Identification of patients with cancer with a high risk to develop delirium

Abstract

Delirium deteriorates the quality of life in patients with cancer, but is frequently underdiagnosed and not adequately treated. In this study, we evaluated the occurrence of delirium and its risk factors in patients admitted to the hospital for treatment or palliative care in order to develop a prediction model to identify patients at high risk for delirium. In a period of 1.5 years, we evaluated the risk of developing delirium in 574 consecutively admitted patients with cancer to our academic oncology department with the Delirium Observation Screening Scale. Risk factors for delirium were extracted from the patient's chart. A delirium prediction algorithm was constructed using tree analysis, and validated with fivefold cross-validation. A total of 574 patients with cancer were acutely (42%) or electively (58%) admitted 1733 times. The incidence rate of delirium was 3.5 per 100 admittances. Tree analysis revealed that the predisposing factors of an unscheduled admittance and a metabolic imbalance accurately predicted the development of delirium. In this group the incidence rate of delirium was 33 per 100 patients (1:3). The AUC of the model was 0.81, and 0.65 after fivefold cross-validation. We identified that especially patients undergoing an unscheduled admittance with a metabolic imbalance do have a clinically relevant high risk to develop a delirium. Based on these factors, we propose to evaluate preventive treatment of these patients when admitted to the hospital in order to improve their quality of life.

The predisposing factors of an unscheduled admittance and a metabolic imbalance accurately predict the development of delirium in patients with cancer (delirium risk 1:3). This prediction algorithm for delirium that can be easily implemented in daily clinical practice should be evaluated for the potential benefit of preventive treatment of patients with cancer who are prone to develop delirium.

http://ift.tt/2sXmYKy

MicroRNAs in Parkinson’s disease

Abstract

Parkinson's disease is the second most common neurodegenerative disease commonly affecting the older population. Loss of dopaminergic neurons in the substantia nigra of brain leads to impairment of motor activities as well as cognitive defects. There are many underlying causes to this disease, both genetic and epigenetic, which are yet to be fully explored. Non-coding RNAs are significant part of our genome and are involved in various cellular processes. MicroRNAs, which are small non-coding RNAs having 20–22 nucleotides, are involved in many underlying mechanisms of pathogenesis of several neurodegenerative diseases including Parkinson's. This review focuses on the role played by microRNAs in regulating various genes responsible for the onset and pathogenesis of Parkinson's disease and various literature evidences pointing at the usefulness of targeting specific microRNAs as a potential alternate therapeutic strategy for successful impairment of the disease progression. This review also discusses about various biofluid-based microRNA markers which may be potentially utilized for diagnostic purposes.

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Control of force during rapid visuomotor force-matching tasks can be described by discrete time PID control algorithms

Abstract

Force trajectories during isometric force-matching tasks involving isometric contractions vary substantially across individuals. In this study, we investigated if this variability can be explained by discrete time proportional, integral, derivative (PID) control algorithms with varying model parameters. To this end, we analyzed the pinch force trajectories of 24 subjects performing two rapid force-matching tasks with visual feedback. Both tasks involved isometric contractions to a target force of 10% maximal voluntary contraction. One task involved a single action (pinch) and the other required a double action (concurrent pinch and wrist extension). 50,000 force trajectories were simulated with a computational neuromuscular model whose input was determined by a PID controller with different PID gains and frequencies at which the controller adjusted muscle commands. The goal was to find the best match between each experimental force trajectory and all simulated trajectories. It was possible to identify one realization of the PID controller that matched the experimental force produced during each task for most subjects (average index of similarity: 0.87 ± 0.12; 1 = perfect similarity). The similarities for both tasks were significantly greater than that would be expected by chance (single action: p = 0.01; double action: p = 0.04). Furthermore, the identified control frequencies in the simulated PID controller with the greatest similarities decreased as task difficulty increased (single action: 4.0 ± 1.8 Hz; double action: 3.1 ± 1.3 Hz). Overall, the results indicate that discrete time PID controllers are realistic models for the neural control of force in rapid force-matching tasks involving isometric contractions.

http://ift.tt/2sX05qS

Coupling dynamics in speech gestures: amplitude and rate influences

Abstract

Speech is a complex oral motor function that involves multiple articulators that need to be coordinated in space and time at relatively high movement speeds. How this is accomplished remains an important and largely unresolved empirical question. From a coordination dynamics perspective, coordination involves the assembly of coordinative units that are characterized by inherently stable coupling patterns that act as attractor states for task-specific actions. In the motor control literature, one particular model formulated by Haken et al. (Biol Cybern 51(5):347–356, 1985) or HKB has received considerable attention in the way it can account for changes in the nature and stability of specific coordination patterns between limbs or between limbs and external stimuli. In this model (and related versions), movement amplitude is considered a critical factor in the formation of these patterns. Several studies have demonstrated its role for bimanual coordination and similar types of tasks, but for speech motor control such studies are lacking. The current study describes a systematic approach to evaluate the impact of movement amplitude and movement duration on coordination stability in the production of bilabial and tongue body gestures for specific vowel–consonant–vowel strings. The vowel combinations that were used induced a natural contrast in movement amplitude at three speaking rate conditions (slow, habitual, fast). Data were collected on ten young adults using electromagnetic articulography, recording movement data from lips and tongue with high temporal and spatial precision. The results showed that with small movement amplitudes there is a decrease in coordination stability, independent from movement duration. These findings were found to be robust across all individuals and are interpreted as further evidence that principles of coupling dynamics operate in the oral motor control system similar to other motor systems and can be explained in terms of coupling mechanisms between neural oscillators (organized in networks) and effector systems. The relevance of these findings for understanding motor control issues in people with speech disorders is discussed as well.

http://ift.tt/2trDqX6

Three-dimensional analysis of linear vestibulo-ocular reflex in humans during eccentric rotation while facing downwards

Abstract

When participants undergo eccentric rotation (ER), i.e., they are rotated while displaced from the axis of rotation, they undergo both rotational stimulation and linear acceleration, which induces both the angular vestibulo-ocular reflex (aVOR) and linear VOR (lVOR). During ER, the lVOR induced by tangential linear acceleration enhances the eye movement induced by aVOR. In this study, we attempted to measure aVOR and lVOR separately, while participants underwent ER while facing the ground in a dark room. We analyzed three-dimensional eye movements using a video-oculography system. The participants sat on the ER chair either directly above the center of rotation, or with their head out, head in, right ear out, or left ear out against the center of rotation. Under these conditions, the rotational axis of the eye was perpendicular to the ground for rotational stimulation (aVOR), and the axis was parallel to the ground for linear stimulation (lVOR). Thus, measured eye movements could be separated into these two components. At 0.1 and 0.3 Hz rotation, we observed aVOR but not lVOR. However, when the stimulation frequency was above 0.5 Hz, we observed both aVOR and lVOR. These data indicate that lVOR is activated when the stimulation frequency is above 0.5 Hz. We conclude that it is possible to separately analyze aVOR and lVOR, and to simultaneously assess the function of aVOR and lVOR by analyzing eye movements induced when participants undergo ER above 0.5 Hz while facing the ground.

http://ift.tt/2sXnRTH

On the contribution of overt tactile expectations to visuo-tactile interactions within the peripersonal space

Abstract

Since the discovery of neural regions in the monkey brain that respond preferentially to multisensory stimuli presented in proximal space, researchers have been studying this specialised spatial representation in humans. It has been demonstrated that approaching auditory or visual stimuli modulate tactile processing, while they are within the peripersonal space (PPS). The aim of the current study is to investigate the additional effects of tactile expectation on the PPS-related multisensory interactions. Based on the output of a computational simulation, we expected that as tactile expectation increases rapidly during the course of the motion of the visual stimulus, the outcome RT curves would mask the multisensory contribution of PPS. When the tactile expectation remains constant during the motion, the PPS-related spatially selective multisensory processes become apparent. The behavioural results on human experiments followed the pattern predicted by the simulation. That is, rapidly changing levels of tactile expectation, caused by dynamic visual stimuli, masks the outcome of the multisensory processes within peripersonal space. This indicates that both PPS-related multisensory interactions and tactile expectations play an important role in anticipating and responding to interactions with the body.

http://ift.tt/2trD8Q7

Tactile feedback is an effective instrument for the training of grasping with a prosthesis at low- and medium-force levels

Abstract

Grasping is a complex task routinely performed in an anticipatory (feedforward) manner, where sensory feedback is responsible for learning and updating the internal model of grasp dynamics. This study aims at evaluating whether providing a proportional tactile force feedback during the myoelectric control of a prosthesis facilitates learning a stable internal model of the prosthesis force control. Ten able-bodied subjects controlled a sensorized myoelectric prosthesis performing four blocks of consecutive grasps at three levels of target force (30, 50, and 70%), repeatedly closing the fully opened hand. In the first and third block, the subjects received tactile and visual feedback, respectively, while during the second and fourth block, the feedback was removed. The subjects also performed an additional block with no feedback 1 day after the training (Retest). The median and interquartile range of the generated forces was computed to assess the accuracy and precision of force control. The results demonstrated that the feedback was indeed an effective instrument for the training of prosthesis control. After the training, the subjects were still able to accurately generate the desired force for the low and medium target (30 and 50% of maximum force available in a prosthesis), despite the feedback being removed within the session and during the retest (low target force). However, the training was substantially less successful for high forces (70% of prosthesis maximum force), where subjects exhibited a substantial loss of accuracy as soon as the feedback was removed. The precision of control decreased with higher forces and it was consistent across conditions, determined by an intrinsic variability of repeated myoelectric grasping. This study demonstrated that the subject could rely on the tactile feedback to adjust the motor command to the prosthesis across trials. The subjects adjusted the mean level of muscle activation (accuracy), whereas the precision could not be modulated as it depends on the intrinsic myoelectric variability. They were also able to maintain the feedforward command even after the feedback was removed, demonstrating thereby a stable learning, but the retention depended on the level of the target force. This is an important insight into the role of feedback as an instrument for learning of anticipatory prosthesis force control.

http://ift.tt/2sXtBN2

Trust in haptic assistance: weighting visual and haptic cues based on error history

Abstract

To effectively interpret and interact with the world, humans weight redundant estimates from different sensory cues to form one coherent, integrated estimate. Recent advancements in physical assistance systems, where guiding forces are computed by an intelligent agent, enable the presentation of augmented cues. It is unknown, however, if cue weighting can be extended to augmented cues. Previous research has shown that cue weighting is determined by the reliability (inversely related to uncertainty) of cues within a trial, yet augmented cues may also be affected by errors that vary over trials. In this study, we investigate whether people can learn to appropriately weight a haptic cue from an intelligent assistance system based on its error history. Subjects held a haptic device and reached to a hidden target using a visual (Gaussian distributed dots) and haptic (force channel) cue. The error of the augmented haptic cue varied from trial to trial based on a Gaussian distribution. Subjects learned to estimate the target location by weighting the visual and augmented haptic cues based on their perceptual uncertainty and experienced errors. With both cues available, subjects were able to find the target with an improved or equal performance compared to what was possible with one cue alone. Our results show that the brain can learn to reweight augmented cues from intelligent agents, akin to previous observations of the reweighting of naturally occurring cues. In addition, these results suggest that the weighting of a cue is not only affected by its within-trial reliability but also the history of errors.

http://ift.tt/2trDq9y

Sensory and motoric influences on attention dynamics during standing balance recovery in young and older adults

Abstract

This study investigated the impact of attention on the sensory and motor actions during postural recovery from underfoot perturbations in young and older adults. A dual-task paradigm was used involving disjunctive and choice reaction time (RT) tasks to auditory and visual stimuli at different delays from the onset of two types of platform perturbations (rotations and translations). The RTs were increased prior to the perturbation (preparation phase) and during the immediate recovery response (response initiation) in young and older adults, but this interference dissipated rapidly after the perturbation response was initiated (<220 ms). The sensory modality of the RT task impacted the results with interference being greater for the auditory task compared to the visual task. As motor complexity of the RT task increased (disjunctive versus choice) there was greater interference from the perturbation. Finally, increasing the complexity of the postural perturbation by mixing the rotational and translational perturbations together increased interference for the auditory RT tasks, but did not affect the visual RT responses. These results suggest that sensory and motoric components of postural control are under the influence of different dynamic attentional processes.

http://ift.tt/2sXgc7A

Exercise and NAFLD: Is it worth the effort?

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Is antibody to surface antigen associated with hepatitis B reactivation in patients with resolved hepatitis B?

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Grazoprevir, Ruzasvir, and Uprifosbuvir for HCV After NS5A Treatment Failure

Abstract

People with hepatitis C virus (HCV) infection who have failed treatment with an all-oral regimen represent a challenging treatment population. The present studies evaluated the safety and efficacy of grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, in participants who had failed an NS5A inhibitor-containing regimen. C-SURGE (PN-3682-021) and C-CREST Part C (PN-3682-011 and -012) were open-label, multicenter studies. Participants who had previously relapsed following an NS5A inhibitor–containing all-oral regimen were retreated with grazoprevir 100 mg, ruzasvir 60 mg, and uprifosbuvir 450 mg alone for 24 weeks or with ribavirin for 16 weeks. The primary efficacy endpoint was undetectable HCV RNA (<15 IU/mL) 12 weeks after treatment completion (SVR12). In C-SURGE, SVR12 was achieved by 49/49 (100%) and 43/44 (98%) genotype (GT)1 participants in the 24-week no ribavirin arm and the 16-week plus ribavirin arm (lost to follow-up, n = 1), respectively. In C-CREST Part C, SVR12 was achieved by 23/24 (96%) participants treated for 16 weeks with ribavirin (GT1, 2/2 [100%]; GT2, 13/14 [93%]; GT3, 8/8 [100%]). One participant with GT2 infection discontinued study medication after a single dose of grazoprevir, ruzasvir, and uprifosbuvir plus ribavirin due to serious adverse events of vomiting and tachycardia. The presence of baseline resistance-associated substitutions had no impact on SVR12. No participant who completed treatment in either study experienced virologic failure. Conclusion: Grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, for 16 or 24 weeks was safe and highly effective in participants with HCV infection who had previously failed NS5A inhibitor–containing therapy. This article is protected by copyright. All rights reserved.

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Influence of common and rare genetic variation on warfarin dose among African–Americans and European–Americans using the exome array

Pharmacogenomics, Ahead of Print.


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The Ubiquitous Pharmacogenomics consortium: making effective treatment optimization accessible to every European citizen

Pharmacogenomics, Ahead of Print.


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Clinical effect of CYP2C9*5/*6 genotype on a patient's warfarin dose requirement

Pharmacogenomics, Ahead of Print.


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Educating patients and providers through comprehensive pharmacogenetic test reports

Pharmacogenomics, Ahead of Print.


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Pharmacogenetics of inflammatory bowel disease: a focus on Crohn's disease

Pharmacogenomics, Ahead of Print.


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Pharmacogenetics and the treatment of functional gastrointestinal disorders

Pharmacogenomics, Ahead of Print.


http://ift.tt/2u27jhZ

Role of dual red imaging to guide intravariceal sclerotherapy injection of esophageal varices (with videos)

Dual red imaging (DRI) is a novel image-enhanced endoscopy technique that can increase the visibility and predict the depth of esophageal varices (EVs). The recurrence rate of EVs after endoscopic injection sclerotherapy (EIS) reportedly decreases by intravariceal injection of a sclerosant. We evaluated prospectively whether the EIS success rate was increased by DRI compared with the white light (WLI) mode.

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Fetal Growth Restriction with Brain Sparing: Neurocognitive and Behavioral Outcomes at 12 Years of Age

To study neurocognitive functions and behavior in children with a history of fetal growth restriction (FGR) with brain sparing. We hypothesized that children with FGR would have poorer outcomes on these domains.

http://ift.tt/2u2cVJo

Real-Life Glycemic Control in Children with Type 2 Diabetes: A Population-Based Study

To characterize children and adolescents with type 2 diabetes mellitus (T2DM) insured by a large health maintenance organization, and to identify variables associated with treatment quality and disease outcome.

http://ift.tt/2uAOfo6

Secretin-Enhanced Magnetic Resonance Cholangiopancreatography for Assessing Pancreatic Secretory Function in Children

To assess the accuracy and interrater reproducibility of measurements of pancreatic secretory function by magnetic resonance cholangiopancreatography in response to secretin administration and to describe our experience using the technique to noninvasively assess pancreatic secretory function in a pediatric population.

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Wula (Voices) of Aboriginal women on barriers to accepting smoking cessation support during pregnancy: Findings from a qualitative study

Publication date: Available online 6 July 2017
Source:Women and Birth
Author(s): M. Bovill, M. Gruppetta, Y. Cadet-James, M. Clarke, B. Bonevski, G.S. Gould
AimTo gather Aboriginal women's stories of smoking and becoming pregnant to identify the barriers in accepting smoking cessation support during pregnancy.MethodsQualitative data were collected through use of yarning methodology between August 2015 and January 2016 by an Aboriginal Researcher with experience in social and community services. A short on-line survey was used to collect quantitative data. Interviews only recorded the therapeutic yarning process, which ranged from 9 to 45min duration, averaging 30min. Audio-recorded interviews were transcribed and independently coded. A general inductive analysis was used to determine emergent themes.ResultsTwenty Aboriginal women between 17–38 years of age, who were pregnant or recently given birth, living in the Hunter New England (HNE) area took part. Eleven women were still smoking; nine had quit. Most were highly aware of the implications of smoking for their babies. Major themes identified for accepting support were: ambivalence towards a need for support, health professional advice, reduction in smoking, and attitudes to Nicotine Replacement Therapy (NRT). Women reported being advised to cut down, rather than to quit; reducing consumption may be a barrier to accepting NRT. Women recommended enhanced clinical support and Aboriginal community engagement in cessation care.Discussion/conclusionsAboriginal women in the HNE area reported quitting or reducing their cigarette intake during pregnancy. Health Professionals working with Aboriginal women during pregnancy should give consistent messages to quit smoking completely, and offer increased, ongoing and extensive smoking cessation support to Aboriginal mothers. Clinical practices could partner with Aboriginal communities to support the delivery of smoking cessation services.



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AAV Gene Therapy for Alcoholism: Inhibition of Mitochondrial Aldehyde Dehydrogenase Enzyme Expression in Hepatoma Cells

Human Gene Therapy , Vol. 0, No. 0.


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PD-L1 and immune escape - insights from melanoma and other lineage-unrelated malignancies

One of the major breakthroughs in oncology in the past decade has been the research and development of immune checkpoint inhibitors. Since the discovery of the PD-1/PD-L1 axis as a key mediator in peripheral self-tolerance and the subsequent discovery of its role promoting immune escape in cancers, the PD-1/PD-L1 pathway has produced considerable excitement from both a scientific and therapeutic stand point. The past decade has seen an explosion in the number of clinical trials utilizing antI-PD-1/PD-L1 therapy.

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Spinal Cord Infarcts: Risk Factors, Management, and Prognosis

Opinion statement

There are no standard guidelines for treatment of spinal cord ischemia due to how rare it is and the diverse etiology and presentations involved. In addition, to date, there have been no large clinical trials examining ideal pharmacologic treatment options for spinal cord infarct. In our practice, we rely on hemodynamic augmentation initiated as soon as possible. Otherwise, treatment is usually geared towards the etiology of spinal cord ischemia. For instance, spinal cord ischemia occurring after aortic aneurysmal repair may improve with CSF drainage through a lumbar catheter in the periprocedural setting. Vertebral artery dissection should be treated with antithrombotics. If no clear etiology is found and there is evidence of atherosclerosis in other vascular beds, then management is focused on risk factor modification with blood pressure and glucose control, statins, and antithrombotics.

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Clinical benefit of sunitinib in gastrointestinal stromal tumors with different exon 11 mutation genotypes

Future Oncology, Ahead of Print.


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Effect of cancer-associated fibroblasts on radiosensitivity of cancer cells

Future Oncology, Ahead of Print.


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Osteopontin polymorphism increases gastric precancerous intestinal metaplasia susceptibility in Helicobacter pylori infected male

Future Oncology, Ahead of Print.


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Investigation of correlation between mutational status in key EGFR signaling genes and prognosis of stage II colorectal cancer

Future Oncology, Ahead of Print.


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Second primary malignancy in acute promyelocytic leukemia: a Surveillance, Epidemiology and End Results database study

Future Oncology, Ahead of Print.


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Circumvent hesitancy between CDK4/6 and mTOR inhibitors in second-line treatment of HR+, erb2- metastatic breast cancer

Future Oncology, Ahead of Print.


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State of the ablation nation: a review of ablative therapies for cure in the treatment of hepatocellular carcinoma

Future Oncology, Ahead of Print.


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What's new in small cell lung cancer – extensive disease? An overview on advances of systemic treatment in 2016

Future Oncology, Ahead of Print.


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Prognostic potential of neutrophil-to-lymphocyte ratio and lymphocyte nadir in stage III non-small-cell lung cancer

Future Oncology, Ahead of Print.


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Differences in Normal Tissue Response in the Esophagus between Proton and Photon Radiation Therapy for Non-Small-Cell Lung Cancer using in-vivo Imaging Biomarkers

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Recent Trends in Radiation Oncology Fellowship Training in the United States

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High frequency activity overriding cortico-cortical evoked potentials reflects altered excitability in the human epileptic focus

The localization of the "epileptogenic zone" is a crucial factor in epilepsy surgery for patients with medically refractory partial epilepsy. While several non-invasive examinations, such as scalp electroencephalogram (EEG), magnetoencephalography, magnetic resonance imaging (MRI), F-18-fluorodeoxyglucose - Positron Emission Tomography (FDG-PET), and ictal single-photon emission computed tomography (SPECT), are useful to evaluate the epileptogenic zone, these results are occasionally insufficient (Lesser et al., 2010), requiring an additional intracranial EEG evaluation.

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Stereo-electroencephalography identifies N2 sleep and spindles in human hippocampus

Physiological activity and related functions of the hippocampus are clearly modulated by sleep. For example, the sequences of hippocampal neuronal discharges in rats occurring during a space exploration are reactivated during both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep (Wilson et al., 1994; O'Neill et al., 2008). In humans, this so-called hippocampal replay was also highlighted in positron emission tomography (PET) in healthy volunteers during slow-wave sleep (SWS) the night following a mnesic episodic learning task (Peigneux et al., 2004).

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Unsupervised Detection and Removal of Muscle Artifacts from Scalp EEG Recordings using Canonical Correlation Analysis, Wavelets and Random Forests

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Synaptic damage underlies EEG abnormalities in postanoxic encephalopathy: a computational study

Of all comatose survivors of cardiac arrest, 46-48% are alive and independent in activities of daily living after 6 months (Hofmeijer et al., 2015; Nielsen et al., 2013). Continuous electroencephalography (cEEG) in the first 24 hours after resuscitation allows reliable identification of 50% of patients with either a good or poor outcome (Hofmeijer et al., 2015). Not only the EEG abnormalities as such, but also their timing and evolution are crucial indicators of the severity of the ischemic injury and prognosis (Tjepkema-Cloostermans et al., 2015).

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Diagnosing liver fibrosis and cirrhosis: Serum, imaging or tissue?

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Bowel Damage in Patients With Long-term Crohn`s Disease, Assessed by Magnetic Resonance Enterography and the Lemann Index

Magnetic Resonance Enterography (MRE) is used to evaluate the extent and complications of Crohn's disease (CD) and has recently been included in a score for bowel damage, the Lemann Index (LI). The long-term outcomes of CD are still uncertain and we aimed to assess the structural bowel changes after 20 years of CD by means of MRE and LI score.

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Ectopic pregnancy in women with inflammatory bowel disease – a 22 year nationwide cohort study

Data on early adverse pregnancy outcomes in inflammatory bowel disease (IBD) such as ectopic pregnancy (EP) remain limited. We assessed the risk of EP in pregnancies of Danish women with IBD compared to all other Danish women over a 22-year period. In addition, we examined the disease-specific risk of EP in pregnancies of women with ulcerative colitis (UC) or Crohn's disease (CD) who underwent IBD-related surgical procedures.

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Inflammatory Bowel Disease and Small Bowel Cancer Risk, Clinical Characteristics, and Histopathology— A Population-based Study

Inflammatory bowel disease (IBD) may increase risk of small bowel cancer (SBC). However, little is known of the characteristics and features of IBD-SBC, due to a low number of cases worldwide. We performed a population-based study of IBD and SBC to calculate risk and increase our understanding of clinical characteristics and histopathological and molecular features.

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High Value Care: Hepatocellular Carcinoma Surveillance

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BET Degradation Is More Effective Than Competitive Inhibition in T-ALL [Research Watch]

The BET degrader dBET6 induces global BRD4 depletion, whereas JQ1 preferentially affects superenhancers.

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A Lymphoreporter Mouse Model Identifies Midkine as a Metastasis Driver [Research Watch]

Midkine systemically induces neo-lymphangiogenesis via mTOR signaling in patients with melanoma.

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Correction: Nods for Atezolizumab and Nivolumab from FDA [Correction]

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The FLT3 Inhibitor Gilteritinib Has Activity in Patients with AML [Research Watch]

Gilteritinib was well tolerated in a phase I/II dose-escalation and dose-expansion study.

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New SNPs from Testicular Cancer GWAS [News in Brief]

Studies link disease to loci involved in transcription regulation, mitochondrial metabolism.

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ILF2 Is Upregulated by 1q21 Amplification in Multiple Myeloma [Research Watch]

ILF2 induces resistance to DNA-damaging agents by enhancing splicing of DNA damage response mRNAs.

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Brain metastases from colorectal cancer: characteristics and management

Background

Brain metastases (BMs) are the most common intracranial neoplasms in adults, but they rarely arise from colorectal cancer (CRC). The objective of this study was to report an overview of the characteristics and current management of CRC BMs.

Methods

A systematic review on CRC BMs was performed using Medline database from 1983 to 2015. The search was limited to studies published in English. Review articles, not relevant case report or studies or studies relating to animal and in vitro experiments were excluded.

Results

BMs occurred in 0.06–4% of patients with CRC. Most BMs were metachronous and were associated with lung (27–92%) and liver (12–80%) metastases. Treatment options depended on the number of BMs, the general conditions of the patient and the presence of other metastases. Most frequent treatment was whole-brain radiotherapy (WBRT) alone (36%), with median overall survival comprised between 2 and 9 months. Median overall survival was better after surgery alone (from 3 to 16.2 months), or combined with WBRT (from 7.6 to 14 months). After stereotactic radiosurgery alone, overall survival could reach 9.5 months. Many favourable prognostic factors were identified, such as high Karnofsky performance status, low recursive partitioning analysis classes, lack of extracranial disease, low number of BMs and possibility to perform surgical treatment.

Conclusion

BMs from CRC are rare. In the presence of favourable prognostic factors, an aggressive management including surgical resection with or without WBRT or stereotactic radiosurgery can improve the overall survival.

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Prognostic value of positron emission tomography/computed tomography for adjuvant chemotherapy of colon cancer

Background

To assess the prognostic value of preoperative ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with high-risk stage II or stage III colon cancer who underwent FOLFOX chemotherapy.

Methods

The study included 166 patients with high-risk stage II or stage III colon cancer who received FOLFOX4 chemotherapy. Retrospective patient data were analysed including pathological stage, histology, disease-free survival (DFS) and the maximum standardized uptake value (SUV_max) of the primary tumour on ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography. The primary end point was DFS.

Results

There were recurrences in 29 of the 166 patients (17.4%). Measuring the area under the receiver operating characteristic curve, the cut-off value of SUV_max with maximum sensitivity and specificity was 10.95. Using the Kaplan–Meier method, the DFS of the patients categorized by SUV_max tended to differ (P = 0.055). In univariate analyses, the risk factors for DFS were age over 70 years, higher N stage and neural invasion. SUV_max ≤ 10.95 showed a tendency, but was not significant (P = 0.0604). In multivariate analyses, the risk factors for DFS were age over 70 and neural invasion.

Conclusions

The results of this study suggest that high fluorodeoxyglucose uptake of the primary mass in high-risk stage II and stage III colon cancer does not significantly correlate with DFS.

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Emergency appendicectomy in Australia: findings from a multicentre, prospective study

Abstract

Background

Emergency appendicectomy is the most common emergency surgical procedure performed in Australia. Despite this frequency, there is a relative paucity of contemporary, broad-based, local data that examine how emergency appendicectomies are currently performed and what are the outcomes from these operations.

Methods

A multicentre, prospective, observational study was performed. Patients were recruited by local investigators for a period of 2 months with 30-day follow-up. Patients were eligible for study inclusion if they underwent an emergency appendicectomy for suspected acute appendicitis. The primary outcome of the study was the negative appendicectomy rate (NAR), with secondary outcomes including 30-day complication rates, method of operation and conversion rates.

Results

A total of 1189 patients were recruited across 27 centres. The NAR across all centres was 19.0%. 98.2% of appendicectomies were performed with a laparoscopic-first approach. The rate of conversion from laparoscopy to open operation was 2.4%. 9.4% of patients were recorded as having one or more of the following complications: readmission (6.6%), surgical site infection (1.9%), intra-abdominal abscess (2.7%) or further intervention (1.5%). Patients who had an open operation had higher rates of readmission and surgical site infection.

Conclusion

The NAR found in this study is within the traditional measures of acceptance; however, this rate is high when measured against modern international benchmarks.

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Adrenalectomy for incidentaloma: lessons learned from a single-centre series of 274 patients

Background

Adrenal incidentalomas are increasingly diagnosed and include a wide spectrum of lesions from benign adenomas to secreting or malignant lesions. The aim of the present study is to report a large single-institution experience of patients undergoing surgery for adrenal incidentaloma with particular attention to their diagnosis and post-operative course and the evolution of surgical practice over time.

Methods

From 1993 to 2013, 274 patients underwent adrenalectomy for incidentaloma. All patients underwent standardized clinical, hormonal and imaging assessments.

Results

Patients were mainly female (63.1%; n = 173), and the median age of patients was 56.5 years. After a complete hormonal evaluation, 47.9% (n = 129) of incidentalomas were classified as secreting tumours, including 24.4% (n = 67) subclinical cortisol-secreting adenomas and 18.9% (n = 52) pheochromocytomas. Adrenocortical carcinomas represented 9.5% (n = 26) of incidentalomas, and the risk of malignancy was significantly correlated with tumour size. The conversion rate after laparoscopic adrenalectomy (90.9%; n = 249) was 3.2% (n = 8). The overall morbidity rate was 13.9%, which included a 4.4% rate of severe morbidity (Clavien–Dindo ≥3). From 2008 onwards, there was a significant decrease (P < 0.001) in the use of surgical approaches for non-secreting adenomas.

Conclusion

After a complete work-up, half of the incidentalomas were classified as subclinical oversecreting adrenal lesions and 10% proved to be malignant adrenocortical carcinomas. The debatable use of surgical approaches for benign nonfunctioning adenomas significantly decreased over time.

http://ift.tt/2sPV4oS

Cancer-Associated Fibroblasts Share Characteristics and Pro-tumorigenic Activity with Mesenchymal Stromal Cells

Cancer-associated fibroblasts (CAF) have been suggested to originate from mesenchymal stromal cells (MSC), but their relationship to MSC is not clear. Here we have isolated from primary human neuroblastoma (NB) tumors a population of αFAP- and FSP-1-expressing CAF that share phenotypic and functional characteristics with bone marrow-derived MSC (BM-MSC). Analysis of human NB tumors also confirmed the presence of αFAP- and FSP-1-positive cells in the tumor stroma, and their presence correlated with that of M2 tumor-associated macrophages. These cells (designated CAF-MSC) enhanced in vitro NB cell proliferation, survival, and resistance to chemotherapy and stimulated NB tumor engraftment and growth in immunodeficient mice, indicating an effect independent of the immune system. The pro-tumorigenic activity of MSC in vitro and in xenografted mice was dependent on the co-activation of JAK2/STAT3 and MEK/ERK1/2 in NB cells. In a mouse model of orthotopically implanted NB cells, inhibition of JAK2/STAT3 and MEK/ERK/1/2 by ruxolitinib and trametinib potentiated tumor response to etoposide and increased overall survival. These data point to a new type pro-tumorigenic CAF in the tumor microenvironment (TME) of NB and to STAT3 and ERK1/2 as mediators of their activity.

http://ift.tt/2tSbgFO

Kindlin-2 regulates the growth of breast cancer tumors by activating CSF-1-mediated macrophage infiltration

Interplay between tumor cells and host cells in the tumor microenvironment dictates the development of all cancers. In breast cancer, malignant cells educate host macrophages to adopt a pro-tumorigenic phenotype. In this study, we show how the integrin regulatory protein kindlin-2 (FERMT2) promotes metastatic progression of breast cancer through the recruitment and subversion of host macrophages. Kindlin-2 expression was elevated in BC biopsy tissues where its levels correlated with reduced patient survival. Based on these observations, we used CRISPR/Cas9 technology to ablate Kindlin-2 expression in human MDA-MB-231 and murine 4T1 breast cancer cells. Kindlin-2 deficiency inhibited invasive and migratory properties in vitro without affecting proliferation rates. However, in vivo tumor outgrowth was inhibited by >80% in a manner associated with reduced macrophage infiltration and secretion of the macrophage attractant and growth factor CSF-1. The observed loss of CSF-1 appeared to be caused by a more proximal deficiency in TGF-β-dependent signaling in Kindlin-2 deficient cells. Collectively, our results illuminate a Kindlin-2/TGF-β/CSF-1 signaling axis employed by breast cancer cells to capture host macrophage functions that drive tumor progression.

http://ift.tt/2szLQbO

Resistance to the antibody-drug conjugate T-DM1 is based in a reduction in lysosomal proteolytic activity

Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate (ADC) that was approved recently to treat HER2+ breast cancers. Despite its impressive clinical efficacy in many patients, intrinsic and acquired resistance to T-DM1 has emerged as a challenge. To identify mechanisms of T-DM1 resistance, we isolated several resistant HER2+ clones exhibiting stable drug refractoriness in vitro and in vivo. Genomic comparisons showed substantial differences among three of the isolated clones, indicating several potential mechanisms of resistance to T-DM1. However, we observed no differences in HER2 levels and signaling among the resistant models and parental HER2+ cells. Bioinformatics studies suggested that intracellular trafficking of T-DM1 could underlie resistance to T-DM1, and systematic analysis of the path followed by T-DM1 showed that the early steps in the internalization of the drug were unaltered. However, in some of the resistant clones T-DM1 accumulated in lysosomes. In these clones, lysosomal pH was increased and the proteolytic activity of these organelles was deranged. These results were confirmed in T-DM1-resistant cells from patient-derived HER2+ samples. We postulate that resistance to T-DM1 occurs through multiple mechanisms, one of which is impaired lysosomal proteolytic activity. Since other ADC may use the same internalization-degradation pathway to deliver active payloads, strategies aimed at restoring lysosomal functionality might overcome resistance to ADC-based therapies and improve their effectiveness.

http://ift.tt/2tSoNNn

Huwe1 sustains normal ovarian epithelial cell transformation and tumor growth through the histone H1.3-H19 cascade

Ubiquitination-directed protein degradation is important in many cancers for tumor initiation and maintenance, and E3 ligases containing HECT domains are emerging as new therapeutic targets. In contrast to many other E3 ligases, the role of HUWE1 in ovarian cancer where HUWE1 is dysregulated has been unclear. Here we report that genetic deletion of Huwe1 in the mouse inhibits transformation of ovary surface epithelium cells without significantly affecting cell survival and apoptosis, and that Huwe1 deletion after tumors have been initiated inhibits tumor growth. In Huwe1-deficient cells, expression of histone H1.3 increased, inhibiting the expression of noncoding RNA H19. H19 silencing phenocopied the effects of Huwe1 deficiency, whereas H1.3 silencing partially rescued the expression of H19 and the Huwe1 null phenotype. Inducible silencing of HUWE1 in human ovarian cancer cells produced a similar phenotype. Mechanistically, HUWE1 bound and ubiquitinated H1.3, which was consequently marked for destruction by proteasomes. Our results establish that HUWE1 plays an essential role in promoting ovarian cancer.

http://ift.tt/2szjajd

Proinflammatory CXCL12-CXCR4/CXCR7 signaling axis drives Myc-induced prostate cancer in obese mice

Obesity is a prognostic risk factor in the progression of prostate cancer (PCa), however, the molecular mechanisms involved are unclear. In this study, we provide preclinical proof of concept for the role of a pro-inflammatory CXCL12-CXCR4/CXCR7 signaling axis in an obesity-driven mouse model of HiMyc prostate cancer. Analysis of the stromal vascular fraction (SVF) from periprostatic white adipose tissue (ppWAT) from obese HiMyc mice at 6 months of age revealed a dramatic increase in mRNAs encoding various chemokines, cytokines, growth factors and angiogenesis mediators, with CXCL12 among the most significantly upregulated genes. Immunofluorescence staining of ventral prostate tissue from obese HiMyc mice revealed high levels of CXCL12 in the stromal compartment as well as high staining for CXCR4 and CXCR7 in the epithelial compartment of tumors. PCa cell lines derived from HiMyc tumors (HMVP2 and derivative cell lines) displayed increased protein expression of both CXCR4 and CXCR7 compared to protein lysates from a non-tumorigenic prostate epithelial cell line (NMVP cells). CXCL12 treatment stimulated migration and invasion of HMVP2 cells but not NMVP cells. These effects of CXCL12 on HMVP2 cells were inhibited by the CXCR4 antagonist AMD3100 as well as knockdown of either CXCR4 or CXCR7. CXCL12 treatment also produced rapid activation of STAT3, NFkB, and MAPK signaling in HMVP2 cells which was again attenuated by either AMD3100 or knockdown of CXCR4 or CXCR7. Collectively, these data suggest that CXCL12 secreted by stromal cells activates invasiveness of PCa cells and may play a role in driving tumor progression in obesity. Targeting the CXCL12-CXCR4/CXCR7 axis could lead to novel approaches for offsetting the effects of obesity on PCa progression.

http://ift.tt/2tStoPR

Post-transcriptional regulation of PARG mRNA by HuR facilitates DNA repair and resistance to PARP inhibitors

The majority of pancreatic ductal adenocarcinomas (PDA) rely on the mRNA stability factor HuR (ELAV-L1) to drive cancer growth and progression. Here we show that CRISPR-Cas9-mediated silencing of the HuR locus increases the relative sensitivity of PDA cells to PARP inhibitors (PARPi). PDA cells treated with PARPi stimulated translocation of HuR from the nucleus to the cytoplasm, specifically promoting stabilization of a new target, polyADP-ribose glycohydrolase (PARG) mRNA, by binding a unique sequence embedded in its 3′ untranslated region (UTR). HuR-dependent upregulation of PARG expression facilitated DNA repair via hydrolysis of polyADP-ribose on related repair proteins. Accordingly, strategies to inhibit HuR directly promoted DNA damage accumulation, inefficient PAR removal, and persistent PARP-1 residency on chromatin (PARP-1 trapping). Immunoprecipitation assays demonstrated that the PARP1 protein binds and post-translationally modifies HuR in PARPi-treated PDA cells. In a mouse xenograft model of human PDA, PARPi monotherapy combined with targeted silencing of HuR significantly reduced tumor growth compared to PARPi therapy alone. Our results highlight the HuR-PARG axis as an opportunity to enhance PARPi-based therapies.

http://ift.tt/2sz2nNj

SOX5/6/21 prevent oncogene-driven transformation of brain stem cells

Molecular mechanisms preventing self-renewing brain stem cells from oncogenic transformation are poorly defined. We show that the expression levels of SOX5, SOX6 and SOX21 (SOX5/6/21) transcription factors increase in stem cells of the subventricular zone (SVZ) upon oncogenic stress, whereas their expression in human glioma decreases during malignant progression. Elevated levels of SOX5/6/21 promoted SVZ cells to exit the cell cycle, while genetic ablation of SOX5/6/21 dramatically increased the capacity of these cells to form glioma-like tumors in an oncogene-driven mouse brain tumor model. Loss-of-function experiments revealed that SOX5/6/21 prevent detrimental hyper proliferation of oncogene expressing SVZ cells by facilitating an anti-proliferative expression profile. Consistently, restoring high levels of SOX5/6/21 in human primary glioblastoma cells enabled expression of CDK inhibitors and decreased p53 protein turnover, which blocked their tumorgenic capacity through cellular senescence and apoptosis. Altogether, these results provide evidence that SOX5/6/21 play a central role in driving a tumor suppressor response in brain stem cells upon oncogenic insult.

http://ift.tt/2tSuXNM

iSepsis – Vena Caval Ultrasonography – Just Don’t Do It!

iSepsis - Vena Caval Ultrasonography is useless for assessing volume status.

EMCrit by Paul Marik.

http://ift.tt/2szz911

Decreased brain serotonin turnover rate following administration of Sharbat-e-Ahmed Shah produces antidepressant and anxiolytic effect in rats

Abstract

Sharbat-e-Ahmed Shah (SAS) has usually been used in Traditional Unani Medicine (TUM) for depression and insomnia but still not evaluated for its anti-depressant and Neuropharmacological activity. In the present study, a Human dose of SAS (0.6 ml/kg/d) was administered orally to the rats for 15 consecutive days. Antidepressant and anxiolytic were screened scientifically in rats by using Forced swim test and light and dark box test. At the end of study high-performance liquid chromatographic (HPLC) method with electrochemical (EC) detector was used for the measurement of blood and brain tryptophan and brain serotonin levels. The present reported results are according to what is known in TUM, where is prescribed as an antidepressant agent. After the administration, SAS (at a human dose for 15 days) reduced the immobility time in rats analogous to Imipramine (positive control) indicating the antidepressant effect of SAS. In the present study, Diazepam or SAS (0.6 ml/kg/day) treated rats stayed in the illuminated side of the light–dark box, as compare to control rats (Veh, 134.62 ± 4.430 s; SAS 0.6 ml/kg, 192.2 ± 8.11 s; DZP 1.0 mg/kg, 205.21.20 ± 10.26 s, p < 0.05). It was also observed that SAS increased the availability of tryptophan in blood and brain and hence increases 5-hydroxytryptamine (Serotonin: 5HT) in the brain. At the end, it was concluded that SAS contains some active principles which increase the availability of neurochemical (tryptophan and 5HT) and decrease the 5HT turnover rate thus causes antidepressant and anxiolytic effects in experimental animals.

http://ift.tt/2sWGln1

A rare case of malignant solitary fibrous tumor in prostate with review of the literature

Solitary fibrous tumor is an uncommon soft tissue neoplasm with intermediate biological behavior, which rarely metastasizes. Malignant solitary fibrous tumor, although not clearly defined, is rarely described ...

http://ift.tt/2uApmsR

Genomic characterization of a large plasmid containing a bla NDM-1 gene carried on Salmonella enterica serovar Indiana C629 isolate from China

The bla NDM-1 gene in Salmonella species is mostly reported in clinical cases, but is rarely isolated from red and white meat in China.

http://ift.tt/2sQ3YTm

ES301A Endoscope Sheath for ES301

FOR VETERINARY USE ONLY

Features

• 5mm Diameter at tip
• 116mm Length
• 0 Degree Angle
• Stainless Steel
• Designed for use with ES301 Endoscope

For more information contact sales@fireflyglobal.com

http://ift.tt/2tqY49T

ES301 Endoscope

FOR VETERINARY USE ONLY

Features

• 2.7mm Diameter
• 107mm Length
• 0 Degree Angle
• Stainless Steel
• Ideal for use with:
  • DE1250 Wireless Endoscope Camera
  • ES201 Portable LED Light Source

For more information contact sales@fireflyglobal.com

http://ift.tt/2tqVvV3

ES302 Endoscope

FOR VETERINARY USE ONLY

Features

• 4mm Diameter
• 175mm Length
• 0 Degree Angle
• Stainless Steel
• Ideal for use with:
  • KT2130 Wireless Veterinary Endoscopy Set
  • DE1250 Wireless Endoscope Camera
  • ES201 Portable LED Light Source

For more information contact sales@fireflyglobal.com

http://ift.tt/2tqLszf

Firefly will be at FIME 2017

Firefly will be in Booth #B.J31 at FIME 2017! Make sure to buy your tickets to Orlando – The show is NOT in Miami this year!

• There will be live demonstrations of:

DE1250 Wireless Endoscope Camera R3800 Redfin Full HD Camera System ES201 Compact LED Light Source DE550 Wireless Video Otoscope

Come by the booth to see a demo!

http://ift.tt/2tqKYcw

A Kidney Graft Survival Calculator that Accounts for Mismatches in Age, Sex, HLA, and Body Size

Background and objectives

Outcomes for transplants from living unrelated donors are of particular interest in kidney paired donation (KPD) programs where exchanges can be arranged between incompatible donor-recipient pairs or chains created from nondirected/altruistic donors.

Design, setting, participants, & measurements

Using Scientific Registry of Transplant Recipients data, we analyzed 232,705 recipients of kidney-alone transplants from 1998 to 2012. Graft failure rates were estimated using Cox models for recipients of kidney transplants from living unrelated, living related, and deceased donors. Models were adjusted for year of transplant and donor and recipient characteristics, with particular attention to mismatches in age, sex, human leukocyte antigens (HLA), body size, and weight.

Results

The dependence of graft failure on increasing donor age was less pronounced for living-donor than for deceased-donor transplants. Male donor–to–male recipient transplants had lower graft failure, particularly better than female to male (5%–13% lower risk). HLA mismatch was important in all donor types. Obesity of both the recipient (8%–18% higher risk) and donor (5%–11% higher risk) was associated with higher graft loss, as were donor-recipient weight ratios of <75%, compared with transplants where both parties were of similar weight (9%–12% higher risk). These models are used to create a calculator of estimated graft survival for living donors.

Conclusions

This calculator provides useful information to donors, candidates, and physicians of estimated outcomes and potentially in allowing candidates to choose among several living donors. It may also help inform candidates with compatible donors on the advisability of joining a KPD program.

http://ift.tt/2tVPgcx

Are Peritoneal Dialysis Center Characteristics a Modifiable Risk Factor to Improve Peritoneal Dialysis Outcomes?

http://ift.tt/2uTLhua

Paroxysmal Atrial Fibrillation in a Patient on Hemodialysis

http://ift.tt/2tVziPM

Kidney Function Can Predict Pregnancy Outcomes

http://ift.tt/2tVbAmD

The Potential of Pharmacogenomics to Advance Kidney Disease Treatment

http://ift.tt/2uTtIKM

Infection Monitoring in Dialysis Units: A Plea for "Cleaner" Data

http://ift.tt/2uTpi6H

Calcium-Sensing Receptor Genotype and Response to Cinacalcet in Patients Undergoing Hemodialysis

Background and objectives

We tested the hypothesis that single nucleotide polymorphisms (SNPs) in the calcium-sensing receptor (CASR) alter the response to the calcimimetic cinacalcet.

Design, setting, participants, & measurements

We analyzed DNA samples in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial, a randomized trial comparing cinacalcet to placebo on a background of usual care. Of the 3883 patients randomized, 1919 (49%) consented to DNA collection, and samples from 1852 participants were genotyped for 18 CASR polymorphisms. The European ancestry (EA; n=1067) and African ancestry (AfAn; n=405) groups were assessed separately. SNPs in CASR were tested for their association with biochemical measures of mineral metabolism at baseline, percent change from baseline to 20 weeks, and risk of clinical fracture as dependent variables.

Results

There were modest associations of CASR SNPs with increased baseline serum parathyroid hormone and bone alkaline phosphatase primarily with the minor allele in the EA group (all P≤0.03), but not in the AfAn sample. In contrast, there was a modest association of decreased baseline serum calcium and FGF23 with CASR SNPs (P=0.04) primarily with the minor allele in the AfAn but not in the EA sample. The minor allele of two SNPs was associated with decreased percent reduction in parathyroid hormone from baseline to 20 weeks in the EA population (P<0.04) and this was not altered with cinacalcet. In both EA and AfAn, the same SNP (rs9740) was associated with decreased calcium with cinacalcet treatment (EA and AfAn P≤0.03). Three SNPs in high linkage disequilibrium were associated with a higher risk of clinical fracture that was attenuated by cinacalcet treatment in the EA sample (P<0.04).

Conclusions

These modest associations, if validated, may provide explanations for differences in CKD–mineral bone disorder observed in EA and AfAn populations, and for differential biochemical responses to calcimimetics.

http://ift.tt/2tVDSh4

Anti-Glomerular Basement Membrane Disease

Anti–glomerular basement membrane (anti-GBM) disease is a rare small vessel vasculitis that affects the capillary beds of the kidneys and lungs. It is an archetypic autoimmune disease, caused by the development of directly pathogenic autoantibodies targeting a well characterized autoantigen expressed in the basement membranes of these organs, although the inciting events that induce the autoimmune response are not fully understood. The recent confirmation of spatial and temporal clustering of cases suggests that environmental factors, including infection, may trigger disease in genetically susceptible individuals. The majority of patients develop widespread glomerular crescent formation, presenting with features of rapidly progressive GN, and 40%–60% will have concurrent alveolar hemorrhage. Treatment aims to rapidly remove pathogenic autoantibody, typically with the use of plasma exchange, along with steroids and cytotoxic therapy to prevent ongoing autoantibody production and tissue inflammation. Retrospective cohort studies suggest that when this combination of treatment is started early, the majority of patients will have good renal outcome, although presentation with oligoanuria, a high proportion of glomerular crescents, or kidney failure requiring dialysis augur badly for renal prognosis. Relapse and recurrent disease after kidney transplantation are both uncommon, although de novo anti-GBM disease after transplantation for Alport syndrome is a recognized phenomenon. Copresentation with other kidney diseases such as ANCA-associated vasculitis and membranous nephropathy seems to occur at a higher frequency than would be expected by chance alone, and in addition atypical presentations of anti-GBM disease are increasingly reported. These observations highlight the need for future work to further delineate the immunopathogenic mechanisms of anti-GBM disease, and how to better refine and improve treatments, particularly for patients presenting with adverse prognostic factors.

http://ift.tt/2tVFFCN

Midterm eGFR and Adverse Pregnancy Outcomes: The Clinical Significance of Gestational Hyperfiltration

Background and objectives

Although hemodynamic adaptation plays a crucial role in maintaining gestation, the clinical significance of midterm renal hyperfiltration (MRH) on pregnancy outcomes is unknown.

Design, setting, participants, & measurements

This was an observational cohort study. Women with a singleton pregnancy and a serum creatinine measurement during their second trimester were followed at two university hospitals in Korea between 2001 and 2015. Those with substantial renal function impairment or who delivered during the second trimester were not considered. MRH was represented by the highest eGFR, which was calculated using the Chronic Kidney Disease Epidemiology Collaboration method. An adverse pregnancy event was defined by the composition of preterm birth (gestational age <37 weeks), low birth weight (<2.5 kg), and preeclampsia.

Results

Data from 1931 pregnancies were included. The relationship between midterm eGFR and adverse pregnancy outcomes, which occurred in 538 mothers, was defined by a nonlinear U-shaped curve. The adjusted odds ratio and associated 95% confidence interval (95% CI) of an adverse pregnancy outcome for eGFR levels below and above the reference level of 120–150 ml/min per 1.73 m² were 1.97 (95% CI, 1.34 to 2.89; P<0.001) for ≥150 ml/min per 1.73 m²; 1.57 (95% CI, 1.23 to 2.00; P<0.001) for 90–120 ml/min per 1.73 m²; and 4.93 (95% CI, 1.97 to 12.31; P<0.001) for 60–90 ml/min per 1.73 m². Moreover, among mothers without baseline CKD, women with adverse pregnancy outcomes had less prominent MRH than those without (P<0.001).

Conclusions

We identified a unique U-shaped relationship between midterm eGFR and adverse pregnancy outcomes, and the optimal range of midterm eGFR levels was 120–150 ml/min per 1.73 m². In those without evident functional renal impairment, the absence of prominent MRH might be a significant risk factor for poor pregnancy outcomes.

http://ift.tt/2uTNl5I

Current Uses of Dietary Therapy for Patients with Far-Advanced CKD

For several decades, inquiry concerning dietary therapy for nondialyzed patients with CKD has focused mainly on its capability to retard progression of CKD. However, several studies published in recent years indicate that, independent of whether diet can delay progression of CKD, well designed low-protein diets may provide a number of benefits for people with advanced CKD who are close to requiring or actually in need of RRT. Dietary therapy may both maintain good nutritional status and safely delay the need for chronic dialysis in such patients, offering the possibility of improving quality of life and reducing health care costs. With the growing interest in incremental dialysis, dietary therapy may enable lower doses of dialysis to be safely and effectively used, even as GFR continues to decrease. Such combinations of dietary and incremental dialysis therapy might slow the rate of loss of residual GFR, possibly reduce mortality in patients with advanced CKD, improve quality of life, and also, reduce health care costs. The amount of evidence that supports these possibilities is limited, and more well designed, randomized clinical trials are clearly indicated.

http://ift.tt/2tVJoQB

Renal Functional Outcomes after Surgery, Ablation, and Active Surveillance of Localized Renal Tumors: A Systematic Review and Meta-Analysis

Background and objectives

Management strategies for localized renal masses suspicious for renal cell carcinoma include radical nephrectomy, partial nephrectomy, thermal ablation, and active surveillance. Given favorable survival outcomes across strategies, renal preservation is often of paramount concern. To inform clinical decision making, we performed a systematic review and meta-analysis of studies comparing renal functional outcomes for radical nephrectomy, partial nephrectomy, thermal ablation, and active surveillance.

Design, settings, participants, & measurements

We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from January 1, 1997 to May 1, 2015 to identify comparative studies reporting renal functional outcomes. Meta-analyses were performed for change in eGFR, incidence of CKD, and AKI.

Results

We found 58 articles reporting on relevant renal functional outcomes. Meta-analyses showed that final eGFR fell 10.5 ml/min per 1.73 m² lower for radical nephrectomy compared with partial nephrectomy and indicated higher risk of CKD stage 3 or worse (relative risk, 2.56; 95% confidence interval, 1.97 to 3.32) and ESRD for radical nephrectomy compared with partial nephrectomy. Overall risk of AKI was similar for radical nephrectomy and partial nephrectomy, but studies suggested higher risk for radical nephrectomy among T1a tumors (relative risk, 1.37; 95% confidence interval, 1.13 to 1.66). In general, similar findings of worse renal function for radical nephrectomy compared with thermal ablation and active surveillance were observed. No differences in renal functional outcomes were observed for partial nephrectomy versus thermal ablation. The overall rate of ESRD was low among all management strategies (0.4%–2.8%).

Conclusions

Renal functional implications varied across management strategies for localized renal masses, with worse postoperative renal function for patients undergoing radical nephrectomy compared with other strategies and similar outcomes for partial nephrectomy and thermal ablation. Further attention is needed to quantify the changes in renal function associated with active surveillance and nephron-sparing approaches for patients with preexisting CKD.

http://ift.tt/2uTZszF

Association of Parameters of Mineral Bone Disorder with Mortality in Patients on Hemodialysis according to Level of Residual Kidney Function

Background and objectives

The relationship between mineral and bone disorders and survival according to residual kidney function status has not been previously studied in patients on hemodialysis. We hypothesized that residual kidney function, defined by renal urea clearance, modifies the association between mineral and bone disorder parameters and mortality.

Design, setting, participants, & measurements

The associations of serum phosphorus, albumin-corrected calcium, intact parathyroid hormone, and alkaline phosphatase with all-cause mortality were examined across three strata (<1.5, 1.5 to <3.0, and ≥3.0 ml/min per 1.73 m²) of baseline residual renal urea clearance using Cox models adjusted for clinical characteristics and laboratory measurements in 35,114 incident hemodialysis patients from a large United States dialysis organization over the period of 2007–2011.

Results

A total of 8102 (23%) patients died during the median follow-up of 1.3 years (interquartile range, 0.6–2.3 years). There was an incremental mortality risk across higher serum phosphorus concentrations, which was pronounced among patients with higher residual renal urea clearance (P_interaction=0.001). Lower concentrations of serum intact parathyroid hormone were associated with higher mortality among patients with low residual renal urea clearance (i.e., <1.5 ml/min per 1.73 m²), whereas higher concentrations showed a higher mortality risk among patients with greater residual renal urea clearance (i.e., ≥1.5 ml/min per 1.73 m²; P_interaction<0.001). Higher serum corrected total calcium and higher alkaline phosphatase concentrations consistently showed higher mortality risk (P_trend<0.001 for both) irrespective of residual renal urea clearance strata (P_interaction=0.34 and P_interaction=0.53, respectively).

Conclusions

Residual kidney function modified the mortality risk associated with serum phosphorus and intact parathyroid hormone among incident hemodialysis patients. Future studies are needed to examine whether taking account for residual kidney function into the assessment of mortality risk associated with serum phosphorus and intact parathyroid hormone improves patient management and clinical outcomes in the hemodialysis population.

http://ift.tt/2tVFsiF

A Systematic Review of the Prevalence and Associations of Limited Health Literacy in CKD

Background and objectives

The self-management and decision-making skills required to manage CKD successfully may be diminished in those with low health literacy. A 2012 review identified five papers reporting the prevalence of limited health literacy in CKD, largely from United States dialysis populations. The literature has expanded considerably since.

Design, setting, participants, & measurements

We used systematic review, pooled prevalence analysis, metaregression, and exploration of heterogeneity in studies of patients with CKD (all stages).

Results

From 433 studies, 15 new studies met the inclusion criteria and were analyzed together with five studies from the 2012 review. These included 13 cross-sectional surveys, five cohort studies (using baseline data), and two using baseline clinical trial data. Most (19 of 20) were from the United States. In total, 12,324 patients were studied (3529 nondialysis CKD, 5289 dialysis, 2560 transplant, and 946 with unspecified CKD; median =198.5; IQR, 128.5–260 per study). Median prevalence of limited health literacy within studies was 23% (IQR, 16%–33%), and pooled prevalence was 25% (95% confidence interval, 20% to 30%) with significant between-study heterogeneity (I²=97%). Pooled prevalence of limited health literacy was 25% (95% confidence interval, 16% to 33%; I²=97%) among patients with CKD not on dialysis, 27% (95% confidence interval, 19% to 35%; I²=96%) among patients on dialysis, and 14% (95% confidence interval, 7% to 21%; I²=97%) among patients with transplants. A higher proportion of nonwhite participants was associated with increased limited health literacy prevalence (P=0.04), but participant age was not (P=0.40). Within studies, nonwhite ethnicity and low socioeconomic status were consistently and independently associated with limited health literacy. Studies were of low or moderate quality. Within-study participant selection criteria had potential to introduce bias.

Conclusions

Limited health literacy is common in CKD, especially among individuals with low socioeconomic status and nonwhite ethnicity. This has implications for the design of self-management and decision-making initiatives to promote equity of care and improve quality. Lower prevalence among patients with transplants may reflect selection of patients with higher health literacy for transplantation either because of less comorbidity in this group or as a direct effect of health literacy on access to transplantation.

http://ift.tt/2uTGHMA

National Healthcare Safety Network (NHSN) Dialysis Event Surveillance Report for 2014

Background and objectives

Persons receiving outpatient hemodialysis are at risk for bloodstream and vascular access infections. The Centers for Disease Control and Prevention conducts surveillance for these infections through the National Healthcare Safety Network. We summarize 2014 data submitted to National Healthcare Safety Network Dialysis Event Surveillance.

Design, setting, participants, & measurements

Dialysis facilities report three types of dialysis events (bloodstream infections; intravenous antimicrobial starts; and pus, redness, or increased swelling at the hemodialysis vascular access site). Denominator data consist of the number of hemodialysis outpatients treated at the facility during the first 2 working days of each month. We calculated dialysis event rates stratified by vascular access type (e.g., arteriovenous fistula, arteriovenous graft, or central venous catheter) and standardized infection ratios (comparing individual facility observed with predicted numbers of infections) for bloodstream infections. We described pathogens identified among bloodstream infections.

Results

A total of 6005 outpatient hemodialysis facilities reported dialysis event data for 2014 to the National Healthcare Safety Network. These facilities reported 160,971 dialysis events, including 29,516 bloodstream infections, 149,722 intravenous antimicrobial starts, and 38,310 pus, redness, or increased swelling at the hemodialysis vascular access site events; 22,576 (76.5%) bloodstream infections were considered vascular access related. Most bloodstream infections (63.0%) and access-related bloodstream infections (69.8%) occurred in patients with a central venous catheter. The rate of bloodstream infections per 100 patient-months was 0.64 (0.26 for arteriovenous fistula, 0.39 for arteriovenous graft, and 2.16 for central venous catheter). Other dialysis event rates were also highest among patients with a central venous catheter. Facility bloodstream infection standardized infection ratio distribution was positively skewed with a median of 0.84. Staphylococcus aureus was the most commonly isolated bloodstream infection pathogen (30.6%), and 39.5% of S. aureus isolates tested were resistant to methicillin.

Conclusions

The 2014 National Healthcare Safety Network Dialysis Event data represent nearly all United States outpatient dialysis facilities. Rates of infection and other dialysis events were highest among patients with a central venous catheter compared with other vascular access types. Surveillance data can help define the epidemiology of important infections in this patient population.

http://ift.tt/2tVnJYW

Characteristics and Outcomes of In-Hospital Palliative Care Consultation among Patients with Renal Disease Versus Other Serious Illnesses

Background and objectives

Despite significant morbidity and mortality associated with ESRD, these patients receive palliative care services much less often than patients with other serious illnesses, perhaps because they are perceived as having less need for such services. We compared characteristics and outcomes of hospitalized patients in the United States who had a palliative care consultation for renal disease versus other serious illnesses.

Design, setting, participants, & measurements

In this observational study, we used data collected by the Palliative Care Quality Network, a national palliative care quality improvement collaborative. The 23-item Palliative Care Quality Network core dataset includes demographics, processes of care, and clinical outcomes of all hospitalized patients who received a palliative care consultation between December of 2012 and March of 2016.

Results

The cohort included 33,183 patients, of whom 1057 (3.2%) had renal disease as the primary reason for palliative care consultation. Mean age was 71.9 (SD=16.8) or 72.8 (SD=15.2) years old for those with renal disease or other illnesses, respectively. At the time of consultation, patients with renal disease or other illnesses had similarly low mean Palliative Performance Scale scores (36.0% versus 34.9%, respectively; P=0.08) and reported similar moderate to severe anxiety (14.9% versus 15.3%, respectively; P=0.90) and nausea (5.9% versus 5.9%, respectively; P>0.99). Symptoms improved similarly after consultation regardless of diagnosis (P≥0.50), except anxiety, which improved more often among those with renal disease (92.0% versus 66.0%, respectively; P=0.002). Although change in code status was similar among patients with renal disease versus other illnesses, from over 60% full code initially to 30% full code after palliative care consultation, fewer patients with renal disease were referred to hospice than those with other illnesses (30.7% versus 37.6%, respectively; P<0.001).

Conclusions

Hospitalized patients with renal disease referred for palliative care consultation had similar palliative care needs, improved symptom management, and clarification of goals of care as those with other serious illnesses.

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Correction

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Multicenter Registry Analysis of Center Characteristics Associated with Technique Failure in Patients on Incident Peritoneal Dialysis

Background and objectives

Technique failure is a major limitation of peritoneal dialysis. Our study aimed to identify center- and patient-level predictors of peritoneal dialysis technique failure.

Design, setting, participants, & measurements

All patients on incident peritoneal dialysis in Australia from 2004 to 2014 were included in the study using data from the Australia and New Zealand Dialysis and Transplant Registry. Center- and patient-level characteristics associated with technique failure were evaluated using Cox shared frailty models. Death-censored technique failure and cause-specific technique failure were analyzed as secondary outcomes.

Results

The study included 9362 patients from 51 centers in Australia. The technique failure rate was 0.35 (95% confidence interval, 0.34 to 0.36) episodes per patient-year, with a sevenfold variation across centers that was mainly associated with center-level characteristics. Technique failure was significantly less likely in centers with larger proportions of patients treated with peritoneal dialysis (>29%; adjusted hazard ratio, 0.83; 95% confidence interval, 0.73 to 0.94) and more likely in smaller centers (<16 new patients per year; adjusted hazard ratio, 1.10; 95% confidence interval, 1.00 to 1.21) and centers with lower proportions of patients achieving target baseline serum phosphate levels (<40%; adjusted hazard ratio, 1.15; 95% confidence interval, 1.03 to 1.29). Similar results were observed for death-censored technique failure, except that center target phosphate achievement was not significantly associated. Technique failure due to infection, social reasons, mechanical causes, or death was variably associated with center size, proportion of patients on peritoneal dialysis, and/or target phosphate achievement, automated peritoneal dialysis exposure, icodextrin use, and antifungal use. The variation of hazards of technique failure across centers was reduced by 28% after adjusting for patient-specific factors and an additional 53% after adding center-specific factors.

Conclusions

Technique failure varies widely across centers in Australia. A significant proportion of this variation is related to potentially modifiable center characteristics, including peritoneal dialysis center size, proportion of patients on peritoneal dialysis, and proportion of patients on peritoneal dialysis achieving target phosphate level.

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A Woman with ESRD with Increasing Need for Erythropoietin to Maintain Hemoglobin

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Frontmatter

Journal Name: Biological Chemistry
Volume: 398
Issue: 8
Pages: i-iii

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Viruses and cancer: molecular relations and perspectives

Journal Name: Biological Chemistry
Volume: 398
Issue: 8
Pages: 815-816

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Chronic viral hepatitis and its association with liver cancer

Journal Name: Biological Chemistry
Volume: 398
Issue: 8
Pages: 817-837

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The biology of JC polyomavirus

Journal Name: Biological Chemistry
Volume: 398
Issue: 8
Pages: 839-855

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Rhadinoviral interferon regulatory factor homologues

Journal Name: Biological Chemistry
Volume: 398
Issue: 8
Pages: 857-870

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Human papillomavirus first and second generation vaccines–current status and future directions

Journal Name: Biological Chemistry
Volume: 398
Issue: 8
Pages: 871-889

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Employing RNA viruses to fight cancer: novel insights into oncolytic virotherapy

Journal Name: Biological Chemistry
Volume: 398
Issue: 8
Pages: 891-909

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MicroRNAs are important regulators of drug resistance in colorectal cancer

Journal Name: Biological Chemistry
Volume: 398
Issue: 8
Pages: 929-938

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In vitro modelling of familial amyloidotic polyneuropathy allows quantitative detection of transthyretin amyloid fibril-like structures in hepatic derivatives of patient-specific induced pluripotent stem cells

Journal Name: Biological Chemistry
Volume: 398
Issue: 8
Pages: 939-954

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Pairing Increases Activation of V1aR, but not OTR, in Auditory Regions of Zebra Finches: The Importance of Signal Modality in Nonapeptide-Social Behavior Relationships

Abstract

Social relationships are complex, involving the production and comprehension of signals, individual recognition, and close coordination of behavior between two or more individuals. The nonapeptides oxytocin and vasopressin are widely believed to regulate social relationships. These findings come largely from prairie voles, in which nonapeptide receptors in olfactory neural circuits drive pair bonding. This research is assumed to apply to all species. Previous reviews have offered two competing hypotheses. The work of Sarah Newman has implicated a common neural network across species, the Social Behavior Network. In contrast, others have suggested that there are signal modality-specific networks that regulate social behavior. Our research focuses on evaluating these two competing hypotheses in the zebra finch, a species that relies heavily on vocal/auditory signals for communication, specifically the neural circuits underlying singing in males and song perception in females. We have demonstrated that the quality of vocal interactions is highly important for the formation of long-term monogamous bonds in zebra finches. Qualitative evidence at first suggests that nonapeptide receptor distributions are very different between monogamous rodents (olfactory species) and monogamous birds (vocal/auditory species). However, we have demonstrated that social bonding behaviors are not only correlated with activation of nonapeptide receptors in vocal and auditory circuits, but also involve regions of the common Social Behavior Network. Here, we show increased Vasopressin 1a receptor, but not oxytocin receptor, activation in two auditory regions following formation of a pair bond. To our knowledge, this is the first study to suggest a role of nonapeptides in the auditory circuit in pair bonding. Thus, we highlight converging mechanisms of social relationships and also point to the importance of studying multiple species to understand mechanisms of behavior.

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Plasmodium Infections in Natural Populations of Anolis sagrei Reflect Tolerance Rather Than Susceptibility

Abstract

Parasites can represent formidable selection pressures for hosts, but the cost of infection is sometimes difficult to demonstrate in natural populations. While parasite exploitation strategies may, in some instances, actually inflict low costs on their hosts, the response of hosts to infection is also likely to determine whether or not these costs can be detected. Indeed, costs of infection may be obscured if infected individuals in the wild are those that are the most tolerant, rather than the most susceptible, to infection. Here we test this hypothesis in two natural populations of Anolis sagrei, one of the most common anole lizard of the Bahamas. Plasmodium parasites were detected in > 7% of individuals and belonged to two distinct clades: P. mexicanum and P. floriensis. Infected individuals displayed greater body condition than non-infected ones and we found no association between infection status, stamina, and survival to the end of the breeding season. Furthermore, we found no significant difference in the immuno-competence (measured as a response to phytohemagglutinin challenge) of infected versus non-infected individuals. Taken together, our results suggest that the infected individuals that are caught in the wild are those most able to withstand the cost of the infection and that susceptible, infected individuals have been removed from the population (i.e., through disease-induced mortality). This study highlights the need for caution when interpreting estimates of infection costs in natural populations, as costs may appear low either when parasites exploitation strategies truly inflict low costs on their hosts or when those costs are so high that susceptible hosts are removed from the population.

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How Do We Measure the Cost of Whole-Organism Performance Traits?

Abstract

Whole-organism performance traits, such as maximal speed and endurance capacity are undoubtedly costly, but we know little about how or when all of the costs associated with performance are paid to individuals or how to measure them. To understand how performance traits might be involved in trade-offs with other life-history traits it is critical to determine the development, production, and maintenance costs of performance traits, as well as how each of these changes with increased or decreased use of the performance trait. We discuss the advantages and disadvantages of several potential phenotypic measures of dynamic whole-organism performance that may be used in life-history studies, including direct performance measures; metabolic rates; ecological cost of transport; and changes in metabolic rate after training. We use the first approach, direct performance measures, to show trade-offs between endurance capacity and several traditional life history variables in phrynosomatid lizards. The largest problem currently in determining the costs of performance traits and how those costs might lead to life-history trade-offs is that there are estimates of performance costs in very few taxa, and when there are, those species typically are not studied with respect to "traditional" life-history traits.

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Integration Free Derivation of Human Induced Pluripotent Stem Cells Using Laminin 521 Matrix

Robust derivation of human induced pluripotent stem (hiPS) cells was achieved by using non-integrating Sendai virus (SeV) vector mediated reprogramming of dermal fibroblasts. hiPS cell maintenance and clonal expansion was performed using xeno-free and chemically defined culture conditions with recombinant human laminin 521 (LN-521) matrix and Essential E8 (E8) Medium.

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Subcellular localization and function study of a secreted phospholipase C from Nocardia seriolae

Abstract

Fish nocardiosis is a chronic systemic granulomatous disease, and Nocardia seriolae is the main pathogen that causes this disease. But the pathogenesis and virulence factors of N. seriolae are not fully understood. A phospholipase C (PLC), which was likely to be a secreted protein targeting host cell mitochondria, was found by the bioinformatics analysis on the whole genome sequence of N. seriolae. In order to determine the subcellular localization and study the preliminary function of PLC from N. seriolae (NsPLC), the gene cloning, secreted protein identification, subcellular localization in host cells and apoptosis detection of NsPLC were carried out in this study. The results showed that NsPLC was a secreted protein by mass spectrometry analysis of extracellular products from N. seriolae. Subcellular localization of NsPLC-GFP fusion protein in FHM cells revealed that the green fluorescence exhibited a punctate distribution near the nucleus and did not co-localize with mitochondria. In addition, apoptosis assay suggested that apoptosis was induced in FHM cells by the overexpression of NsPLC. This study may lay the foundation for further study on the function of NsPLC and promote the understanding of the virulence factors and pathogenic mechanism of N. seriolae.

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Congressional action on rising drug prices remains a possibility [News]

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New drugs and dosage forms [News]

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Development of a pharmacy resident rotation to expand decentralized clinical pharmacy services [Descriptive Report]

Purpose

The development of a pharmacy resident rotation to expand decentralized clinical pharmacy services is described.

Summary

In an effort to align with the initiatives proposed within the ASHP Practice Advancement Initiative, the department of pharmacy at Cleveland Clinic, a 1,400-bed academic, tertiary acute care medical center in Cleveland, Ohio, established a goal to provide decentralized clinical pharmacy services for 100% of patient care units within the hospital. Patient care units that previously had no decentralized pharmacy services were evaluated to identify opportunities for expansion. Metrics analyzed included number of medication orders verified per hour, number of pharmacy dosing consultations, and number of patient discharge counseling sessions. A pilot study was conducted to assess the feasibility of this service and potential resident learning opportunities. A learning experience description was drafted, and feedback was solicited regarding the development of educational components utilized throughout the rotation. Pharmacists who were providing services to similar patient populations were identified to serve as preceptors. Staff pharmacists were deployed to previously uncovered patient care units, with pharmacy residents providing decentralized services on previously covered areas. A rotating preceptor schedule was developed based on geographic proximity and clinical expertise. An initial postimplementation assessment of this resident-driven service revealed that pharmacy residents provided a comparable level of pharmacy services to that of staff pharmacists. Feedback collected from nurses, physicians, and pharmacy staff also supported residents' ability to operate sufficiently in this role to optimize patient care.

Conclusion

A learning experience developed for pharmacy residents in a large medical center enabled the expansion of decentralized clinical services without requiring additional pharmacist full-time equivalents.

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Site-independent indication widens targets for immunotherapy product [News]

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Allometric versus consensus guideline dosing in achieving target vancomycin trough concentrations [Clinical Research Report]

Purpose

Results of a study comparing the performance of allometric versus consensus guideline–recommended vancomycin dosing in achieving initial trough concentrations within the desired range are reported.

Methods

A retrospective study was conducted to compare selected outcomes with 2 vancomycin dosing methods: (1) dosing by total body weight, as recommended in current consensus guidelines, and (2) a new empirical vancomycin dosing strategy grounded in allometry (the study of the relationship between body size and physiology). The primary outcome was attainment of an initial vancomycin trough concentration within the target range (10–20 mg/L). Rates of nephrotoxicity associated with the 2 dosing methods were compared.

Results

Allometric dosing resulted in 77% of the evaluated patient sample (n = 81) achieving vancomycin trough concentration targets at the initial measurement, as compared with a target attainment rate of 57% (n = 81) with guideline-recommended dosing (p = 0.0121); the rate of target attainment in obese patients was also improved with allometric dosing (73% versus 46%, p = 0.0327). Nephrotoxicity rates did not differ significantly between the 2 groups, but a lower rate was observed with allometric versus guideline-based dosing (1.2% versus 7.4%, p = 0.0584).

Conclusion

In hospitalized adults, allometric vancomycin dosing achieved a higher frequency of initial vancomycin trough concentrations within the target range of 10–20 mg/L, compared with dosing as recommended by consensus guidelines. The difference between methods in the percentage of troughs within the target range was most pronounced in obese patients.

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Innovative models for providing clinical pharmacy services to remote locations using clinical video telehealth [Notes]

Purpose

The use of videoconferencing and other telehealth technologies to expand access to clinical pharmacy services at multiple Veterans Affairs (VA) clinics in rural areas of Alaska and the northwestern United States is described.

Summary

Beginning in 2014, clinical pharmacy specialists at a regional VA Telehealth Hub based at Boise VA Medical Center in Idaho have provided telehealth services for 16 clinics. In one telehealth model, a pharmacist and other remotely located primary care team members (a medical provider, a medical support assistant, a social worker, and a psychologist) conduct telehealth visits with veterans located at VA clinics, with support provided by clinic-based nursing staff; this model has been used to improve medication management services for veterans in sparsely populated areas. In the second VA telehealth model, a remotely located pharmacist uses telehealth technology to participate in clinical encounters along with primary care team members located at the patient site; this model allows on-demand remote coverage in the event of planned or unplanned absences of clinic-based pharmacists. Since the Telehealth Hub was established, pharmacists have engaged in video encounters and provided other telehealth-based clinical services to more than 1,200 veterans with diabetes, hyperlipidemia, hypertension, and other chronic conditions.

Conclusion

Within the VA healthcare system, telehealth technology has been demonstrated to be a cost-effective and well-received means of providing clinical pharmacy services in rural areas.

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CMS paves way for pharmacists to help blunt metabolic effects of antipsychotics [News]

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Visual compatibility of colistin injection with other antibiotics during simulated Y-site administration [Notes]

Purpose

The compatibility of colistin with other antibiotics at concentrations commonly used in intensive care units was studied.

Methods

A vial of colistin was dissolved in sterile water for injection. The reconstituted solution (colistin base 75 mg/mL) was then diluted in 0.9% sodium chloride injection in polyvinyl chloride (PVC) infusion bag to give a total volume of 100 mL (colistin 1.5 mg/mL). Secondary drugs, including cefoperazone–sulbactam, ceftazidime, ertapenem, fosfomycin, imipenem–cilastatin, linezolid, meropenem, piperacillin–tazobactam, and vancomycin, were reconstituted if necessary and then diluted in 0.9% sodium chloride injection in PVC infusion bags to give final study concentrations of one-hundredth of their initial concentrations. The admixtures were collected in beakers at the end of the i.v. line and stored at 26 °C under constant fluorescent light throughout the study. Compatibility was assessed visually during delivery of each drug pair at time 0 and at 1 hour after starting the infusion. Compatibility was defined as the absence of visually detected particulate formation, haze, precipitation, color change, or gas evolution. Each combination was tested in triplicate.

Results

No particulate formation or other evidence of incompatibility was found in any of the studied drug combinations when observed immediately after mixing or at 1 hour. No particulate matter was observed with the unaided eyes, during microscopic evaluation, or against black and white backgrounds.

Conclusion

Colistin 1.5 mg/mL was visually compatible with single concentrations of 9 other antimicrobial products during simulated Y-site injection at 26 °C without light protection for at least 1 hour.

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News briefs [News]

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Hyponatremia induced by hyperinsulinemia-euglycemia therapy [Case Report]

Purpose

A case of symptomatic hyponatremia induced by hyperinsulinemia–euglycemia (HIE) therapy is reported.

Summary

A 59-year-old, 81.65-kg woman with hypertension, major depressive disorder, and anxiety arrived at a tertiary medical center 1.5 hours after an intentional overdose of oral amlodipine 200 mg, metoprolol tartrate 2,000 mg, and isosorbide mononitrate 1,200 mg. Upon arrival, her pulse was 63 beats/min and blood pressure was 106/56 mm Hg. The patient's blood pressure was refractory to fluids, calcium gluconate, and norepinephrine, resulting in initiation of HIE therapy. She had recurrent episodes of hypoglycemia, which required increases of the dextrose infusion and resulted in the patient receiving a total of 6.9 L of dextrose with free water. Seventeen hours into the hospitalization, the patient became obtunded due to hyponatremia (serum sodium concentration, 121 mmol/L). HIE therapy was discontinued, an infusion of 5% dextrose injection with sodium bicarbonate added was started, and a bolus of 3% sodium chloride was administered. Nine hours after the presentation of hyponatremia, the patient's serum sodium concentration normalized (137 mmol/L), and her symptoms resolved. The patient's blood pressure, pulse, and mental status continued to improve, and the patient was transferred out of the medical intensive care unit 41 hours after her arrival at the hospital.

Conclusion

A woman who overdosed on amlodipine, metoprolol tartrate, and isosorbide mononitrate was treated with HIE therapy and developed symptomatic hyponatremia. Hyponatremia resolved after administration of dextrose with sodium bicarbonate infusion and 3% sodium chloride infusion and cessation of HIE therapy.

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Implementation of a direct oral anticoagulant discharge service [Frontline Pharmacist]

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Influence of drug class and healthcare setting on systemic antifungal expenditures in the United States, 2005-15 [Practice Research Report]

Purpose

Overall and specific class trends in systemic antifungal expenditures in various U.S. healthcare settings from 2005 through 2015 were evaluated.

Methods

Systemic antifungal expenditures from January 1, 2005, through December 31, 2015, were obtained from the QuintilesIMS National Sales Perspective database, which provides a statistically valid projection of medication purchases from multiple markets throughout the United States. Summary data for total antifungal expenditures over the entire period are reported, as are growth and the percentage change in expenditures from one year to the next. Expenditures were also assessed specifically by year, class, and healthcare setting. Expenditure trends over the study period were assessed using simple linear trend regression models.

Results

Overall expenditures for the 11-year period were $9.37 billion. The greatest proportion of expenditures occurred in nonfederal hospitals (47.2%) and for triazoles (57.6%). From 2005 through 2015, total expenditures decreased from $1.1 billion to $894 million (–18.8%, p = 0.09); however, expenditures in clinics and retail pharmacies increased (202%, p < 0.01, and 13.8%, p = 0.04, respectively), a trend most pronounced after 2012. Expenditures for flucytosine also increased (968.1%, p < 0.01), particularly in clinics where there was a dramatic 6,640.9% increase (p < 0.01).

Conclusion

From 2005 through 2015, an increase in systemic antifungal expenditures was observed in community settings, despite an overall decrease in total antifungal expenditures in the United States. Large increases in flucytosine expenditures were observed, particularly in the community.

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Sofosbuvir-velpatasvir: A single-tablet treatment for hepatitis C infection of all genotypes [Clinical Review]

Purpose

The pharmacology, pharmacokinetics, interaction potential, efficacy, and safety of the newest direct-acting antiviral (DAA) medication for the treatment of chronic hepatitis C are reviewed.

Summary

Nonstructural proteins 5A (NS5A) and 5B (NS5B) are key drivers of hepatitis C virus (HCV) replication. Velpatasvir, an inhibitor of NS5A, was coformulated with the NS5B inhibitor sofosbuvir to provide a single-tablet combination DAA (Epclusa, Gilead Sciences). Sofosbuvir–velpatasvir was shown to have excellent activity against the 6 most prevalent HCV genotypes in the United States, with reported rates of sustained virological response at 12 weeks after treatment completion ranging from 95% to 100% in various HCV-infected populations, including patients with compensated cirrhosis and prior treatment failures. In patients with decompensated cirrhosis or HIV coinfection, reported cure rates are 85–100% and 92–100%, respectively. The duration of treatment with sofosbuvir–velpatasvir is 12 weeks regardless of the HCV genotype involved, previous treatment, and the presence of cirrhosis or baseline resistance-associated NS5A mutations. In patients with decompensated cirrhosis, sofosbuvir–velpatasvir must be used in combination with ribavirin. Sofosbuvir–velpatasvir was well tolerated in clinical trials; adverse effects reported at a rate of ≥10% were fatigue, headache, nausea, and nasopharyngitis.

Conclusion

Sofosbuvir–velpatasvir is a DAA and the first single-tablet regimen to treat HCV infection caused by all genotypes. The efficacy and tolerability of sofosbuvir–velpatasvir have been observed in patients with types of HCV infection that traditionally have been difficult to treat.

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Nebulized opioids for the palliation of dyspnea in terminally ill patients [Clinical Consultation]

Purpose

The use of nebulized opioids for the palliation of dyspnea in terminally ill patients is reviewed.

Summary

More than 50% of patients with advanced diseases experience dyspnea during their final stages of life. Systemically administered opioids are recommended for the management of dyspnea in these patients, but adverse effects may limit their use. Nebulization offers an alternative route for administering opioids, providing relief of dyspnea while minimizing adverse events. An extensive literature search was conducted to identify publications evaluating nebulized opioids for the palliation of dyspnea in patients at end-of-life. Ten studies that evaluated nebulized morphine, fentanyl, hydromorphone, and morphine-6-glucuronide were reviewed; 1 of these studies evaluated 4 different opioids. Of these 10 studies, 2 had double-blind, placebo-controlled, randomized crossover designs; 1 was retrospective, and the remaining 7 were prospective studies. A total of 181 patients, all adults, were evaluated. Subjective improvement in dyspnea from baseline was observed in 9 of the 10 studies. Nebulized morphine 20 mg every 4 hours was the most common opioid studied. Other doses of nebulized opioids included fentanyl 25 and 100 μg and hydromorphone 5 mg. Nine studies reported subjective improvement of dyspnea from baseline after administering nebulized opioids. Six studies evaluated objective outcomes and showed decreased respiratory rate (morphine, fentanyl, and hydromorphone) and heart rate (hydromorphone) and increased oxygen saturation (fentanyl). Mild-to-moderate adverse effects such as claustrophobia due to nebulizer mask, drowsiness, cough, and bitter taste were described.

Conclusion

Nebulized opioids may provide subjective relief of dyspnea in terminally ill patients with mild-to-moderate adverse effects.

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Strategic thinking in pharmacy [CPO Perspectives]

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Generation and Long-term Maintenance of Nerve-free Hydra

Through a double treatment with colchicine, a plant-derived toxin that kills dividing cells, nerve-free Hydra vulgaris can be generated. These Hydra cannot feed or egest on their own. This paper describes an improved method for long-term maintenance of nerve free Hydra vulgaris in the laboratory.

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Anterior pedicle spreader reduction for unilateral cervical facet dislocation

Publication date: Available online 6 July 2017
Source:Injury
Author(s): Zhengfeng Zhang
ObjectiveThe anterior only surgical procedure including discectomy, open reduction and fusion is used as a recommended approach in the treatment of unilateral cervical facet dislocations, but is difficult to achieve satisfactory anterior open reduction by vertebra distractor to spread the facet joints, especially for delayed management of unilateral cervical facet dislocation (7 to 21 days). The goal of this study was to report an anterior pedicle spreader technique to distract directly the facet joint for anterior reduction and the results of 4 patients with successful application and describe safety.MethodsFour patients with unilateral cervical facet dislocation who failed to open anterior reduction by vertebra spreader procedure were surgically treated by the anterior pedicle spreader reduction. In these 4 patients (3 males and 1 female), the distribution of spine level was from C4/5 to C6/7; the neurological status was comprised 2 patients with ASIA E, 1 with D and 1 with A; the surgical management was ranged from 7 to 18 days. After discectomy, if failed to open anterior reduction procedure, the anterior pedicle spreader was inserted along the pedicle axis with the fluoroscope-assisted view imaging. The spreader was distracted directly to the facet joint and pushed in a caudad direction to achieve posterior translation of the upper segment.ResultsPostoperatively, all patients had obtained successful reduction and satisfactory anatomic sagittal alignment. There was no complication owing to the use of this technique. The ASIA A showed no neurological improvement; the patient with ASIA D was improved neurologically to ASIA E; no ASIA E patients showed neurological deterioration.ConclusionsAnterior pedicle spreader reduction represents an efficacious but technically challenging option for the delayed treatment of unilateral cervical facet dislocation.



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