital stay by 6.0 days (95% confidence interval, 3.5-8.5 days) and vascular complications (eg, stroke or congestive heart failure). The usage of an oral anticoagulant at the time of hospital discharge among patients with new AF and a CHADS2 score of 0, 1, 2, 3, and >=4 was 6.9%, 10.2%, 23.0%, 9.4%, and 33.3%, respectively. Two independent predictors of patients developing new clinically important AF were identified (ie, age and surgery). The prediction rule included the following factors and assigned weights: age >=85 years (4 points), age 75 to 84 years (3 points), age 65 to 74 years (2 points), intrathoracic surgery (3 points), major vascular surgery (2 points), and intra-abdominal surgery (1 point). The incidence of new AF based on scores of 0 to 1, 2, 3 to 4, and 5 to 6 was 0.5%, 1.0%, 3.1%, and 5.3%, respectively. CONCLUSIONS: Age and surgery are independent predictors of new clinically important AF in the perioperative setting. A minority of patients developing new clinically important AF with high CHADS2 scores are discharged on an oral anticoagulant. There is a need to develop effective and safe interventions to prevent this outcome and to optimize the management of this event when it occurs. (C) 2017 International Anesthesia Research Society

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Impact of Sternotomy and Pericardial Opening in Patients With Ventricular Septal Defects: Assess Before Sawing!

No abstract available

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Postoperative Respiratory Complications in Patients at Risk for Obstructive Sleep Apnea: A Single-Institution Cohort Study.

BACKGROUND: Obstructive sleep apnea (OSA) is a prevalent condition that is associated with early postoperative respiratory complications (PRCs). As the majority of patients with OSA are undiagnosed, preoperative screening remains the most efficient method to identify suspected OSA. METHODS: This retrospective study was performed on patients undergoing anesthesia in a single academic medical center. We assigned OSA risk class retrospectively to all patients in the study by using the Perioperative Sleep Apnea Prediction (PSAP) score. We evaluated the relationship between PSAP categories and early postoperative invasive airway placement after adjusting for several preoperative and intraoperative factors (including surgical risk) previously associated with PRC occurrence. RESULTS: A total of 108,479 patients were included in the final analysis with an incidence of PRC was 0.3% (n = 280). High PSAP score was associated with postoperative intubation (adjusted odds ratio, 2.3; 95% confidence interval, 1.5-3.7). Several risk factors reflecting anesthetic agents, neuromuscular blocking agents, and opioids were also independently associated with early PRC. CONCLUSIONS: We report that suspected OSA based on the PSAP score is independently associated with increased risk of early PRC. Specific anesthetic agents are independently associated with early PRC, pointing to the potential for examining risk modification through these exposures in future studies. (C) 2017 International Anesthesia Research Society

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Labor Analgesia Onset With Dural Puncture Epidural Versus Traditional Epidural Using a 26-Gauge Whitacre Needle and 0.125% Bupivacaine Bolus: A Randomized Clinical Trial.

BACKGROUND: Lumbar epidurals (LEs) provide excellent analgesia. Combined spinal epidural and dural puncture epidural (DPE) are 2 techniques to expedite neuraxial analgesia onset. In DPE, dura is punctured but medication is not administered in the cerebrospinal fluid. Expedited analgesia onset has been demonstrated with DPE, using 0.25% bupivacaine; however, this concentration may impede an unassisted vaginal birth and is not currently used for induction and maintenance of labor analgesia. The primary goal of this study was to compare the percentage of patients who achieved adequate labor analgesia following DPE or LE with an epidural bolus of 0.125% bupivacaine. Adequate labor analgesia was defined as Visual Analog Scale (VAS) measurement

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Phenotypic and functional characterization of T cells in white matter lesions of multiple sclerosis patients

Abstract

T cells are considered pivotal in the pathology of multiple sclerosis (MS), but their function and antigen specificity are unknown. To unravel the role of T cells in MS pathology, we performed a comprehensive analysis on T cells recovered from paired blood, cerebrospinal fluid (CSF), normal-appearing white matter (NAWM) and white matter lesions (WML) from 27 MS patients with advanced disease shortly after death. The differentiation status of T cells in these compartments was determined by ex vivo flow cytometry and immunohistochemistry. T-cell reactivity in short-term T-cell lines (TCL), generated by non-specific stimulation of T cells recovered from the same compartments, was determined by intracellular cytokine flow cytometry. Central memory T cells predominated in CSF and effector memory T cells were enriched in NAWM and WML. WML-derived CD8⁺ T cells represent chronically activated T cells expressing a cytotoxic effector phenotype (CD95L and granzyme B) indicative for local antigenic stimulation (CD137). The same lesions also contained higher CD8⁺ T-cell frequencies expressing co-inhibitory (TIM3 and PD1) and co-stimulatory (ICOS) T-cell receptors, yet no evidence for T-cell senescence (CD57) was observed. The oligoclonal T-cell receptor (TCR) repertoire, particularly among CD8⁺ T cells, correlated between TCL generated from anatomically separated WML of the same MS patient, but not between paired NAWM and WML. Whereas no substantial T-cell reactivity was detected towards seven candidate human MS-associated autoantigens (cMSAg), brisk CD8⁺ T-cell reactivity was detected in multiple WML-derived TCL towards autologous Epstein–Barr virus (EBV) infected B cells (autoBLCL). In one MS patient, the T-cell response towards autoBLCL in paired intra-lesional TCL was dominated by TCRVβ2⁺CD8⁺ T cells, which were localized in the parenchyma of the respective tissues expressing a polarized TCR and CD8 expression suggesting immunological synapse formation in situ. Collectively, the data suggest the involvement of effector memory cytotoxic T cells recognizing antigens expressed by autoBLCL, but not the assayed human cMSAg, in WML of MS patients.

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Extraskeletal Osteosarcoma: Outcomes and the Role of Chemotherapy.

Objectives: Extraskeletal osteosarcoma (EO) is a malignant neoplasm that produces osteoid, bone, and chondroid material without direct attachment to bone or periosteum. Surgical resection is the mainstay of treatment; the role of chemotherapy is not well defined. Therefore, we evaluated the impact of chemotherapy in the survival of patients with EO. Methods: All EO patients seen at Mayo Clinic between 1990 and 2014 were assessed. Forty-three patients were included after all archived pathology slides were reviewed to confirm the diagnosis of EO. Results: Of 43 patients, 37 patients had localized disease and 6 patients had metastatic disease at diagnosis. Chemotherapy was used in 73% and 75% of patients, respectively. Chemotherapy was predominantly anthracycline based, and included platinum in 22 patients (84%). Median overall survival (OS) and progression-free survival (PFS) were 50 months (95% confidence interval, 25-99), and 21 months (95% confidence interval, 13-not reached), respectively. There was a trend towards longer OS and PFS in patients who received chemotherapy. Those who received platinum-based therapy had remarkably prolonged OS (median, 182 vs. 18 mo; 5-year, 61% vs. 0%; P=0.01) and PFS (median, not reached vs. 10 mo; 5-year, 56% vs. 0%; P=0.005). Baseline characteristics were similar in the platinum and nonplatinum group. In patients who received chemotherapy, relapse/recurrence rate was lower in the platinum-based group (41%) as opposed to the nonplatinum-based group (100%; P=0.02). In the neoadjuvant setting, the overall response rate of platinum-containing regimens was 27%. Conclusions: Our results suggest a clinical benefit when platinum-based chemotherapy is incorporated in the management of patients with EO. We plan to validate this further with an expanded multicenter analysis. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Hemorrhagic ganglioglioma of the third ventricle with atypical pathological findings

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When Science is Not Enough: A Framework Towards More Customer-Focused Drug Development

Abstract

Introduction

The purpose of this study was to identify the key barriers to a customer-focused drug development process and develop a comprehensive framework to overcome them.

Methods

The paper draws on existing literature, both academic and practitioner, across a range of disciplines (innovation management, marketing, organizational behavior, behavioral economics, health economics, industry reports). On the basis of this extensive review, a conceptual framework is developed that offers concrete suggestions on how organizations can overcome the barriers and enable a more customer-focused development process.

Results

The barriers to collaboration are organized into three distinct categories (economic, behavioral, organizational), and within each category, a one-to-one mapping between barriers and solutions is developed.

Conclusion

The framework is specifically designed with the objective of offering actionable and practical advice to executives who face these challenges in their organizations. The paper provides a unique theoretical contribution by synthesizing findings from several academic disciplines with concrete examples from the pharmaceutical industry.

Funding

Mundipharma International Limited.

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Acute Care Nurse Practitioners and Physician Assistants in Critical Care: Transforming Education and Practice

No abstract available

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Noninvasive iPhone Measurement of Left Ventricular Ejection Fraction Using Intrinsic Frequency Methodology*

Objective: The study is based on previously reported mathematical analysis of arterial waveform that extracts hidden oscillations in the waveform that we called intrinsic frequencies. The goal of this clinical study was to compare the accuracy of left ventricular ejection fraction derived from intrinsic frequencies noninvasively versus left ventricular ejection fraction obtained with cardiac MRI, the most accurate method for left ventricular ejection fraction measurement. Design: After informed consent, in one visit, subjects underwent cardiac MRI examination and noninvasive capture of a carotid waveform using an iPhone camera (The waveform is captured using a custom app that constructs the waveform from skin displacement images during the cardiac cycle.). The waveform was analyzed using intrinsic frequency algorithm. Setting: Outpatient MRI facility. Subjects: Adults able to undergo MRI were referred by local physicians or self-referred in response to local advertisement and included patients with heart failure with reduced ejection fraction diagnosed by a cardiologist. Interventions: Standard cardiac MRI sequences were used, with periodic breath holding for image stabilization. To minimize motion artifact, the iPhone camera was held in a cradle over the carotid artery during iPhone measurements. Measurements and Main Results: Regardless of neck morphology, carotid waveforms were captured in all subjects, within seconds to minutes. Seventy-two patients were studied, ranging in age from 20 to 92 years old. The main endpoint of analysis was left ventricular ejection fraction; overall, the correlation between ejection fraction–iPhone and ejection fraction–MRI was 0.74 (r = 0.74; p

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The authors reply

No abstract available

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Diaphragm Activation in Ventilated Patients Using a Novel Transvenous Phrenic Nerve Pacing Catheter

Objectives: Over 30% of critically ill patients on positive-pressure mechanical ventilation have difficulty weaning from the ventilator, many of whom acquire ventilator-induced diaphragm dysfunction. Temporary transvenous phrenic nerve pacing using a novel electrode-bearing catheter may provide a means to prevent diaphragm atrophy, to strengthen an atrophied diaphragm, and mitigate the harms of mechanical ventilation. We tested the initial safety, feasibility, and impact on ventilation of this novel approach. Design: First-in-Humans case series. Setting: Angiogram suite. Patients: Twenty-four sedated, mechanically ventilated patients immediately prior to an elective atrial septal defect repair procedure. Interventions: A 9.5-Fr central venous catheter with 19 embedded electrodes was placed via Seldinger technique into the left subclavian vein and superior vena cava and evaluated for up to 90 minutes. The electrode combinations determined to provide best transvenous stimulation of the right and left phrenic nerves were activated in synchrony with mechanically ventilated breaths. Measurements and Main Results: One patient could not be tested for reasons unrelated to the device. In the 23 patients who underwent the full protocol, transvenous stimulation activated the diaphragm in 22 of 23 (96%) left phrenic capture attempts and 20 of 23 (87%) right phrenic capture attempts. In one subject, a congenital left-sided superior vena cava precluded right-sided capture. Significant reductions in ventilator pressure-time-product were achieved during stimulation assisted breaths in all 22 paced subjects (range, 9.9–48.6%; p

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Withholding Pantoprazole for Stress Ulcer Prophylaxis in Critically Ill Patients: A Pilot Randomized Clinical Trial and Meta-Analysis*

Introduction: A decreased frequency of upper gastrointestinal bleeding and a possible association of proton pump inhibitor use with Clostridium difficile and ventilator-associated pneumonia have raised concerns recently. The Reevaluating the Inhibition of Stress Erosions Pilot Trial determined the feasibility of undertaking a larger trial investigating the efficacy and safety of withholding proton pump inhibitors in critically ill patients. Methods: In 10 ICUs, we randomized adult ICU patients anticipated to be mechanically ventilated for greater than or equal to 48 hours to receive 40 mg of IV pantoprazole daily or placebo. We excluded patients who had acute or recent gastrointestinal bleed, used dual antiplatelet agents, had a medical condition requiring proton pump inhibitor treatment, or had already received more than one dose of acid suppression daily. Patients, families, clinicians, and research staff were blinded. We conducted a systematic review and meta-analysis of similar trials. Main Results: Ninety-one patients (49 pantoprazole and 42 placebo) from 10 centers in Canada, Saudi Arabia, and Australia were enrolled. All feasibility goals were met: 1) recruitment rate was 2.6 patients per month; 2) consent rate was 77.8%; and 3) protocol adherence was 97.7%. Upper gastrointestinal bleeding developed in 6.1% of patients in the pantoprazole group and 4.8% in the placebo group (p = 1.0). Ventilator-associated pneumonia developed in 20.4% of patients in the pantoprazole group and 14.3% in the placebo group (p = 0.58). C. difficile was identified in 4.1% pantoprazole patients and in 2.4% placebo patients (p = 1.0). We meta-analyzed five trials (604 patients) of proton pump inhibitors versus placebo; there was no statistically significant difference in the risk of upper gastrointestinal bleeding, infections, or mortality. Conclusions: Our results support the feasibility of a larger trial to evaluate the safety of withholding stress ulcer prophylaxis. Although the results are imprecise, there was no alarming increase in the risk of upper gastrointestinal bleeding; the effect of proton pump inhibitors on ventilator-associated pneumonia and C. difficile remain unclear.

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