Issue Information

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“…in every…art, fundamental matters are perennially being discovered, discredited, forgotten, rediscovered and reaffirmed”

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Prostate-induced orgasms: A concise review illustrated with a highly relevant case study

Current medical literature does not describe precisely the activation and mechanisms of prostate orgasms. This brief review describes what we know about the anatomy and physiology of the prostate and its involvement in reproduction and especially its stimulation for sexual recreation. It is illustrated with a highly relevant case history. Clin. Anat. 31:81–85, 2018. © 2017 Wiley Periodicals, Inc.

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In Memoriam E. Milly Haagedoorn, MD, PhD

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Palliative Oncologic Care Curricula for Providers in Resource-Limited and Underserved Communities: a Systematic Review

Abstract

Familiarity with principles of palliative care, supportive care, and palliative oncological treatment is essential for providers caring for cancer patients, though this may be challenging in global communities where resources are limited. Herein, we describe the scope of literature on palliative oncological care curricula for providers in resource-limited settings. A systematic literature review was conducted using PubMed, Embase, Cochrane Library, Web of Science, Cumulative Index to Nursing and Allied Health Literature, Med Ed Portal databases, and gray literature. All available prospective cohort studies, case reports, and narratives published up to July 2017 were eligible for review. Fourteen articles were identified and referenced palliative care education programs in Argentina, Uganda, Kenya, Australia, Germany, the USA, or multiple countries. The most common teaching strategy was lecture-based, followed by mentorship and experiential learning involving role play and simulation. Education topics included core principles of palliative care, pain and symptom management, and communication skills. Two programs included additional topics specific to the underserved or American Indian/Alaskan Native community. Only one program discussed supportive cancer care, and no program reported educational content on resource-stratified decision-making for palliative oncological treatment. Five programs reported positive participant satisfaction, and three programs described objective metrics of increased educational or research activity. There is scant literature on effective curricula for providers treating cancer patients in resource-limited settings. Emphasizing supportive cancer care and palliative oncologic treatments may help address gaps in education; increased outcome reporting may help define the impact of palliative care curriculum within resource-limited communities.

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Severity of arterial defects in the retina correlates with the burden of intracerebral haemorrhage in COL4A1-related stroke

ABSTRACT

Mutations in the α1 (COL4A1) or α2 (COL4A2) chains of collagen type IV, a major component of the vascular basement membrane, cause intracerebral haemorrhages with variable expressivity and reduced penetrance by mechanisms that remain poorly understood. Here we sought to investigate the cellular mechanisms of COL4A1-related intracerebral haemorrhage and identify a marker for haemorrhage risk-stratification. A combination of histological, immunohistochemical and electron microscopy analyses were used to analyse the brain parenchyma, cerebrovasculature, and retinal vessels of mice expressing the disease-causing COL4A1 p.G498V mutation. Mutant mice developed cerebral microhaemorrhages and macroscopic haemorrhages (macrohaemorrhages), the latter with reduced penetrance, mimicking the human disease. Microhaemorrhages that occurred in early postnatal life were associated with a transient, generalized increase in blood-brain barrier permeability at the level of capillaries. Macrohaemorrhages, which occurred later in life, originated from deep brain arteries with focal loss of smooth muscle cells. Similar smooth muscle cell loss was detected in retinal arteries, and a time-course analysis of arterial lesions showed that smooth muscle cells are recruited normally in arterial wall during development, but undergo progressive apoptosis-mediated degeneration. By assessing in parallel the extent of these retinal arterial lesions and the presence/absence of macrohaemorrhages, we found that the arterial lesion load in the retina is strongly correlated with the burden of macrohaemorrhages. We conclude that microhaemorrhages and macrohaemorrhages are driven by two distinct mechanisms. Moreover smooth muscle cell degeneration is a critical factor underlying the partial penetrance of COL4A1-related macrohaemorrhages, and retinal imaging is a promising tool for identifying high-risk patients.

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Artificial neural network model to distinguish follicular adenoma from follicular carcinoma on fine needle aspiration of thyroid

Background

To distinguish follicular adenoma (FA) and follicular carcinoma (FC) of thyroid in fine needle aspiration cytology (FNAC) is a challenging problem.

Aims and objectives

In this article, we attempted to build an artificial neural network (ANN) model from the cytological and morphometric features of the FNAC smears of thyroid to distinguish FA from FC.

Material and methods

The cytological features and morphometric analysis were done on the FNAC smears of histology proven cases of FA (26) and FC (31). The cytological features were analysed semi-quantitatively by two independent observers (RS and PD). These data were used to make an ANN model to differentiate FA versus FC on FNAC material. The performance of this ANN model was assessed by analysing the confusion matrix and receiving operator curve.

Result

There were 39 cases in training set, 9 cases each in validation and test sets. In the test group, ANN model successfully distinguished all cases (9/9) of FA and FC. The area under receiver operating curve was 1.

Conclusion

The present ANN model is efficient to diagnose follicular adenoma and carcinoma cases on cytology smears without any error. In future, this ANN model will be able to diagnose follicular adenoma and carcinoma cases on thyroid aspirate. This study has immense potential in future. This is an open ended ANN model and more parameters and more cases can be included to make the model much stronger.

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Social Media and the Plastic Surgery Patient

A plastic surgeon's social media platform can play an important role in engaging and educating patients.
Plastic and Reconstructive Surgery

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Boys in a famous choir: Singing and ticcing

This informal observational study on the tic prevalence in 40 young singers was carried out during a public concert of Bach's Christmas Oratorio. Tics were highly prevalent (present in 35% = 14 boys). Given the possibility of an overrepresentation of perioral tics in this group of highly achieving young vocal artists, one might speculate that there is a relationship between the ability of the motor system to produce a surplus of movements (tics) and high performance (exquisite singing). Despite the unusual study design, with all its limitations, our observations strengthen the view that tics may be related to motor learning. However, alternative explanations, for example, that repetitive motor performance or personality traits in singers drive tic development, could also be true. In light of the boys choir's enchantment, the sole perception of tics as a disorder falls short of the properties of the motor system. Ann Neurol 2017;82:1029–1031

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Histopathological regression predicts treatment outcome in locally advanced esophagogastric adenocarcinoma

Publication date: February 2018
Source:European Journal of Cancer, Volume 90
Author(s): Silvia Spoerl, Alexander Novotny, Salah-Eddin Al-Batran, Florian Lordick, Peter Thuss-Patience, Claudia Pauligk, Bernhard Haller, Marcus Feith, Sylvie Lorenzen
BackgroundNeoadjuvant chemotherapy (neoCTx) improves survival outcomes of patients with localised esophagogastric adenocarcinoma (EGA). This analysis evaluates the predictive value of histopathological response after neoCTx.MethodsA total of 461 patients with locally advanced EGA (≥T2 and/or N+) who received neoCTx followed by surgery were analysed: 314 (68.1%) with intestinal, 94 (20.4%) with diffuse and 53 (11.5%) with mixed histological type according to Lauren classification. Histopathological response evaluation was available for 363 patients and performed locally. This analysis evaluates the predictive value of histopathological subtype on histopathological response after neoCTx. Response was correlated with survival.ResultsMedian patients' age was 63 years, 79.8% were male. Tumours were localised in the stomach in 32.5% and EG junction in 67.5% of the patients. With a median follow-up of 49.4 months, median disease-free (DFS) and overall survival (OS) were 38.0 and 66.4 months, respectively.Pathological complete response (TRG1a) was 8.8% and combined complete and subtotal regression (TRG1a/b) was 27.3% for all patients. Around 9.2% of patients with intestinal type had a TRG1a compared with 6.2% with diffuse and 10.8% with mixed type. TRG1a/b rate was higher in intestinal (31.0%) than in diffuse (15.4%) and in mixed type (21.6%).For patients with intestinal type, 3-year DFS was 78.4% with TRG1a and 54.3% with other regression grades (p = 0.031). All patients with diffuse and mixed type and TRG1a were disease free after 3 years compared with 31.1% (p = 0.056) and 47.7% (p = 0.044) with other regression grades.ConclusionHistopathological subtype is predictive for histopathological response and outcome after neoCTx, with the highest response rates in intestinal differentiated EGA.



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The Danish Head and Neck Cancer fast-track program: a tertiary cancer centre experience

Publication date: Available online 19 December 2017
Source:European Journal of Cancer
Author(s): Anders B. Roennegaard, Tine Rosenberg, Kristine Bjørndal, Jens Ahm Sørensen, Jørgen Johansen, Christian Godballe
IntroductionDuring the 1990s, all Nordic countries except for Denmark experienced a general increase in 5-year survival rates for cancer patients. In 2007, the Danish National Board of Health in collaboration with national multidisciplinary cancer groups and the Danish regions initiated fast-track clinical pathway solutions.ObjectivesThe objectives of this study were 1) to present the setup of the head and neck cancer (HNC) fast-track program at Odense University Hospital (OUH) as an example of the Danish model and 2) to present patient characteristics, diagnostic outcome, cancer detection rate, and duration of the fast-track patient courses.Materials and methodsFrom 1st July 2012 to 1st September 2015, all patients referred to the HNC fast-track program at OUH for diagnostics and treatment were consecutively included in the study resulting in 3165 patient courses.ResultsThe overall malignancy detection rate was 40.6% and for HNC it was 29.2%. The overall median fast-track course duration was 12 days (range 0–74). Overall 2990 (94.5%) of 3165 patients completed their fast-track course within the maximally permitted course duration.Discussion and conclusionBased on our findings, it was concluded that: 1) a HNC fast-track program build on pre-booked slots for diagnostics and treatment is feasible and can secure acceptable course durations for more than 90% of patient courses, 2) by using private ENT specialists as a 'filter-function', an acceptable detection rate can be achieved.



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Progression patterns under BRAF inhibitor treatment and treatment beyond progression in patients with metastatic melanoma

Abstract

Despite markedly improved treatment options for metastatic melanoma, resistance to targeted therapies such as BRAF inhibitors (BRAFi) or BRAFi plus MEK inhibitors (MEKi) remains a major problem. Our aim was to characterize progression on BRAFi therapy and outcome of subsequent treatment. One hundred and eighty patients with BRAF-mutant metastatic melanoma who had progressed on treatment with single-agent BRAFi from February 2010 to April 2015 were included in a retrospective data analysis focused on patterns of progression, treatment beyond progression (TBP) and subsequent treatments after BRAFi therapy. Analysis revealed that 51.1% of patients progressed with both new and existing metastases opposed to progression of only preexisting (28.3%) or only new (20.6%) metastases. Exclusive extracranial progression occurred in 50.6% of patients compared to both extra- and intracranial (29.4%) or sole cerebral progression (20%). Multivariable analyses demonstrated that single site progression and primary response to BRAFi were associated with improved progression-free survival. Progression with exclusively new or only existing metastases and a baseline Eastern Cooperative Oncology Group (ECOG) of 0 were associated with prolonged overall survival (OS). TBP had no significant impact on OS. Other subsequent treatments showed low efficacy with the exception of anti-PD-1 antibodies. In conclusion we identified specific patterns of progression which significantly correlate with further prognosis after progression on BRAFi treatment. In contrast to previously published data, we could not demonstrate a significant survival benefit for BRAFi TBP. Subsequent therapies had strikingly low efficacy except for PD-1 inhibitors.

We identified patterns of progression that significantly correlate with further prognosis after progression on BRAF inhibitor (BRAFi) treatment. In contrast to previously published studies, we did not find a significant survival benefit for BRAFi treatment beyond progression, whereas subsequent therapies (ipilimumab, chemotherapy) had strikingly low efficacy except for PD-1 inhibitors.

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Drug Induced Lupus Erythematous Secondary to Pirfenidone

Drug related cutaneous lupus erythematous is characterised by clinical and immunopathological findings similar to lupus but which is temporarily related to drug exposure. Multiple drugs have been described in association with drug induced lupus.(1) To date there have been no documented cases of pirfenidone induced lupus erythematous.

This article is protected by copyright. All rights reserved.

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Genomic classifications of renal cell carcinoma: a critical step towards the future application of personalized kidney cancer care with pan-omics precision

Abstract

Over the past twenty years, classifications of kidney cancer have undergone major revisions based on morphological refinements and molecular characterizations. The 2016 WHO classification of renal tumors recognizes more than 10 different renal cell carcinoma (RCC) subtypes. Furthermore, the marked inter- and intra-tumor heterogeneity of RCC is now well-appreciated. Nevertheless, contemporary multi-omics studies of RCC, encompassing genomics, transcriptomics, proteomics, and metabolomics, not only highlight apparent diversity but also showcase and underline commonality. Here, we wish to provide an integrated perspective concerning the future "functional" classification of renal cancer by bridging gaps among morphology, biology, multi-omics and therapeutics. This review focuses on recent progress and elaborates the potential value of contemporary pan-omics approaches with a special emphasis on cancer genomics unveiled through next generation sequencing technology, and how an integrated multi-omics approach might impact precision-based personalized kidney cancer care in the near future.

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Automatic temporal ranking of children’s engagement levels using multi-modal cues

Publication date: Available online 19 December 2017
Source:Computer Speech & Language
Author(s): Jaebok Kim, Khiet P. Truong, Vanessa Evers
As children of ages 5 to 8 often play with each other in small groups, their differences in social development and personality traits usually cause various levels of engagement among others. For example, one child may just observe without engaging at all with others while another child may be interested in both the other children as well as the activity. To develop child-friendly interaction technology such as social robots that can adapt robot behaviours to the social situation of a group of children and facilitate harmonious engagement, we aim to study how we can automatically detect these children's engagement levels. In this paper, we present a novel automatic method that ranks children in a group according to their engagement level in a temporal way based on non-verbal cues that are robust in naturalistic group settings. Our method combines the omission probability of each rank transformed from discriminative outputs from an SVM ranking method and the transition probability between ranks in time. In comparing our proposed method to other existing methods (such as rule-based ranking, basic SVM, SVM ordinal regression, SVM ranking, and SVMHMM), we found that our novel method yields promising results.



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Spatial versus temporal inhibition in dystonia

Dystonia is a motor disorder characterized by involuntary muscle contractions, frequently causing twisted postures. A pathophysiological hallmark of dystonia is reduced motor inhibition at multiple levels of the central nervous system including the spinal cord, brainstem and cortex. In addition, it is widely accepted that the sensory system is involved in dystonia. A well-known and fascinating phenomenon is the sensory trick. Touching a body part, usually at a location close to where dystonia occurs such as the neck or face in cervical dystonia or blepharospasm, alleviates dystonia symptoms.

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The implant effect after intracranial electrode placement: is transient clinical improvement explained by post-implantation electrophysiological changes?

It has been repeatedly observed that implanting electrodes in the brain or on the brain is occasionally associated with a transient improvement in seizure control. This improvement was observed with responsive neurostimulation (Morrell et al., 2011), deep brain stimulation (Velasco et al., 2006; Fisher et al., 2010; Valentin et al., 2013), and even diagnostic intracranial electrode implantation (Schulze-Bonhage et al., 2010; Roth et al., 2012; Kovac et al., 2014). In the pivotal trial of anterior thalamic stimulation, there was a 21-22% median seizure frequency reduction in the first month after implantation, prior to randomization (Fisher et al., 2010).

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The effect of resorbable membranes on one-stage ridge augmentation in anterior single-tooth replacement: A randomized, controlled clinical trial

Abstract

Aim

To evaluate the effect of resorbable membranes on one-stage ridge augmentation procedures in small (2-4 mm) buccal bony dehiscences in anterior maxillary single-tooth replacement.

Materials and methods

Patients with a buccal bony dehiscence after implant placement in the esthetic zone were randomly allocated to one-stage ridge augmentation with (M+) or without a membrane (M−). Second-phase surgery was performed after 8 weeks, and follow-up was performed 1, 6, and ≥12 months after loading. Outcomes included implant survival and success, complications, clinical and radiographic parameters, esthetic results and patient satisfaction.

Results

Fifty-two patients were randomized to one-stage ridge augmentation with (n = 25) or without use of a membrane (n = 27). No significant differences in implant survival and success have been observed. The risk of having a small mucosal dehiscence was more than six times higher in the M+ group than in the M− group (RR 6.24, 95% CI 0.81 to 48.21). At the last follow-up, the bleeding index (BI) was marginally higher in the M+ group (14/9/2/0) compared to the M- group (24/2/0/0) (U = 205, Z = −2.97, p = .003, r = .42). The median change in marginal bone level was statistically lower in the M+ group (0.06 mm) than the M− group (0.60 mm) at last follow-up (U = 120, Z = −2.73 a p = .006 r = .42). Total pink esthetic index (PES) and white esthetic score (WES) and combined PES/WES were not significantly different between treatment groups at more than 12 months after loading. Only the subcategory root convexity/soft tissue color scored significantly lower in the M+ group (1.5) compared to the M− group (2.0) at the last follow-up (U = 172, Z = −2.34, p = .019 r = .34). No differences were found in patient satisfaction.

Conclusion

The use of a resorbable membrane in small buccal bony dehiscences in anterior maxillary single-tooth replacement resulted in less marginal bone loss, but showed more mucosal dehiscences, higher bleeding scores and lower scores on root convexity and soft tissue color after at least one year of loading. No effect was seen on implant survival and success, overall esthetic results, and patient satisfaction.

The research protocol was registered at the Dutch Trial Register (NTR) with ID NTR6137.

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ASBA Diplomate Dr. Steve Wilk Welcomes Former NFL Players to a Special Event at His Office in Denver, CO

November 20, 2017 saw Pro Player Health Alliance (PPHA) host another of their sleep apnea awareness events. This time it was at the office of Dr. Steve Wilk, DDS. Dr. Wilk had previously attended a Living Heart Foundation screening at Centura Hospital that had approximately 60 former NFL players get screened for sleep disorders. The event was so successful, some of the players agreed to return and share their testimonies at Dr. Wilk's public awareness event at The Viewhouse.

It was incredibly rewarding meeting people who truly needed care with their sleep apnea come to our event. Some also brought cards and photos for the players to sign. Everyone had a great time and Dr. Wilk used the event to reach out to members of the local community who are seeking treatment for their OSA. David Gergen, CEO of the American Sleep and Breathing Academy (ASBA), Pro Player Health Alliance (PPHA) and Gergen's Orthodontic Lab, flew out to Denver, CO for a 3^rd time on behalf of the former players. "ESPN and NBC were there to cover the event, and it is working well, while also getting better each and every time. I'm excited for our next event." says Gergen.

He and Dr. Wilk's Denver Sleep Apnea Center team greeted the former NFL players and current Broncos lineman Billy Turner who gathered to learn about the dental and sleep benefits they receive from the time they spent playing football in the NFL. "Back in the day, these players were really beat up," said Wilk. "These are really big men, and while we hear about concussions now, they have a lot of other health issues."

Dr. Wilk, David Gergen, Former Broncos Billy Thompson, Broncos Lineman Billy Turner, NFLPA Chapter President Wade Manning

Wilk, who is a Diplomate of the American Sleep and Breathing Academy, has been called a "life-saver" by his patients. With over 2800 hours of continued education and decades of experience in treating patients for sleep, TMD and dentistry, Dr. Wilk is one of the country's most experienced and educated dentists. After becoming involved in the Denver area with Pro Player Health Alliance and treating the retired NFL players for dental and sleep apnea needs, one of the players joked, "Word has quickly spread with how friendly and efficient Dr. Wilk and team are; now he's starting to get fans of his own."

To learn more about the ASBA, membership, diplomacy or future events, email info@myasba.com or call 602-478-9713.

 

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ConsensusDriver Improves upon Individual Algorithms for Predicting Driver Alterations in Different Cancer Types and Individual Patients

Existing cancer driver prediction methods are based on very different assumptions and each of them can detect only a particular subset of driver genes. Here we perform a comprehensive assessment of 18 driver prediction methods on more than 3,400 tumor samples from 15 cancer types, all to determine their suitability in guiding precision medicine efforts. We categorized these methods into five groups: functional impact on proteins in general (FI) or specific to cancer (FIC), cohort-based analysis for recurrent mutations (CBA), mutations with expression correlation (MEC), and methods that use gene interaction network-based analysis (INA). The performance of driver prediction methods varied considerably, with concordance with a gold standard varying from 9% to 68%. FI methods showed relatively poor performance (concordance <22%), while CBA methods provided conservative results but required large sample sizes for high sensitivity. INA methods, through the integration of genomic and transcriptomic data, and FIC methods, by training cancer-specific models, provided the best trade-off between sensitivity and specificity. As the methods were found to predict different subsets of driver genes, we propose a novel consensus-based approach, ConsensusDriver, which significantly improves the quality of predictions (20% increase in sensitivity) in patient subgroups or even individual patients. Consensus-based methods like ConsensusDriver promise to harness the strengths of different driver prediction paradigms.Significance: These findings assess state-of-the-art cancer driver prediction methods and develop a new and improved consensus-based approach for use in precision oncology. Cancer Res; 78(1); 1–12. ©2017 AACR.

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Tenascin-C promotes tumor cell migration and metastasis through integrin {alpha}9{beta}1 -mediated YAP inhibition

Tenascin-C is an extracellular matrix molecule that drives progression of many types of human cancer but the basis for its actions remain obscure. In this study, we describe a cell-autonomous signaling mechanism explaining how tenascin-C promotes cancer cell migration in the tumor microenvironment. In a murine xenograft model of advanced human osteosarcoma, tenascin-C and its receptor integrin α9β1 were determined to be essential for lung metastasis of tumor cells. We determined that activation of this pathway also reduced tumor cell-autonomous expression of target genes for the transcription factor YAP. In clinical specimens, a genetic signature comprising four YAP target genes represents prognostic impact. Taken together, our results illuminate how tumor cell deposition of tenascin-C in the tumor microenvironment promotes invasive migration and metastatic progression. 

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Oncogenic RAS-Induced Perinuclear Signaling Complexes Requiring KSR1 Regulate Signal Transmission to Downstream Targets

The precise characteristics that distinguish normal and oncogenic RAS signaling remain obscure. Here we show that oncogenic RAS and BRAF induce perinuclear re-localization of several RAS pathway proteins, including the kinases CK2 and p-ERK1/2 and the signaling scaffold KSR1. This spatial reorganization requires endocytosis, the kinase activities of MEK-ERK and CK2, and the presence of KSR1. CK2α co-localizes with KSR1 and Rab11, a marker of recycling endosomes, whereas p-ERK associates predominantly with a distinct KSR1-positive endosomal population. Notably, these perinuclear signaling complexes (PSCs) are present in tumor cell lines, mouse lung tumors and mouse embryonic fibroblasts undergoing RAS-induced senescence. PSCs are also transiently induced by growth factors (GFs) in non-transformed cells with delayed kinetics (4-6 hr), establishing a novel late phase of GF signaling that appears to be constitutively activated in tumor cells. PSCs provide an essential platform for RAS-induced phosphorylation and activation of the pro-senescence transcription factor C/EBPβ in primary MEFs undergoing senescence. Conversely, in tumor cells C/EBPβ activation is suppressed by 3'UTR-mediated localization of Cebpb transcripts to a peripheral cytoplasmic domain distinct from the PSC region. Collectively, our findings indicate that sustained PSC formation is a critical feature of oncogenic RAS/BRAF signaling in cancer cells that controls signal transmission to downstream targets by regulating selective access of effector kinases to substrates such as C/EBPβ.

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Inactivation of cancer-associated-fibroblasts (CAF) disrupts oncogenic signaling in pancreatic cancer cells and promotes its regression

Resident fibroblasts that contact tumor epithelial cells (TEC) can become irreversibly activated as cancer-associated-fibroblasts (CAF) which stimulate oncogenic signaling in TEC. In this study, we evaluated the crosstalk between CAF and TEC isolated from tumors generated in a mouse model of KRAS/mutp53-induced pancreatic cancer (KPC mice). Transcriptomic profiling conducted after treatment with the anticancer compound Minnelide revealed deregulation of the TGF-β signaling pathway in CAF, resulting in an apparent reversal of their activated state to a quiescent, non-proliferative state. TEC exposed to media conditioned by drug-treated CAF exhibited a decrease in oncogenic signaling as manifested by downregulation of the transcription factor Sp1. This inhibition was rescued by treating TEC with TGF-β. Given promising early clinical studies with minnelide, our findings suggest that approaches to inactivate CAF and prevent tumor-stroma crosstalk may offer a viable strategy to treat pancreatic cancer. 

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ER stress signaling promotes the survival of cancer 'persister cells' tolerant to EGFR tyrosine kinase inhibitors

An increasingly recognized component of resistance to tyrosine kinase inhibitors (TKI) involves persistence of a drug-tolerant subpopulation of cancer cells which survive despite effective eradication of the majority of the cell population. Multiple groups have demonstrated that these drug-tolerant persister cells undergo transcriptional adaptation via an epigenetic state change that promotes cell survival. Because this mode of TKI drug tolerance appears to involve transcriptional addiction to specific genes and pathways, we hypothesized that systematic functional screening of EGFR TKI/transcriptional inhibitor combination therapy would yield important mechanistic insights and alternative drug escape pathways. We therefore performed a genome-wide CRISPR/Cas9 enhancer/suppressor screen in EGFR-dependent lung cancer PC9 cells treated with erlotinib + THZ1 (CDK7/12 inhibitor) combination therapy,a combination previously shown to suppress drug tolerant cells in this setting. As expected, suppression of multiple genes associated with transcriptional complexes (EP300, CREBBP and MED1) enhanced erlotinib/THZ1 synergy. Unexpectedly, we uncovered nearly every component of the recently described ufmylation pathway in the synergy suppressor group. Loss of ufmylation did not affect canonical downstream EGFR signaling. Instead, absence of this pathway triggered a protective unfolded protein response (UPR) associated with STING upregulation, promoting pro-tumorigenic inflammatory signaling but also unique dependence on Bcl-xL. These data reveal that dysregulation of ufmylation and ER stress comprise a previously unrecognized TKI drug tolerance pathway that engages survival signaling, with potentially important therapeutic implications.

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The CARMA3-Bcl10-MALT1 Signalosome Drives NF-{kappa}B Activation and Promotes Aggressiveness in Angiotensin II Receptor-positive Breast Cancer.

The angiotensin II receptor AGTR1, which mediates vasoconstrictive and inflammatory signaling in vascular disease, is overexpressed aberrantly in some breast cancers. In this study, we established the significance of an AGTR1-responsive NF-κB signaling pathway in this breast cancer subset. We documented that AGTR1 overexpression occurred in the luminal A and B subtypes of breast cancer, was mutually exclusive of HER2 expression, and correlated with aggressive features that include increased lymph node metastasis, reduced responsiveness to neoadjuvant therapy, and reduced overall survival. Mechanistically, AGTR1 overexpression directed both ligand-independent and ligand-dependent activation of NF-κB, mediated by a signaling pathway that requires the triad of CARMA3, Bcl10, and MALT1 (CBM signalosome). Activation of this pathway drove cancer cell-intrinsic responses that include proliferation, migration and invasion. In addition, CBM-dependent activation of NF-κB elicited cancer cell-extrinsic effects, impacting endothelial cells of the tumor microenvironment to promote tumor angiogenesis. CBM/NF-κB signaling in AGTR1+ breast cancer therefore conspires to promote aggressive behavior through pleiotropic effects. Overall, our results point to the prognostic and therapeutic value of identifying AGTR1 overexpression in a subset of HER2-negative breast cancers, and they provide a mechanistic rationale to explore the repurposing of drugs that target angiotensin II-dependent NF-κB signaling pathways to improve the treatment of this breast cancer subset.

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FIH is an oxygen sensor in ovarian cancer for G9a/GLP-driven epigenetic regulation of metastasis-related genes

The prolyl hydroxlyases PHD1-3 and the asparaginly hydroxlyase FIH are oxygen sensors for HIF-driven transcription of hypoxia-induced genes, but whether these sensors affect oxygen-dependent epigenetic regulation more broadly is not known. Here we show that FIH exerts an additional role as an oxygen sensor in epigenetic control by the histone lysine methyltransferases G9a and GLP. FIH hydroxylated and inhibited G9a and GLP under normoxia. When the FIH reaction was limited under hypoxia, G9a and GLP were activated and repressed metastasis suppressor genes, thereby triggering cancer cell migration and peritoneal dissemination of ovarian cancer xenografts. In clinical specimens of ovarian cancer, expression of FIH and G9a were reciprocally associated with patient outcomes. We also identified mutations of FIH target motifs in G9a and GLP, which exhibited excessive H3K9 methylation and facilitated cell invasion. This study provides insight into a new function of FIH as an upstream regulator of oxygen-dependent chromatin remodeling. It also implies that the FIH-G9a/GLP pathway could be a potential target for inhibiting hypoxia-induced cancer metastasis.

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Inhibition of translesion DNA synthesis as a novel therapeutic strategy to treat brain cancer

Temozolomide is a DNA alkylating agent used to treat brain tumors but resistance to this drug is common. In this study, we provide evidence that efficacious responses to this drug can be heightened significantly by co-administration of an artificial nucleoside (5-NIdR) that efficiently and selectively inhibits the replication of DNA lesions generated by temozolomide. Conversion of this compound to the corresponding nucleoside triphosphate 5-NITP in vivo creates a potent inhibitor of several human DNA polymerases that can replicate damaged DNA. Accordingly, 5-NIdR synergized with temozolomide to increase apoptosis of tumor cells. In a murine xenograft model of glioblastoma, whereas temozolomide only delayed tumor growth its co-administration with 5-NIdR caused complete tumor regression. Exploratory toxicology investigations showed that high doses of 5-NIdR did not produce the side effects commonly seen with conventional nucleoside analogs. Collectively, our results offer a preclinical pharmacological proof of concept for the coordinate inhibition of translesion DNA synthesis as a strategy to improve chemotherapeutic responses in aggressive brain tumors.

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LSD1 stimulates cancer-associated fibrobasts to drive Notch3-dependent self-renewal of liver cancer stem-like cells

Cancer stem-like cells (CSC) in hepatocellular carcinoma (HCC) are thought to mediate therapeutic resistance and poor survival outcomes, but their intrinsic and extrinsic control is not well understood. In this study, we found that the chromatin modification factor LSD1 is highly expressed in HCC CSC where it decreases during differentiation. LSD1 was responsible for maintaining CSC self-renewal and tumorigenicity in HCC and its overexpression was sufficient to drive self-renewal of non-CSC.Levels of acetylated LSD1 were low in CSC with high LSD1 activity, and these CSC were capable of self-renewal. Notch signaling activated LSD1 through induction of the sirtuin SIRT1, leading to deacetylation and activation of LSD1 and CSC self-renewal. Notably, we found that LSD1 expression was increased in cancer-associated fibroblasts (CAF) as an upstream driver of Notch3-mediated CSC self-renewal. In clinical specimens of HCC, the presence of CAF, LSD1 and Notch3 strongly associated with poor patient survival. Overall, our results reveal that CAF-induced expression of Notch3 is responsible for LSD1 activation in CSC, driving their self-renewal in HCC.

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Loss of RASSF4 expression in multiple myeloma promotes RAS-driven malignant progression.

RAS mutations occur frequently in multiple myeloma (MM), but apart from driving progression they can also stimulate antitumor effects by activating tumor suppressive RASSF proteins. While this family of death effector molecules are often silenced in cancers, functional data about RASSF proteins in MM are lacking. Here we report that RASSF4 is downregulated during MM progression and correlates with a poor prognosis. Promoter methylation analysis in human cell lines revealed an inverse correlation between RASSF4 mRNA levels and methylation status. Epigenetic modulating agents restored RASSF4 expression. Enforced expression of RASSF4 induced G2 phase cell cycle arrest and apoptosis in human cell lines, reduced primary MM cell viability, and blocked MM growth in vivo. Mechanistic investigations showed that RASSF4 linked RAS to several pro-death pathways including those regulated by the kinases MST1, JNK and p38. By activating MST1 and the JNK/c-Jun pathway, RASSF4 sensitized MM cells to bortezomib. Genetic or pharmacological elevation of RASSF4 levels increased the anti-MM effects of the clinical relevant MEK1/2 inhibitor trametinib. Kinome analysis revealed this effect was mediated by concomitant activation of the JNK/c-Jun pathway along with inactivation of the MEK/ERK and PI3K/mTOR/Akt pathways. Overall, our findings establish RASSF4 as a tumor suppressive hub in MM and provide a mechanistic rationale for combining trametinib with HDAC inhibitors or bortezomib to treat patients with tumors exhibiting low RASSF4 expression.

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CXCR4 promotes neuroblastoma growth and therapeutic resistance through miR-15a/16-1 mediated ERK and BCL2/cyclin D1 pathways

CXCR4 expression in neuroblastoma (NB) tumors correlates with disease severity. In this study, we describe mechanisms by which CXCR4 signaling controls NB tumor growth and response to therapy. We found that overexpression of CXCR4 or stimulation with CXCL12 supports NB tumorigenesis. Moreover, CXCR4 inhibition with the high affinity CXCR4 antagonist, BL-8040 prevented tumor growth and reduced survival of tumor cells. These effects were mediated by the upregulation of miR-15a/16-1, which resulted in downregulation of their target genes BCL-2 and cyclin D1, as well as inhibition of ERK. Overexpression of miR-15a/16-1 in cells increased cell death, whereas antagomirs to miR-15a/16-1 abolished the pro-apoptotic effects of BL-8040. CXCR4 overexpression also increased miR-15a/16-1 shifting their oncogenic dependency from the BCL-2 to the ERK signaling pathway. Overall, our results demonstrate the therapeutic potential of CXCR4 inhibition in neuroblastoma treatment and provide a rationale to test combination therapies employing CXCR4 and BCL-2 inhibitors to increase the efficacy of these agents.

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Amplification of oncolytic vaccinia virus widespread tumor cell killing by sunitinib through multiple mechanisms

Oncolytic viruses pose many questions in their use in cancer therapy. In this study, we assessed the potential of mpJX-594 (mouse-prototype JX-594), a replication-competent vaccinia virus administered by intravenous injection, to target the tumor vasculature, produce immune activation and tumor cell killing more widespread than the infection, and suppress invasion and metastasis. These actions were examined in RIP-Tag2 transgenic mice with pancreatic neuroendocrine tumors (PNET) that developed spontaneously and progress as in humans. mpJX-594 initially infected tumor vascular endothelial cells, leading to vascular pruning and prolonged leakage in tumors but not in normal organs; parallel effects were observed in U87 gliomas. Viral infection spread to tumor cells, where tumor cell killing was much more widespread than the infection. Widespread tumor cell killing at 5 days was prevented by depletion of CD8+ T lymphocytes and did not require GM-CSF, as mpJX-594 variants that expressed human, mouse, or no GM-CSF produced equivalent amounts of killing. The antivascular, antitumor, and antimetastatic effects of mpJX-594 were amplified by concurrent or sequential administration of sunitinib, a multi-targeted receptor tyrosine kinase inhibitor (TKI). These effects were not mimicked by selective inhibition of VEGFR-2 despite equivalent vascular pruning, but were accompanied by suppression of regulatory T cells (Tregs) and greater influx of activated CD8+ T cells. Together, our results showed that mpJX-594 targets tumor blood vessels, spreads secondarily to tumor cells, and produces widespread CD8+ T-cell-dependent tumor cell killing in primary tumors and metastases, and that these effects can be amplified by co-administration of sunitinib.

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Filaggrin Mutations Increase Allergic Airway Disease in Childhood and Adolescence Through Interactions with Eczema and Aeroallergen Sensitization

Abstract

Background

Filaggrin loss-of-function (FLG-LOF) mutations are an established genetic cause of eczema. These mutations have subsequently been reported to increase the risk of aeroallergen sensitization and allergic airway disease. However, it is unclear whether FLG variants require both eczema and aeroallergen sensitization to influence airway disease development long-term outcomes.

Objective

To examine the effects of FLG-LOF mutations on allergic airway disease outcomes, with eczema and aeroallergen sensitization as intermediate variables, using the Isle of Wight birth cohort.

Methods

Study participants were evaluated at ages 1, 2, 4, 10 and 18 years to ascertain the development of allergic diseases (eczema, asthma and allergic rhinitis) and aeroallergen sensitization (determined by skin prick tests). FLG-LOF mutations were genotyped in 1150 subjects. To understand the complex associations between FLG mutations, intermediate variables (eczema and aeroallergen sensitization) and airway disease, path analysis was performed.

Results

There were significant total effects of FLG-LOF mutations on both asthma and allergic rhinitis at all ages as well as on aeroallergen sensitization up till 10 years old. In the filaggrin-asthma analysis, a direct effect of FLG-LOF mutations was observed on early childhood eczema (age 1 and 2 years) (relative risk (RR) 2.01, 95% CI: 1.74 - 2.31, p < 0.001), and all significant indirect pathways on asthma outcomes passed through eczema at these ages. In contrast, for the filaggrin-rhinitis model, FLG-LOF mutations exerted significant direct effects on early eczema as well as rhinitis at 10 years (RR 1.99; 95% CI: 1.72 - 2.29, p = 0.002).

Conclusion

FLG-LOF mutations are a significant risk factor for later childhood asthma and rhinitis. However, the pathway to asthma is only through early childhood eczema while a direct effect was observed for childhood rhinitis.

This article is protected by copyright. All rights reserved.

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Optical analysis of glioma: Fourier-transform infrared spectroscopy reveals the IDH1 mutation status.

Purpose: Somatic mutations in human cytosolic isocitrate dehydrogenase 1 (IDH1) gene cause profound changes in cell metabolism and are a common feature of gliomas with unprecedented predictive and prognostic impact. Fourier-transform infrared (FT-IR) spectroscopy addresses the molecular composition of cells and tissue and was investigated to deduct the IDH1-mutation status. Experimental Design: We tested the technique on human cell lines that were transduced with IDH1 wild-type or mutated IDH1 and on 34 human glioma samples. IR spectra were acquired at 256 positions from cell pellets or tissue cryosections. Moreover, IR spectra were obtained from fresh, unprocessed biopsies of 64 glioma patients. Results: IDH1 mutation was linked to changes in spectral bands assigned to molecular groups of lipids and proteins in cell lines and human glioma. The spectra of cryosections of brain tumor samples showed high inter-patient variability, for example bands related to calcifications at 1113 cm-1. However, supervised classification recognized relevant spectral regions at 1103, 1362, 1441, 1485 and 1553 cm-1 and assigned 88% of the tumor samples to the correct group. Similar spectral positions allowed the classification of spectra of fresh biopsies with an accuracy of 86%.  Conclusions: Here, we show that vibrational spectroscopy reveals the IDH1 genotype of glioma. Because it can provide information in seconds, an implementation into the intraoperative workflow might allow simple and rapid online diagnosis of IDH1 genotype. The intraoperative confirmation of IDH1 mutation status might guide the decision to pursue definitive neurosurgical resection and guide future in situ therapies of infiltrative gliomas.

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Issue Information

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The implant effect after intracranial electrode placement: is transient clinical improvement explained by post-implantation electrophysiological changes?

Publication date: Available online 19 December 2017
Source:Clinical Neurophysiology
Author(s): Bassel Abou-Khalil, Antonio Valentin




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Spatial versus temporal inhibition in dystonia

Publication date: Available online 19 December 2017
Source:Clinical Neurophysiology
Author(s): Robert Chen




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Impact of overbite and overjet on oral health-related quality of life of children and adolescents

Abstract

Background

Usually, morphological parameters of the teeth are recorded to help assess the indication for orthodontic treatment. It is assumed that significant deviations from average values compromise the quality of life. The aim of this study is to analyse the impact of overbite and overjet on oral health-related quality of life (OHRQoL) of children and adolescents.

Patients and methods

A total of 748 subjects, aged 9.5–15.5 years, participated in the LIFE child project of the University of Leipzig, where they underwent a general medical and dental examination. Overbite and overjet were measured, and aberrations of the OHRQoL were recorded by the probands themselves, who completed the German version of the Child Perceptions Questionnaire (CPQ-G11-14). The OHRQoL is divided into four domains ("oral symptoms", "functional limitations", "emotional well-being" and "social well-being") and is analysed by means of a CPQ score depending on age, gender, socioeconomic status and orthodontic treatment.

Results

On average, the participants listed 10.5 (±13.1) problem issues on a CPQ scale ranging from 0 to 140. Subjects with current orthodontic treatment had a CPQ score about 2.5 (±2.4) higher than those without treatment. The aberrations were mainly observed in the domains "oral symptoms" and "functional limitations". Multiple linear regression showed that deviations of the overbite had only little influence on the OHRQoL, but deviations of an overjet—especially of >6 mm increased the CPQ summary score about 6 points.

Conclusion

Children and adolescents with overjet deviations of >6 mm in comparison to the norm are associated with significant limitations of the OHRQoL. However, overbite deviations have only little influence.

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Vascular Complications After Chin Augmentation Using Hyaluronic Acid

Abstract

Vascular complications after hyaluronic acid (HA) filling of the chin have rarely been reported. In this report, two cases of vascular occlusion after HA augmentation of the mentum are presented. The first case involved local skin necrosis that resulted from a massive microcirculatory embolism and/or external compression of the chin skin microvasculature. The second case involved vascular compromise in the tongue that resulted from HA injection in the chin. The diagnosis was established on the basis of interventional angiography findings. Concerning the pathogenesis, we hypothesized that the filler embolus flowed into the branches of the deep lingual artery through the rich vascular anastomoses among the submental, sublingual, and deep lingual arteries, after being accidentally injected into the submental artery (or its branches).

Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://ift.tt/18t7xNj.

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Reconstruction of Mandibular Contour Using Individualized High-Density Porous Polyethylene (Medpor ® ) Implants Under the Guidance of Virtual Surgical Planning and 3D-Printed Surgical Templates

Abstract

Background

The mandibular contour plays a significant role in the beautiful and youthful look but the reconstruction remains a challenging problem. The objective of this study was to evaluate the use of individualized high-density porous polyethylene (Medpor^®) implants for comprehensive reconstruction of mandibular contour with the aid of computer-aided design/computer-aided manufacturing (CAD/CAM).

Methods

From 2010 to 2014, 12 patients with mandibular contour deformities were enrolled in our retrospective study. Mandible models and individualized surgical templates were fabricated by three-dimensional (3D) printing and Medpor^® implants were made according to the surgical templates. The Medpor^® implants were used for both unilateral and bilateral mandibular contour deformities. In four cases, simultaneous mandibular orthognathic surgery was performed with unilateral mandibular contour reconstruction.

Results

Eleven patients had a reposeful postoperative recovery with no complication. Delayed infection was shown in one patient and the Medpor^® implant was removed. All the 11 patients had the mandibular contour reconstructed satisfactorily.

Conclusion

The technique and cases presented demonstrate the utility of Medpor^® implants with CAD/CAM in comprehensive mandibular contour reconstruction.

Level of Evidence IV

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://ift.tt/18t7xNj.

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Pediatric Cochlear implant soft failure

Hard cochlear implant failures are diagnosed by objective tests whereas soft failures are suspected on the basis of clinical signs and symptoms. This study reviews our experience with children in tertiary pediatric medical center who underwent revision cochlear implantation, with emphasis on soft failures.

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Reconstruction of a skull base defect after endoscopic endonasal resection of a pituitary adenoma: Sphenoid mucosal flaps

This report describes a bilateral sphenoid sinus mucosal flap for the repair of a sellar floor defect and CSF leak following endoscopic endonasal skull base surgery. The key advantage of this technique is enabling the sphenoid mucosal flaps to remain vascularized, which reduces postoperative complications including CSF leakage, recurrent sinusitis, meningitis, encephalitis and pneumocephalus. The use of this technique is a viable and possibly favorable alternative to free grafts in the reconstruction of small to medium sized sellar defects with low flow or absent CSF leaks base surgery.

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Communication pathways to and from the inner ear and their contributions to drug delivery

Publication date: Available online 19 December 2017
Source:Hearing Research
Author(s): Alec N. Salt, Keiko Hirose
The environment of the inner ear is highly regulated in a manner that some solutes are permitted to enter while others are excluded or transported out. Drug therapies targeting the sensory and supporting cells of the auditory and vestibular systems require the agent to gain entry to the fluid spaces of the inner ear, perilymph or endolymph, which surround the sensory organs. Access to the inner ear fluids from the vasculature is limited by the blood-labyrinth barriers, which include the blood-perilymph and blood-strial barriers. Intratympanic applications provide an alternative approach in which drugs are applied locally. Drug from the applied solution enters perilymph through the round window membrane, through the stapes, and under some circumstances, through thin bone in the otic capsule. The amount of drug applied to the middle ear is always substantially more than the amount entering perilymph. As a result, significant amounts of the applied drug can pass to the digestive system, to the vasculature, and to the brain. Drugs in perilymph pass to the vasculature and to cerebrospinal fluid via the cochlear aqueduct. Conversely, drugs applied to cerebrospinal fluid, including those given intrathecally, can enter perilymph through the cochlear aqueduct. Other possible routes in or out of the ear include passage by neuronal pathways, passage via endolymph and the endolymphatic sac, and possibly via lymphatic pathways. A better understanding of the pathways for drug movements in and out of the ear will enable better intervention strategies.



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Comparative Effectiveness of Preoperative Paravertebral Block for Post-Mastectomy Reconstruction: A Systematic Review of the Literature

Abstract

Introduction

Paravertebral block (PVB) has emerged as a viable strategy for improving postoperative outcomes in breast surgery; however, it is unclear whether these benefits extend to recipients of post-mastectomy reconstruction (PMR).

Methods

A systematic search of the PubMed, EMBASE, Web of Science and Cochrane Library electronic databases was conducted for all studies matching the a priori inclusion criteria (inception to 1 March 2017). Independent assessment by two reviewers, in stages, of the title/abstract and full text was performed. Data relating to study design, patient characteristics, PVB medications and technique, and outcomes, including pain, opioid consumption, length of stay (LOS), postoperative nausea and vomiting (PONV), and PVB-related complications was abstracted.

Results

Of the 1243 identified articles, nine met the inclusion criteria, accounting for 936 patients (PVB, n = 518; non-PVB, n = 418) in two randomized controlled trials (RCT) and seven retrospective cohort studies. Of these studies, six described PVB for prosthetic PMR, and three described PVB for autologous PMR. Overall, there is a subtle trend towards improved pain control, less opioid requirement and shorter LOS, while PONV was largely unchanged in patients receiving PVB for PMR. In two studies, technical failure was reported at 7.4 and 10%, although no study reported a PVB-related complication. Study quality varied, and risk of bias in the included studies was high. Heterogeneity precluded a meta-analysis.

Conclusions

Although recent reports and RCTs advocate for PVB use in PMR, our review highlights significant heterogeneity and knowledge gaps that must be addressed in order for PVB to become part of the optimal anesthetic protocol in PMR.

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Exploring the Neural Bases of Primary Muscle Tension Dysphonia: A Case Study Using Functional Magnetic Resonance Imaging

Primary muscle tension dysphonia (pMTD) is a voice disorder that occurs in the absence of laryngeal pathology. Dysregulated activity of the paralaryngeal muscles is considered the proximal cause; however, the central origin of this aberrant laryngeal muscle activation is unclear. The Trait Theory (Roy and Bless, 2000a,b) proposed that specific personality traits can predispose one to laryngeal motor inhibition and pMTD, and this inhibition is mediated by a hyperactive "behavioral inhibition system (BIS)" composed of limbic system structures (and associated prefrontal connections).

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Voice Acoustic Analysis of Pediatric Vocal Nodule Patients Using Ratios Calculated With Biomedical Image Segmentation

The aim of this study was to determine nodules using newly developed software with a computer-assisted visual process technique for the calculation of size. The effects of the ratios of nodule base and width were evaluated with voice acoustic analysis.

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Comparative Effectiveness of Preoperative Paravertebral Block for Post-Mastectomy Reconstruction: A Systematic Review of the Literature

Abstract

Introduction

Paravertebral block (PVB) has emerged as a viable strategy for improving postoperative outcomes in breast surgery; however, it is unclear whether these benefits extend to recipients of post-mastectomy reconstruction (PMR).

Methods

A systematic search of the PubMed, EMBASE, Web of Science and Cochrane Library electronic databases was conducted for all studies matching the a priori inclusion criteria (inception to 1 March 2017). Independent assessment by two reviewers, in stages, of the title/abstract and full text was performed. Data relating to study design, patient characteristics, PVB medications and technique, and outcomes, including pain, opioid consumption, length of stay (LOS), postoperative nausea and vomiting (PONV), and PVB-related complications was abstracted.

Results

Of the 1243 identified articles, nine met the inclusion criteria, accounting for 936 patients (PVB, n = 518; non-PVB, n = 418) in two randomized controlled trials (RCT) and seven retrospective cohort studies. Of these studies, six described PVB for prosthetic PMR, and three described PVB for autologous PMR. Overall, there is a subtle trend towards improved pain control, less opioid requirement and shorter LOS, while PONV was largely unchanged in patients receiving PVB for PMR. In two studies, technical failure was reported at 7.4 and 10%, although no study reported a PVB-related complication. Study quality varied, and risk of bias in the included studies was high. Heterogeneity precluded a meta-analysis.

Conclusions

Although recent reports and RCTs advocate for PVB use in PMR, our review highlights significant heterogeneity and knowledge gaps that must be addressed in order for PVB to become part of the optimal anesthetic protocol in PMR.

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Association of polysomnographic parameters with clinical symptoms severity grading in Robin sequence patients: a cohort nested cross-sectional study

Abstract.

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Pre-Sleep Arousal Scale (PSAS): Psychometric study of a European Portuguese version

/Background: Pre-sleep arousal constitutes one of the major features of insomnia. As such, it is imperative to have adequate instruments to measure this construct in both clinical and research settings. The Pre-Sleep Arousal Scale (PSAS) is the most well-known measure to evaluate pre-sleep arousal. The current study aimed to examine some of the psychometric properties of a European Portuguese version of the scale.

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Gene Expression Profiling of Bronchoalveolar Lavage Cells during Aspergillus Colonization of the Lung Allograft

AbstractBackgroundAspergillus colonization after lung transplant is associated with an increased risk of chronic lung allograft dysfunction (CLAD). We hypothesized that gene expression during Aspergillus colonization could provide clues to CLAD pathogenesis.MethodsWe examined transcriptional profiles in 3 or 6-month surveillance bronchoalveolar lavage fluid cell pellets from recipients with A. fumigatus colonization (n=12) and without colonization (n=10). Among the Aspergillus colonized, we also explored profiles in those who developed CLAD (n=6) or remained CLAD free (n=6). Transcription profiles were assayed with the HG-U133 Plus 2.0 microarray (Affymetrix). Differential gene expression was based upon an absolute fold difference ≥2.0, and unadjusted P-value

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EphrinB2 signaling enhances osteogenic/odontogenic differentiation of human dental pulp stem cells

Publication date: March 2018
Source:Archives of Oral Biology, Volume 87
Author(s): Boon Chin Heng, Shuai Wang, Ting Gong, Jianguang Xu, Changyong Yuan, Chengfei Zhang
ObjectiveTo investigate the role of the EphrinB2 signaling pathway in the osteogenesis/odontogenesis of human dental pulp stem cells (DPSCs).DesignThe endogenous expression levels of EphrinB2 and its cognate receptors EphB2 and EphB4 in DPSCs were analyzed by qRT-PCR and Western blotting after 7, 14 and 21 days of osteogenic/odontogenic induction culture. Additionally, the phosphorylation of EphrinB2, EphB4 and ERK1/2 proteins at early time-points following osteogenic induction, were also investigated by Western blots. Subsequently, we investigated whether supplementation of recombinant EphrinB2-Fc within the induction milieu can enhance the osteogenic/odontogenic differentiation of DPSCs.ResultsEndogenous gene and protein expression levels of EphrinB2, EphB2 and EphB4 were upregulated in induced versus non-induced DPSCs, over 21 days of osteogenic/odontogenic induction. Western blots showed increase in phosphorylated EphrinB2, EphB4 and ERK1/2 proteins at early time-points following osteogenic induction. Preliminary investigation of a concentration range (0, 0.5, 1 and 2 μg/ml) of recombinant EphrinB2-Fc within osteogenic induction media, showed that 0.5 μg/ml was optimal for enhancing the osteogenic/odontogenic differentiation of DPSCs over a culture duration of 14 days. Subsequently, more comprehensive qRT-PCR analysis with 0.5 μg/ml EphrinB2-Fc revealed significant upregulation of several key osteogenic marker genes in treated versus untreated DPSCs after 21 days of osteogenic/odontogenic induction. By 7 days of osteogenic induction, DPSCs treated with 0.5 μg/ml EphrinB2-Fc exhibited significantly more calcium mineralization (Alizarin red S staining) and alkaline phosphatase activity than the untreated control.ConclusionsEphrinB2 signaling plays a key role in the osteogenic/odontogenic differentiation of DPSCs.



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The Effectiveness of Progressive Aerobic Interval Training in Cardiac Rehabilitation

AbstractIntroductionAerobic interval training (AIT) has recently emerged as a more effective strategy than moderate intensity continuous exercise (MICE) for improving VO2peak in CAD patients. The primary purpose of this retrospective study was to describe the change in VO2peak, and CV risk profile characteristics (secondary outcomes) after progressive AIT practiced in the largest, outpatient cardiac rehabilitation (CR) program in North America compared to usual care CR involving MICE.MethodsElectronic database records were retrieved from consecutively enrolled patients with CAD who attended the Toronto Rehabilitation Institute, between January 1, 2005 to December 31, 2015. Patients were then separated into two, age and sex propensity score matched groups: 772 patients were prescribed 26 weeks of MICE (60-80% of VO2peak, 5 times/week) as per usual care CR (56.0±9.2 years; 12% female/88% male; VO2peak: 20.8±5.9 ml⋅kg-1⋅min-1), and 772 patients were prescribed 26 weeks of progressive walk/jog intervals (15min/mile walking pace, 12min/mile jogging pace, 5 times/week) (55.9±9.3 years; 12% female/88% male; VO2peak: 24.8±5.7 ml⋅kg-1 ⋅min-1). Treatment effect analysis of AIT on VO2peak and CV risk profile characteristics was performed using multiple regression with baseline values as covariates.ResultsTreatment effect analysis revealed a 3.84 ml⋅kg-1⋅min-1 superior improvement in VO2peak in the AIT group compared to usual care MICE group (p

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Application of “Omics” and Systems Biology to Sarcoidosis Research

Annals of the American Thoracic Society, Volume 14, Issue Supplement_6, Page S445-S451, December 2017.


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Executive Summary of the NHLBI Workshop Report: Leveraging Current Scientific Advancements to Understand Sarcoidosis Variability and Improve Outcomes

Annals of the American Thoracic Society, Volume 14, Issue Supplement_6, Page S415-S420, December 2017.


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Disease Burden and Variability in Sarcoidosis

Annals of the American Thoracic Society, Volume 14, Issue Supplement_6, Page S421-S428, December 2017.


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Genetic, Immunologic, and Environmental Basis of Sarcoidosis

Annals of the American Thoracic Society, Volume 14, Issue Supplement_6, Page S429-S436, December 2017.


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High-Risk Sarcoidosis. Current Concepts and Research Imperatives

Annals of the American Thoracic Society, Volume 14, Issue Supplement_6, Page S437-S444, December 2017.


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Lithium-Associated Hypercalcemia: Pathophysiology, Prevalence, Management

Abstract

Background

Lithium-associated hypercalcemia (LAH) is an ill-defined endocrinopathy. The aim of the present study was to determine the prevalence of hypercalcemia in a cohort of bipolar patients (BP) with and without concomitant lithium treatment and to study surgical outcomes for lithium-associated hyperparathyroidism.

Methods

Retrospective data, including laboratory results, surgical outcomes and medications, were collected from 313 BP treated with lithium from two psychiatric outpatient units in central Sweden. In addition, data were collected from 148 BP without lithium and a randomly selected control population of 102 individuals. Logistic regression was used to compare odds of hypercalcemia in these respective populations.

Results

The prevalence of lithium-associated hypercalcemia was 26%. Mild hypercalcemia was detected in 87 out of 563 study participants. The odds of hypercalcemia were significantly higher in BP with lithium treatment compared with BP unexposed to lithium (adjusted OR 13.45; 95% CI 3.09, 58.55; p = 0.001). No significant difference was detected between BP without lithium and control population (adjusted OR 2.40; 95% CI 0.38, 15.41; p = 0.355). Seven BP with lithium underwent surgery where an average of two parathyroid glands was removed. Parathyroid hyperplasia was present in four patients (57%) at the initial operation. One patient had persistent disease after the initial operation, and six patients had recurrent disease at follow-up time which was on average 10 years.

Conclusion

The high prevalence of LAH justifies the regular monitoring of calcium homeostasis, particularly in high-risk groups. If surgery is necessary, bilateral neck exploration should be considered in patients on chronic lithium treatment. Prospective studies are needed.

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Transgender Women May Get Small Breasts With Hormones

Transgender women who take sex hormones to feminize their bodies may not experience as much breast development as they expect, a new European study suggests.
Reuters Health Information

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FDA to Get More Aggressive on Homeopathic Meds

The FDA is adopting a more aggressive stance when it comes to regulating homeopathic remedies.
WebMD Health News

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At a Hotel Near You: Cadavers in the Banquet Room

Just outside the operating theater, the organizers of a medical conference wore Minnie Mouse ears.
Reuters Health Information

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#MeToo Stories: Sexual Harassment Pervasive in Medicine

In recounting her own and other women's sexual harassment experience, a physician who researches sexual harassment reveals the challenge ahead that the field must begin taking seriously.
Medscape Medical News

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Effect of postoperative radiotherapy on survival in duodenal adenocarcinoma: a propensity score-adjusted analysis of Surveillance, Epidemiology, and End Results database

Abstract

Purpose

The use of adjuvant treatment has not been sufficiently investigated in duodenal adenocarcinoma. This study evaluated the effect of postoperative radiotherapy (PORT) on survival outcomes in this rare malignancy.

Methods

We identified patients who were diagnosed between 2004 and 2013 in the Surveillance, Epidemiology, and End Results database. Overall survival (OS) and disease-specific survival (DSS) were analyzed before and after propensity score matching.

Results

Among the 701 eligible patients, 116 (17%) underwent PORT. There were no significant differences in OS and DSS according to receipt of PORT in the unmatched population (P = 0.982 and 0.496, respectively), whereas the propensity-matched analysis showed improved OS and DSS with PORT (P = 0.053 and 0.019, respectively). No receipt of PORT was an independent poor prognostic factor in multivariate analysis of both OS (P = 0.022) and DSS (P = 0.005). The potential survival benefits of PORT were observed in subgroups of T4 stage, larger tumor size, higher lymph node ratio, and total/radical resection.

Conclusions

We provide useful insights into the therapeutic role of PORT in adenocarcinoma of the duodenum. Adjuvant strategy with PORT needs to be considered in locally advanced tumors.

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Preoperative Blood Tests Conducted Before Low-Risk Surgery in Japan: A Retrospective Observational Study Using a Nationwide Insurance Claims Database

BACKGROUND: Routine preoperative testing is discouraged before low-risk surgery because testing does not provide any beneficial effect in terms of patient outcome. However, few studies have assessed the utilization of hospital health care resources in terms of preoperative tests in a real-world setting. Here, we aimed to assess the prevalence and factors associated with preoperative blood tests before low-risk surgery in Japan. METHODS: In this retrospective observational study, we used the nationwide insurance claims data of Japan. Patients who underwent low-risk surgeries between April 1, 2012, and March 31, 2016, were included. Our primary outcome was the receipt of any preoperative tests within 60 days before an index procedure: complete blood count, basic metabolic panel, coagulation tests, and liver function tests. We performed a descriptive analysis to estimate the proportions of preoperative blood tests, and examined the associations between patient-level and institutional-level factors and preoperative blood tests, using multilevel logistic regression analysis. Interinstitutional variation in the utilization of preoperative tests was summarized using the median odds ratio (OR). RESULTS: The study sample included 59,818 patients (mean [standard deviation] age, 44.0 [11.3] years; 33,574 [56.1%] women) from 9746 institutions. The overall proportion of each test was: complete blood count, 58.7%; metabolic panel, 47.8%; coagulation tests, 36.6%; and liver function tests, 48.5%. The proportion receiving any preoperative tests in the overall sample was 59.5%. Multilevel logistic regression analysis indicated that preoperative blood tests were associated with the Charlson comorbidity index score (score ≥3: adjusted OR, 4.21; 95% confidence interval [CI], 3.69–4.80), anticoagulant use (adjusted OR, 4.12; 95% CI, 2.35–7.22), type of anesthesia (general anesthesia: adjusted OR, 5.69; 95% CI, 4.85–6.68; regional anesthesia: adjusted OR, 3.76; 95% CI, 3.28–4.30), surgical setting (inpatient procedure: adjusted OR, 3.64; 95% CI, 3.30–4.00), and number of beds (≥100 beds: adjusted OR, 3.61; 95% CI, 3.19–4.08). The median institutional-specific proportion of preoperative tests was 40.0% (interquartile range, 0%–100%). The median OR for interinstitutional variation in ordering preoperative tests was 4.34. These findings were consistent across a sensitivity analysis. CONCLUSIONS: Preoperative blood tests were performed before 59.5% of low-risk surgeries. Preoperative tests were associated with the type of anesthesia, patient characteristics, and medical facility status. There was a substantial interinstitutional variation in the utilization of preoperative tests. Accepted for publication November 8, 2017. Funding: Support was provided solely from institutional and/or departmental sources. Conflicts of Interest: See Disclosures at the end of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Koji Kawakami, MD, PhD, Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Yoshida Konoecho, Sakyoku, Kyoto 6068501, Japan. Address e-mail to kawakami.koji.4e@kyoto-u.ac.jp. © 2017 International Anesthesia Research Society

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Modifiable and Nonmodifiable Factors Associated With Perioperative Failure of Extraglottic Airway Devices

BACKGROUND: Extraglottic airway device (EGA) failure can be associated with severe complications and adverse patient outcomes. Prior research has identified patient- and procedure-related predictors of EGA failure. In this retrospective study, we assessed the incidence of perioperative EGA failure at our institution and identified modifiable factors associated with this complication that may be the target of preventative or mitigating interventions. METHODS: We performed a 5-year retrospective analysis of adult general anesthesia cases managed with EGAs in a single academic center. Univariable and multivariable logistic regressions were used to identify clinically modifiable and nonmodifiable factors significantly associated with 3 different types of perioperative EGA failure: (1) "EGA placement failure," (2) "EGA failure before procedure start," and (3) "EGA failure after procedure start." RESULTS: A total of 19,693 cases involving an EGA were included in the analysis dataset. EGA failure occurred in 383 (1.9%) of the cases. EGA placement failure occurred in 222 (1.13%) of the cases. EGA failure before procedure start occurred in 76 (0.39%) of the cases. EGA failure after procedure start occurred in 85 (0.43%) of the cases. Factors significantly associated with each type of failure and controllable by the anesthesia team were as follows: (1) EGA placement failure: use of desflurane (odds ratio [OR], 1.67; 95% confidence interval [CI], 1.23–2.25) and EGA size 4 or 5 vs 2 or 3 (OR, 0.07; 95% CI, 0.05–0.10); (2) EGA failure before procedure start: use of desflurane (OR, 2.05; 95% CI, 1.23–3.40) and 3 or more placement attempts (OR, 4.69; 95% CI, 2.57–8.56); and (3) EGA failure after procedure start: 3 or more placement attempts (OR, 2.06; 95% CI, 1.02–4.16) and increasing anesthesia time (OR, 1.35; 95% CI, 1.17–1.55). CONCLUSIONS: The overall incidence of EGA failure was 1.9%, and EGA placement failure was the most common type of failure. We also found that use of desflurane and use of smaller EGA sizes in adult patients were factors under the direct control of anesthesia clinicians associated with EGA failure. An increasing number of attempts at EGA placement was associated with later device failures. Our findings also confirm the association of EGA failure with previously identified patient- and procedure-related factors such as increased body mass index, male sex, and position other than supine. Accepted for publication September 29, 2017. Funding: None. The authors declare no conflicts of interest. This study was entirely conducted at Barnes Jewish Hospital and the School of Medicine of Washington University in St Louis. Reprints will not be available from the authors. Address correspondence to Andrea Vannucci, MD, DEAA, Department of Anesthesiology, University of Mississippi Medical Center-School of Medicine, 2500 N State St, Jackson, MS 39216. Address e-mail to avannucci@umc.edu. © 2017 International Anesthesia Research Society

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Surveying the Literature

No abstract available

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Differential Effects of Anesthetics and Opioid Receptor Activation on Cardioprotection Elicited by Reactive Oxygen Species–Mediated Postconditioning in Sprague-Dawley Rat Hearts

BACKGROUND: Despite an array of cardioprotective interventions identified in preclinical models of ischemia–reperfusion (IR) injury, successful clinical translation has not been achieved. This study investigated whether drugs routinely used in clinical anesthesia influence cardioprotective effectiveness by reducing effects of reactive oxygen species (ROS), upstream triggers of cardioprotective signaling. Effects of propofol, sevoflurane, or remifentanil were compared on postischemic functional recovery induced by ROS-mediated postconditioning with Intralipid. METHODS: Recovery of left ventricular (LV) work, an index of IR injury, was measured in isolated Sprague-Dawley rat hearts subjected to global ischemia (20 minutes) and reperfusion (30 minutes). Hearts were either untreated or were treated with postconditioning with Intralipid (1%, throughout reperfusion). Propofol (10 μM), sevoflurane (2 vol%), remifentanil (3 nM), or combinations thereof were administered peri-ischemically (before and during IR). The effects of anesthetics on ROS production were measured in LV cardiac fibers by Amplex Red assay under phosphorylating and nonphosphorylating conditions. RESULTS: Recovery of LV work (expressed as percentage of the preischemic value ± standard deviation) in untreated hearts was poor (20% ± 7%) and was improved by Intralipid postconditioning (58% ± 8%, P = .001). In the absence of Intralipid postconditioning, recovery of LV work was enhanced by propofol (28% ± 9%, P = .049), sevoflurane (49% ± 5%, P

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Macintosh Blade Videolaryngoscopy Combined With Rigid Bonfils Intubation Endoscope Offers a Suitable Alternative for Patients With Difficult Airways

BACKGROUND: In the armamentarium of an anesthesiologist, videolaryngoscopy is a valuable addition to secure the airway. However, when the videolaryngoscope (VLS) offers no solution, few options remain. Earlier, we presented an intubation technique combining Macintosh blade VLS and Bonfils intubation endoscope (BIE) for a patient with a history of very difficult intubation. In the present study, we evaluated this technique to establish whether it is a valuable alternative. METHODS: In this single-blinded nonrandomized study, 38 patients with a history of difficult intubation or 1 or more predictors of difficult intubation, scoring a Cormack & Lehane (C&L) grade III or IV using Macintosh blade VLS, were included. Patients were intubated combining the VLS with the BIE. The C&L grade was scored 3 times during (1) direct laryngoscopy; (2) indirect videolaryngoscopy; and (3) using the combined technique (VLS + BIE). Afterward, 2 blinded anesthesiologists assessed the C&L grade using the pictures taken during the procedure. RESULTS: Data of 38 patients were analyzed. An improvement of the C&L grade with the combined technique occurred in 33 of 38 patients (86.8%; 95% confidence interval, 71.9%–95.6%). Reviewer 1 reported an improvement of the C&L grade with the combined technique in 37 of 38 patients. Reviewer 2 reported improvement in 33 and deterioration in 2 of the patients. No complications occurred. CONCLUSIONS: The combined use of a VLS with Macintosh blade and BIE gives the anesthesiologist a valuable alternative intubation option in patients with extremely difficult airways. Accepted for publication November 2, 2017. Funding: None of the study members has received funding from the device manufacturer of the Bonfils intubation endoscope. All devices used for the study were readily available from the department. No funding was obtained from the device manufacturers. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). Clinical trial registration: ClinicalTrials.gov—NCT01691703. Reprints will not be available from the authors. Address correspondence to Barbe M. Pieters, MD, PhD, Department of Anesthesiology, University Medical Centre Utrecht, Postbus 85090, 3508 AB Utrecht, the Netherlands. Address e-mail to bmapieters@gmail.com. © 2017 International Anesthesia Research Society

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Impact of Inhalational Anesthetics on Liver Regeneration After Living Donor Hepatectomy: A Propensity Score-Matched Analysis

BACKGROUND: Although desflurane and sevoflurane, the most commonly used inhalational anesthetics, have been linked to postoperative liver injury, their impact on liver regeneration remains unclear. We compared the influence of these anesthetics on the postoperative liver regeneration index (LRI) after living donor hepatectomy (LDH). METHODS: We conducted a retrospective chart review of 1629 living donors who underwent right hepatectomy for LDH between January 2008 and August 2016. The patients were divided into sevoflurane (n = 1206) and desflurane (n = 423) groups. Factors associated with LRI were investigated using multivariable logistic regression analysis. Propensity score matching analysis compared early (1 postoperative week) and late (within 1–2 months) LRIs and delayed recovery of hepatic function between the 2 groups. RESULTS: The mean early and late LRIs in the 1629 patients were 63.3% ± 41.5% and 93.7% ± 48.1%, respectively. After propensity score matching (n = 403 pairs), there were no significant differences in early and late LRIs between the sevoflurane and desflurane groups (early LRI: 61.2% ± 41.5% vs 58.9% ± 42.4%, P = .438; late LRI: 88.3% ± 44.3% vs 94.6% ± 52.4%, P = .168). Male sex (regression coefficient [β], 4.6; confidence interval, 1.6–7.6; P = .003) and remnant liver volume (β, –4.92; confidence interval, –5.2 to –4.7; P

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Sources of Variation in Anesthetic Drug Costs

BACKGROUND:Increasing attention has been focused on health care expenditures, which include anesthetic-related drug costs. Using data from 2 large academic medical centers, we sought to identify significant contributors to anesthetic drug cost variation.METHODS:Using anesthesia information management systems, we calculated volatile and intravenous drug costs for 8 types of inpatient surgical procedures performed from July 1, 2009, to December 31, 2011. For each case, we determined patient age, American Society of Anesthesiologists (ASA) physical status, gender, institution, case duration, in-room provider, and attending anesthesiologist. These variables were then entered into 2 fixed-effects linear regression models, both with logarithmically transformed case cost as the outcome variable. The first model included duration, attending anesthesiologist, patient age, ASA physical status, and patient gender as independent variables. The second model included case type, institution, patient age, ASA physical status, and patient gender as independent variables. When all variables were entered into 1 model, redundancy analyses showed that case type was highly correlated (R2 = 0.92) with the other variables in the model. More specifically, a model that included case type was no better at predicting cost than a model without the variable, as long as that model contained the combination of attending anesthesiologist and case duration. Therefore, because we were interested in determining the effect both variables had on cost, 2 models were created instead of 1. The average change in cost resulting from each variable compared to the average cost of the reference category was calculated by first exponentiating the β coefficient and subtracting 1 to get the percent difference in cost. We then multiplied that value by the mean cost of the associated reference group.RESULTS:A total of 5504 records were identified, of which 4856 were analyzed. The median anesthetic drug cost was $38.45 (25th percentile = $23.23, 75th percentile = $63.82). The majority of the variation was not described by our models—35.2% was explained in the model containing case duration, and 32.3% was explained in the model containing case type. However, the largest sources of variation our models identified were attending anesthesiologist, case type, and procedure duration. With all else held constant, the average change in cost between attending anesthesiologists ranged from a cost decrease of $41.25 to a cost increase of $95.67 (10th percentile = −$19.96, 90th percentile = +$20.20) when compared to the provider with the median value for mean cost per case. The average change in cost between institutions was significant but minor ($5.73).CONCLUSIONS:The majority of the variation was not described by the models, possibly indicating high per-case random variation. The largest sources of variation identified by our models included attending anesthesiologist, procedure type, and case duration. The difference in cost between institutions was statistically significant but was minor. While many prior studies have found significant savings resulting from cost-reducing interventions, our findings suggest that because the overall cost of anesthetic drugs was small, the savings resulting from interventions focused on the clinical practice of attending anesthesiologists may be negligible, especially in institutions where access to more expensive drugs is already limited. Thus, cost-saving efforts may be better focused elsewhere. BACKGROUND: Increasing attention has been focused on health care expenditures, which include anesthetic-related drug costs. Using data from 2 large academic medical centers, we sought to identify significant contributors to anesthetic drug cost variation. METHODS: Using anesthesia information management systems, we calculated volatile and intravenous drug costs for 8 types of inpatient surgical procedures performed from July 1, 2009, to December 31, 2011. For each case, we determined patient age, American Society of Anesthesiologists (ASA) physical status, gender, institution, case duration, in-room provider, and attending anesthesiologist. These variables were then entered into 2 fixed-effects linear regression models, both with logarithmically transformed case cost as the outcome variable. The first model included duration, attending anesthesiologist, patient age, ASA physical status, and patient gender as independent variables. The second model included case type, institution, patient age, ASA physical status, and patient gender as independent variables. When all variables were entered into 1 model, redundancy analyses showed that case type was highly correlated (R2 = 0.92) with the other variables in the model. More specifically, a model that included case type was no better at predicting cost than a model without the variable, as long as that model contained the combination of attending anesthesiologist and case duration. Therefore, because we were interested in determining the effect both variables had on cost, 2 models were created instead of 1. The average change in cost resulting from each variable compared to the average cost of the reference category was calculated by first exponentiating the β coefficient and subtracting 1 to get the percent difference in cost. We then multiplied that value by the mean cost of the associated reference group. RESULTS: A total of 5504 records were identified, of which 4856 were analyzed. The median anesthetic drug cost was $38.45 (25th percentile = $23.23, 75th percentile = $63.82). The majority of the variation was not described by our models—35.2% was explained in the model containing case duration, and 32.3% was explained in the model containing case type. However, the largest sources of variation our models identified were attending anesthesiologist, case type, and procedure duration. With all else held constant, the average change in cost between attending anesthesiologists ranged from a cost decrease of $41.25 to a cost increase of $95.67 (10th percentile = −$19.96, 90th percentile = +$20.20) when compared to the provider with the median value for mean cost per case. The average change in cost between institutions was significant but minor ($5.73). CONCLUSIONS: The majority of the variation was not described by the models, possibly indicating high per-case random variation. The largest sources of variation identified by our models included attending anesthesiologist, procedure type, and case duration. The difference in cost between institutions was statistically significant but was minor. While many prior studies have found significant savings resulting from cost-reducing interventions, our findings suggest that because the overall cost of anesthetic drugs was small, the savings resulting from interventions focused on the clinical practice of attending anesthesiologists may be negligible, especially in institutions where access to more expensive drugs is already limited. Thus, cost-saving efforts may be better focused elsewhere. Accepted for publication November 8, 2017. Funding: Supported by departmental funding. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Jonathan P. Wanderer, MD, MPhil, The Vanderbilt Clinic, 1301 Medical Center Dr, Suite 4648, Nashville, TN 37232. Address e-mail to Jonathan.p.wanderer@vanderbilt.edu. © 2017 International Anesthesia Research Society

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Promoting a Restrictive Intraoperative Transfusion Strategy: The Influence of a Transfusion Guideline and a Novel Software Tool

BACKGROUND: The effect of neither transfusion guidelines nor decision support tools on intraoperative transfusion has been previously evaluated. The University of Michigan introduced a transfusion guideline in 2009, and in 2011, the Department of Anesthesiology developed a transfusion decision support tool. The primary aim of this study was to assess the associations of the transfusion guideline and the optional use of the software transfusion tool with intraoperative behaviors; pretransfusion hematocrit assessment (whether or not a hematocrit was checked before each red cell unit) and restrictive red cell use (withholding transfusion unless the hematocrit was ≤21%). METHODS: This was a before–after retrospective study without a concurrent control group of patients transfused 1–3 units of red cells intraoperatively. Three phases were studied to provide data both before and after the implementation of the transfusion guideline and the intraoperative software tool. Within each phase, trends of checking hematocrits before transfusion and restrictive transfusion were charted against time. F tests were used to measure differences of slopes. The difference between means of each phase was measured using Mann-Whitney U tests. Independent associations were measured using mixed-effects multivariable logistic regression. A secondary outcome analysis was conducted for 30-day mortality, myocardial infarction, renal injury, and their combination. RESULTS: The transfusion guideline was associated with increased pretransfusion hematocrit evaluation (67.4%, standard deviation [SD] 3.9 vs 76.5%, SD 2.7; P

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An Environment Is More Than a Climate

No abstract available

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Preoperative Radiosurgery for Soft Tissue Sarcoma

Objectives: Preoperative radiation followed by surgical resection is a standard treatment for soft tissue sarcomas (STSs). The conventional method of radiation is 5 weeks to approximately 50 Gy. We report on our initial experience and phase II single-arm study assessing 5 fractions of stereotactic body radiotherapy (SBRT), followed by surgical resection for STS. Methods: Thirteen patients and 14 tumors were treated with preoperative SBRT; tumors were mostly poorly differentiated (5) or myxoid (5) and were located on the leg (10), arm (2) or groin (2). The median tumor size in greatest dimension was 7.6 cm (maximum 16 cm). Twelve patients received 35 Gy in 5 fractions; for 2 deeper tumors the dose was 40 Gy in 5 fractions. Ten patients were administered 0.5 cm bolus to improve the dose. Gross tumor volume was expanded 0.5 cm radially and 3 cm along the tissue plane. Treatment was to an isodose line (median 81%) and was delivered every other day. Maximum dose to the skin was 46 Gy (median 41 Gy). Results: The median follow-up period was 279 days. Surgical resection occurred a median of 37 days after completion of SBRT. Four patients had acute toxicity consisting of 2 grade 2 and 2 grade 3 skin reactions; all cases of skin toxicity resolved by the time of surgery. Percent tumor necrosis ranged from 10% to 95% (median 60%). All patients had negative margins. Planned vacuum-assisted wound closure was used in 4 patients; there were no other major wound complications. There was 1 local recurrence and 7 distant recurrences. Conclusion: This is the initial experience of radiosurgery for preoperative treatment of STSs. We have found this to be well tolerated, convenient for the patients, and a much shorter treatment course, allowing patients to undergo surgery and subsequent chemotherapy quicker. Surgical complications and control rates are satisfactory. The initial results are encouraging for further investigation.

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Predictors of Hematologic Toxicity and Chemotherapy Dose Intensity in Patients Undergoing Chemoradiation for Pancreatic Cancer

Objectives: Intensity-modulated radiation therapy (IMRT) has been shown to decrease abdominal toxicity in patients undergoing chemoradiation (CRT) for pancreatic cancer. We evaluated whether IMRT impacts the rates of hematologic toxicity and chemotherapy dose intensity in patients undergoing CRT. Methods: We retrospectively reviewed patients with borderline resectable or locally advanced pancreatic cancer undergoing CRT between 2006 and 2012. Exclusion criteria included receipt of non-gemcitabine therapy, chemotherapy before CRT, or abnormal baseline hematologic indices. Endpoints included total gemcitabine dose received, dose intensity, unplanned dose reductions, and hematologic toxicity (WBC, ANC, platelet, and hemoglobin). Patient/treatment factors were evaluated for their relationship to the above endpoints during CRT and within the first 3 months post-CRT. Statistical analysis was performed using the Fisher exact test and regression models. Because of the multiple comparisons in the presented analysis, a false discovery rate adjustment was performed at the 5% false discovery rate level. Results: Eighty-five patients met the inclusion criteria. Fifty-eight (68.2%) patients received treatment with IMRT, and 27 (31.8%) patients were treated with 3D-conformal radiation. During CRT, there was no relationship between radiation technique and gemcitabine dose received, dose intensity, or hematologic grade 3+ toxicity. Post-CRT, there was no relationship between radiation technique and total gemcitabine dose received, dose intensity, or dose reduction. Patients receiving IMRT were more likely to have ANC grade 3+ toxicity (P=0.007) post-CRT, although this was no longer statistically significant after correction. There were no other relationships between treatment technique and hematologic toxicity. Conclusions: IMRT technique may be associated with higher hematologic toxicity in patients undergoing CRT for pancreatic cancer. Given the expanding use of CRT, additional study is needed to identify the impact of IMRT on myelosuppression in these patients.

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Self-reported Conflicts of Interest and Trial Sponsorship of Clinical Trials in Prostate Cancer Involving Radiotherapy

Objectives: To examine the association between trial sponsorship and conflicts of interest (COI) with clinical trial conclusions for prostate cancer trials related to radiotherapy. Materials and Methods: The MEDLINE database was searched for all prostate cancer clinical trials published between 2004 and 2013 and identified 1396 studies. Two investigators independently identified trials published in the English language of ≥30 patients, and extracted relevant data. Clinical trials were classified according to trial characteristics, sponsorship source and type, COI, and study conclusion, and analyzed by univariable and multivariable logistic regression. Results: Of 240 eligible trials, 160 (67.5%) evaluated drugs without radiotherapy, 60 (25%) involved radiotherapy, and 18 (7.5%) involved procedures without radiotherapy. Of the 60 radiotherapy trials eligible for analysis, positive sponsorship and potential COI were present in 58.3% and 20% of trials, respectively. Study conclusions were positive, negative, or neutral in 78.3%, 5%, and 16.7% of trials, respectively. No association was found between positive conclusions and either industry support of potential COI. Positive conclusions were reported in 86.7% and 83.3% of trials with sponsorship and COI, respectively, as compared with 75.6% and 77.1% of those without sponsorship (P=0.37) and COI (P=0.64). Sponsorship was significantly associated with radiotherapy trials combined with drugs (odds ratio 5.5, P=0.01) and higher-risk disease (odds ratio 4.71, P=0.01). Conclusions: The presence of sponsorship was associated with radiotherapy trials involving drugs or studying higher-risk prostate cancer. However, there were no identified associations between study conclusion and sponsorship type or COI.

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