IL-36 in hidradenitis suppurativa: Evidence for a distinctive pro-inflammatory role and a key factor in the development of an inflammatory loop

Abstract

Background

A possible regulatory involvement of the interleukin (IL)-36 family in inflammatory diseases has been suggested.

Objectives

To analyze the expression of IL-36α, β, γ, and the antagonistic cytokines IL-36Ra, IL-37, and IL38 in the skin of hidradenitis suppurativa (HS) patients.

Methods

Skin samples from lesional and corresponding perilesional HS skin, and from healthy controls were included in this study and analyzed by quantitative real-time RT-PCR. To evaluate the PCR results of IL-36α, β, and γ, a subset of skin samples was studied by immunohistochemistry.

Results

Expression levels of IL-36α, β, γ, and IL-36Ra were all significantly higher in lesional HS skin compared to healthy controls. IL-37 and IL-38 were significantly higher in perilesional HS skin compared to healthy controls and decreased in lesional HS skin.

Limitations

Descriptive study and small sample size.

Conclusions

Our results showed a possible involvement of IL-36 cytokines in the inflammatory network of HS and a dysbalance between the agonistic and antagonistic cytokines in HS skin.

This article is protected by copyright. All rights reserved.

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Systemic retinoids and psychiatric disorders in patients with skin diseases: a multifactorial relationship

Abstract

Le Moigne and colleagues reviewed case reports to examine a possible causal linkage between systemic retinoids and psychiatric disorders.¹ The authors conclude that systemic retinoids should be prescribed with vigilance for patients with psychiatric disorders. While we agree with a need for vigilance, we caution against prematurely concluding that there is a causal association.

This article is protected by copyright. All rights reserved.

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Assessment of facial harmony among Caucasian Spaniards 18 to 60 years of age and its relationship with the golden ratio

Abstract

Background

Throughout history, the perception and definition of beauty and attractiveness have changed and have been influenced by cultural norms. This article analyzes the concept of "facial normality" (faces that are considered normal by 90% of respondents and, therefore, do not require esthetic surgery) among Spaniards of Caucasian ancestry. We also sought to determine the relationship between faces that are considered "normal" and the golden ratio.

Methods

We surveyed 54 respondents (equal numbers of women and men) between the ages of 18 and 60. The surveys followed the visual analog scale (VAS) protocol, and 13,514 responses were obtained. The respondents were asked to evaluate up to nine photographed faces according to their degree of attractiveness.

Results

According to the data obtained, "facial normality" or facial beauty can be defined by the following characteristics: (a) the sizes of the three facial segments (equal in proportion), (b) the width of the nose (narrow in women and average in men), and (c) the profile (straight or slightly retracted in women and straight or slightly prominent in men). In addition, five specific facial proportions were directly related to the golden ratio. Thus, the concept of "normal" can be applied to 90% of faces whose proportions fall within distinct ranges that encompass the value of the golden ratio.

Conclusions

We conclude that a standard perception of "facial normality" and facial beauty does exist. We also observed a general correlation between specific facial proportions and the golden ratio.

Level of Evidence: Not ratable.

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Comprehensive analysis of 225 Castleman’s diseases in the oral maxillofacial and neck region: a rare disease revisited

Abstract

Objectives

The aim of the present study was to comprehensively summarize the epidemiological, clinicopathological characteristics, treatments as well as prognosis of Castleman's disease (CD) identified in the oral maxillofacial and neck region.

Materials and methods

Patients with CD in the oral maxillofacial and neck were retrieved from disease registry at our institution from Jan. 1990 to Dec. 2015. Systematic reviews from both English and Chinese literature were performed to collect the detailed information about the oral maxillofacial and neck CD. The epidemiological, clinicopathological data and treatment outcomes were further statistically analyzed.

Results

Four patients with the oral maxillofacial and neck CD were identified and histologically confirmed as hyaline-vascular type. They underwent surgical excision without recurrence during the follow-up. Systematic literature reviews identified 221 cases from 123 eligible articles which satisfied the inclusion criteria. In 225 patients, most patients were diagnosed as unicentric (207) or hyaline-vascular type (205) of CD and identified in the neck, and treated by surgical resection with good prognosis. In contrast, the minority of patients was multicentric or plasma-cell/mixed type and treated by chemotherapy with inferior outcomes. Kaplan-Meir analyses revealed that both clinical and pathological types were significantly associated with patients' overall survival.

Conclusions

Although rare, most cases of the oral maxillofacial neck CD are found in adults and classified as unicentric and hyaline-vascular type of CD. Complete surgical excision is preferred with favorable prognosis for unicentric disease, whereas chemotherapy is usually exploited for multicentric disease with inferior outcomes.

Clinical relevance

These data provide comprehensive information about the epidemiology, clinicopathological features, treatments, and outcomes of the oral maxillofacial and neck CD.

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Impact of a Saharan dust intrusion over southern Spain on DNI estimation with sky cameras

Publication date: Available online 3 October 2017
Source:Atmospheric Environment
Author(s): J. Alonso-Montesinos, J. Barbero, J. Polo, G. López, J. Ballestrín, F.J. Batlles
To operate Central Tower Solar Power (CTSP) plants properly, solar collector systems must be able to work under varied weather conditions. Therefore, knowing the state of the atmosphere, and more specifically the level of incident radiation, is essential operational information to adapt the electricity production system to atmospheric conditions. In this work, we analyze the impact of a strong Saharan dust intrusion on the Direct normal irradiance (DNI) registered at two sites 35 km apart in southeastern Spain: the University of Almería (UAL) and the Plataforma Solar de Almería (PSA). DNI can be inputted into the European Solar Radiation Atlas (ESRA) clear sky procedure to derive Linke turbidity values, which proved to be extremely high at the UAL. By using the Simple Model of the Atmospheric Radiative Transfer of Sunshine (SMARTS) at the PSA site, AERONET data from PSA and assuming dust dominated aerosol, DNI estimations agreed strongly with the measured DNI values. At the UAL site, a SMARTS simulation of the DNI values also seemed to be compatible with dust dominated aerosol.



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A novel method for estimating methane emissions from underground coal mines: The Yanma coal mine, China

Publication date: December 2017
Source:Atmospheric Environment, Volume 170
Author(s): Zhong-Min Ji, Zhi-Jian Chen, Jie-Nan Pan, Qing-He Niu
As the world's largest coal producer and consumer, China accounts for a relatively high proportion of methane emissions from coal mines. Several estimation methods had been established for the coal mine methane (CMM) emission. However, with large regional differences, various reservoir formation types of coalbed methane (CBM) and due to the complicated geological conditions in China, these methods may be deficient or unsuitable for all the mining areas (e.g. Jiaozuo mining area). By combing the CMM emission characteristics and considering the actual situation of methane emissions from underground coal mine, we found that the methane pre-drainage is a crucial reason creating inaccurate evaluating results for most estimation methods. What makes it so essential is the extensive pre-drainage quantity and its irrelevance with annual coal production. Accordingly, the methane releases were divided into two categories: methane pre-drainage and methane release during mining. On this basis, a pioneering method for estimating CMM emissions was proposed. Taking the Yanma coal mine in the Jiaozuo mining area as a study case, the evaluation method of the pre-drainage methane quantity was established after the correlation analysis between the pre-drainage rate and time. Thereafter, the mining activity influence factor (MAIF) was first introduced to reflect the methane release from the coal and rock seams around where affected by mining activity, and the buried depth was adopted as the predictor of the estimation for future methane emissions. It was verified in the six coal mines of Jiaozuo coalfield (2011) that the new estimation method has the minimum errors of 12.11%, 9.23%, 5.77%, −5.20%, −8.75% and 4.92% respectively comparing with other methods. This paper gives a further insight and proposes a more accurate evaluation method for the CMM emissions, especially for the coal seams with low permeability and strong tectonic deformation in methane outburst coal mines.



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The influence of roadside solid and vegetation barriers on near-road air quality

Publication date: December 2017
Source:Atmospheric Environment, Volume 170
Author(s): Masoud Ghasemian, Seyedmorteza Amini, Marko Princevac
The current study evaluates the influence of roadside solid and vegetation barriers on the near-road air quality. Reynolds Averaged Navier-Stokes (RANS) technique coupled with the k−ε realizable turbulence model is utilized to investigate the flow pattern and pollutant concentration. A scalar transport equation is solved for a tracer gas to represent the roadway pollutant emissions. In addition, a broad range of turbulent Schmidt numbers are tested to calibrate the scalar transport equation. Three main scenarios including flat terrain, solid barrier, and vegetative barrier are studied. To validate numerical methodology, predicted pollutant concentration is compared with published wind tunnel data. Results show that the solid barrier induces an updraft motion and lofts the vehicle emission plume. Therefore, the ground-level pollutant concentration decreases compared to the flat terrain. For the vegetation barrier, different sub-scenarios with different vegetation densities ranging from approximately flat terrain to nearly solid barrier are examined. Dense canopies act in a similar manner as a solid barrier and mitigate the pollutant concentration through vertical mixing. On the other hand, the high porosity vegetation barriers reduce the wind speed and lead to a higher pollutant concentration. As the vegetation density increases, i.e. the barrier porosity decreases, the recirculation zone behind the canopy becomes larger and moves toward the canopy. The dense plant canopy with LAD=3.33m−2m3 can improve the near-road air quality by 10% and high porosity canopy with LAD=1m−2m3 deteriorates near-road air quality by 15%. The results of this study can be implemented as green infrastructure design strategies by urban planners and forestry organizations.



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An optimized inverse modelling method for determining the location and strength of a point source releasing airborne material in urban environment

Publication date: December 2017
Source:Atmospheric Environment, Volume 170
Author(s): George C. Efthimiou, Ivan V. Kovalets, Alexandros Venetsanos, Spyros Andronopoulos, Christos D. Argyropoulos, Konstantinos Kakosimos
An improved inverse modelling method to estimate the location and the emission rate of an unknown point stationary source of passive atmospheric pollutant in a complex urban geometry is incorporated in the Computational Fluid Dynamics code ADREA-HF and presented in this paper. The key improvement in relation to the previous version of the method lies in a two-step segregated approach. At first only the source coordinates are analysed using a correlation function of measured and calculated concentrations. In the second step the source rate is identified by minimizing a quadratic cost function. The validation of the new algorithm is performed by simulating the MUST wind tunnel experiment. A grid-independent flow field solution is firstly attained by applying successive refinements of the computational mesh and the final wind flow is validated against the measurements quantitatively and qualitatively. The old and new versions of the source term estimation method are tested on a coarse and a fine mesh. The new method appeared to be more robust, giving satisfactory estimations of source location and emission rate on both grids. The performance of the old version of the method varied between failure and success and appeared to be sensitive to the selection of model error magnitude that needs to be inserted in its quadratic cost function. The performance of the method depends also on the number and the placement of sensors constituting the measurement network. Of significant interest for the practical application of the method in urban settings is the number of concentration sensors required to obtain a "satisfactory" determination of the source. The probability of obtaining a satisfactory solution – according to specified criteria –by the new method has been assessed as function of the number of sensors that constitute the measurement network.



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The ozone-climate penalty in the Midwestern U.S.

Publication date: December 2017
Source:Atmospheric Environment, Volume 170
Author(s): Ping Jing, Zifeng Lu, Allison L. Steiner
This paper investigates the relationship between ground-level ozone (O3) and temperature in the Midwestern U.S. during the period 1990–2015. From 1990 to 2015, the overall trend of 95th percentile temperature showed an increase of 0.04 K yr⁻¹, while summertime 95th percentile O3 concentrations in the Midwest decreased at an average rate of 0.7 ppb yr⁻¹ largely because NO2 concentrations decreased by more than 50%. The ozone-climate penalty, defined as the slope of O3 change with increasing temperature (ΔO3/ΔT), was by average 0.43 ppb K⁻¹ less in 1999–2007 than in 1990–1998, indicating the early success of NOx emission controls. However, the slope did not continue to decrease in 2008–2015 despite further NOx emission reductions, and it increased more rapidly with increasing temperature (Δ²O3/ΔT²) by 0.03–0.09 ppb K⁻² in most urban areas of the Midwest. This was accompanied by more frequent dry tropical (DT) weather in the Midwest since 2008. We find that O3 in DT weather was 12 ppb and 17 ppb higher than in non-DT weather in rural and urban areas, respectively. Furthermore, the 2008–2015 period experienced 8% more surface air stagnation days than in 1990–1998. This demonstrates that, in addition to the impact of warmer temperatures, the ozone-climate penalty could be aggravated by altered weather conditions under climate change. It will be challenging for Midwestern cities to attain the National Ambient Air Quality Standard for O3 if such conditions persist in the future, and future air quality improvements may require even greater efforts to reduce both NOx and VOC emissions in the Midwest.



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Direct observation of new particle formation during ozonolysis of isoprene and ethene competing against the growth of preexisting particles

Publication date: December 2017
Source:Atmospheric Environment, Volume 170
Author(s): Satoshi Inomata, Kei Sato, Yosuke Sakamoto, Jun Hirokawa
Secondary organic aerosol formation during the ozonolysis of isoprene and ethene in the presence of ammonium nitrate seed particles (surface area concentrations = (0.8–3) × 10⁷ nm² cm⁻³) was investigated using a 1 nm scanning mobility particle sizer. Based on the size distribution of formed particles, particles with a diameter smaller than the minimum diameter of the seed particles (less than ∼6 nm) formed under dry conditions, but the formation of such particles was substantially suppressed during isoprene ozonolysis and was not observed during ethane ozonolysis under humid conditions. We propose that oligomeric hydroperoxides generated by stabilized Criegee intermediates (sCIs), including C1-sCI (CH2OO), contribute to new particle formation while competing to be taken up onto preexisting particles. The OH reaction products of isoprene and ethene seem to not contribute to new particle formation; however, they are taken up onto preexisting particles and contribute to particle growth.

Graphical abstract

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A modified Brownian force for ultrafine particle penetration through building crack modeling

Publication date: December 2017
Source:Atmospheric Environment, Volume 170
Author(s): Chen Chen, Bin Zhao
Combustion processes related to industry, traffic, agriculture, and waste treatment and disposal increase the amount of outdoor ultrafine particles (UFPs), which have adverse effects on human health. Given that people spend the majority of their time indoors, it is critical to understand the penetration of outdoor UFPs through building cracks in order to estimate human exposure to outdoor-originated UFPs. Lagrangian tracking is an efficient approach for modeling particle penetration. However, the Brownian motion for Lagrangian tracking in ANSYS Fluent^®, a widely used software for particle dispersion modeling, is not able to model UFP dispersion accurately. In this study, we modified the Brownian force by rewriting the Brownian diffusion coefficient and particle integration time step with a user-defined function in ANSYS Fluent^® to model particle penetration through building cracks. The results obtained using the modified model agree much better with the experimental results, with the averaged relative error less than 14% for the smooth crack cases and 21% for the rough crack case. We expect the modified Brownian force model proposed herein to be applied for UFP dispersion modeling in more indoor air quality studies.



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Assessment of facial harmony among Caucasian Spaniards 18 to 60 years of age and its relationship with the golden ratio

Abstract

Background

Throughout history, the perception and definition of beauty and attractiveness have changed and have been influenced by cultural norms. This article analyzes the concept of "facial normality" (faces that are considered normal by 90% of respondents and, therefore, do not require esthetic surgery) among Spaniards of Caucasian ancestry. We also sought to determine the relationship between faces that are considered "normal" and the golden ratio.

Methods

We surveyed 54 respondents (equal numbers of women and men) between the ages of 18 and 60. The surveys followed the visual analog scale (VAS) protocol, and 13,514 responses were obtained. The respondents were asked to evaluate up to nine photographed faces according to their degree of attractiveness.

Results

According to the data obtained, "facial normality" or facial beauty can be defined by the following characteristics: (a) the sizes of the three facial segments (equal in proportion), (b) the width of the nose (narrow in women and average in men), and (c) the profile (straight or slightly retracted in women and straight or slightly prominent in men). In addition, five specific facial proportions were directly related to the golden ratio. Thus, the concept of "normal" can be applied to 90% of faces whose proportions fall within distinct ranges that encompass the value of the golden ratio.

Conclusions

We conclude that a standard perception of "facial normality" and facial beauty does exist. We also observed a general correlation between specific facial proportions and the golden ratio.

Level of Evidence: Not ratable.

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Comprehensive analysis of 225 Castleman’s diseases in the oral maxillofacial and neck region: a rare disease revisited

Abstract

Objectives

The aim of the present study was to comprehensively summarize the epidemiological, clinicopathological characteristics, treatments as well as prognosis of Castleman's disease (CD) identified in the oral maxillofacial and neck region.

Materials and methods

Patients with CD in the oral maxillofacial and neck were retrieved from disease registry at our institution from Jan. 1990 to Dec. 2015. Systematic reviews from both English and Chinese literature were performed to collect the detailed information about the oral maxillofacial and neck CD. The epidemiological, clinicopathological data and treatment outcomes were further statistically analyzed.

Results

Four patients with the oral maxillofacial and neck CD were identified and histologically confirmed as hyaline-vascular type. They underwent surgical excision without recurrence during the follow-up. Systematic literature reviews identified 221 cases from 123 eligible articles which satisfied the inclusion criteria. In 225 patients, most patients were diagnosed as unicentric (207) or hyaline-vascular type (205) of CD and identified in the neck, and treated by surgical resection with good prognosis. In contrast, the minority of patients was multicentric or plasma-cell/mixed type and treated by chemotherapy with inferior outcomes. Kaplan-Meir analyses revealed that both clinical and pathological types were significantly associated with patients' overall survival.

Conclusions

Although rare, most cases of the oral maxillofacial neck CD are found in adults and classified as unicentric and hyaline-vascular type of CD. Complete surgical excision is preferred with favorable prognosis for unicentric disease, whereas chemotherapy is usually exploited for multicentric disease with inferior outcomes.

Clinical relevance

These data provide comprehensive information about the epidemiology, clinicopathological features, treatments, and outcomes of the oral maxillofacial and neck CD.

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Radiation Therapy and Immediate Breast Reconstruction

Publication date: Available online 3 October 2017
Source:Clinics in Plastic Surgery
Author(s): Marlene Sue-Fen See, Jian Farhadi

Teaser

Patients who undergo breast reconstruction experience higher complication rates if they have had a history of radiotherapy. However, implant-based reconstruction confers significantly higher complication and reconstruction failure rates compared with autologous reconstruction. This article analyses the factors that contribute to the complications of the different breast reconstruction modalities and the strategies described to mitigate these problems.


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NMDAR encephalitis: passive transfer from man to mouse by a recombinant antibody

Abstract

Objective

Autoimmune encephalitis is most frequently associated with anti-NMDAR autoantibodies. Their pathogenic relevance has been suggested by passive transfer of patients' cerebrospinal fluid (CSF) in mice in vivo. We aimed to analyze the intrathecal plasma cell repertoire, identify autoantibody-producing clones, and characterize their antibody signatures in recombinant form.

Methods

Patients with recent onset typical anti-NMDAR encephalitis were subjected to flow cytometry analysis of the peripheral and intrathecal immune response before, during, and after immunotherapy. Recombinant human monoclonal antibodies (rhuMab) were cloned and expressed from matching immunoglobulin heavy- (IgH) and light-chain (IgL) amplicons of clonally expanded intrathecal plasma cells (cePc) and tested for their pathogenic relevance.

Results

Intrathecal accumulation of B and plasma cells corresponded to the clinical course. The presence of cePc with hypermutated antigen receptors indicated an antigen-driven intrathecal immune response. Consistently, a single recombinant human GluN1-specific monoclonal antibody, rebuilt from intrathecal cePc, was sufficient to reproduce NMDAR epitope specificity in vitro. After intraventricular infusion in mice, it accumulated in the hippocampus, decreased synaptic NMDAR density, and caused severe reversible memory impairment, a key pathogenic feature of the human disease, in vivo.

Interpretation

A CNS-specific humoral immune response is present in anti-NMDAR encephalitis specifically targeting the GluN1 subunit of the NMDAR. Using reverse genetics, we recovered the typical intrathecal antibody signature in recombinant form, and proved its pathogenic relevance by passive transfer of disease symptoms from man to mouse, providing the critical link between intrathecal immune response and the pathogenesis of anti-NMDAR encephalitis as a humorally mediated autoimmune disease.

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Sailing in a sea of disbelief: In vivo measurements of transcranial electric stimulation in human subcortical structures

Publication date: Available online 3 October 2017
Source:Brain Stimulation
Author(s): P. Ruhnau, K.S. Rufener, H.-J. Heinze, T. Zaehle




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Beyond variability: Subjective timing and the neurophysiology of motor cognition

Publication date: Available online 3 October 2017
Source:Brain Stimulation
Author(s): David Perruchoud, Mirta Fiorio, Paola Cesari, Silvio Ionta
BackgroundMovement simulation helps increasing the chances to reach goals. A cognitive task used to study the neuro-behavioral aspects of movement simulation is mental rotation: people mentally re-orient rotated pictures of hands. However, the involvement of the primary motor cortex (M1) in mental rotation is largely controversial.HypothesisSuch inconsistency could arise from potential methodological flaws in experimental procedures and data analysis. In particular, until now, the timing of M1 activity has been computed in absolute terms: from the onset of mental rotation (onset-locked), neglecting intra- and inter-subject variability.MethodsA novel phase-locked approach is introduced to synchronize the same phases of cognitive processing among different subjects and sessions. This approach was validated in the particular case of corticospinal excitability of the motor cortex during mental rotation.ResultsWe identified the relative time-windows during which the excitability of M1 is effector-specifically modulated by different features of mental rotation. These time windows correspond to the 55%–85% of the subjective timing.ConclusionsIn sum, (i) we introduce a new method to study the neurophysiology of motor cognition, and (ii) validating this method, we shed new light on the involvement of M1 in movement simulation.



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What you need to know about airway management

Sponsored by BoundTree and Ambu By Jonathan Lee for EMS1 BrandFocus Airway management in the prehospital environment is messy business. A recent study of prehospital intubation in trauma found that 44.3 percent of the patients had gross contamination of the airway at the time of intubation (most commonly blood, followed by vomit, teeth or brain). While the literature is divided on whether prehospital ...

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How linear response shaped models of neural circuits and the quest for alternatives

Publication date: October 2017
Source:Current Opinion in Neurobiology, Volume 46
Author(s): Tim Herfurth, Tatjana Tchumatchenko
In the past decades, many mathematical approaches to solve complex nonlinear systems in physics have been successfully applied to neuroscience. One of these tools is the concept of linear response functions. However, phenomena observed in the brain emerge from fundamentally nonlinear interactions and feedback loops rather than from a composition of linear filters. Here, we review the successes achieved by applying the linear response formalism to topics, such as rhythm generation and synchrony and by incorporating it into models that combine linear and nonlinear transformations. We also discuss the challenges encountered in the linear response applications and argue that new theoretical concepts are needed to tackle feedback loops and non-equilibrium dynamics which are experimentally observed in neural networks but are outside of the validity regime of the linear response formalism.



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The many worlds hypothesis of dopamine prediction error: implications of a parallel circuit architecture in the basal ganglia

Publication date: October 2017
Source:Current Opinion in Neurobiology, Volume 46
Author(s): Brian Lau, Tiago Monteiro, Joseph J Paton
Computational models of reinforcement learning (RL) strive to produce behavior that maximises reward, and thus allow software or robots to behave adaptively [1]. At the core of RL models is a learned mapping between 'states'—situations or contexts that an agent might encounter in the world—and actions. A wealth of physiological and anatomical data suggests that the basal ganglia (BG) is important for learning these mappings [2,3]. However, the computations performed by specific circuits are unclear. In this brief review, we highlight recent work concerning the anatomy and physiology of BG circuits that suggest refinements in our understanding of computations performed by the basal ganglia. We focus on one important component of basal ganglia circuitry, midbrain dopamine neurons, drawing attention to data that has been cast as supporting or departing from the RL framework that has inspired experiments in basal ganglia research over the past two decades. We suggest that the parallel circuit architecture of the BG might be expected to produce variability in the response properties of different dopamine neurons, and that variability in response profile may not reflect variable functions, but rather different arguments that serve as inputs to a common function: the computation of prediction error.



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Common TDP1 polymorphisms in relation to survival among small cell lung cancer patients: a multicenter study from the International Lung Cancer Consortium

Purpose: DNA topoisomerase inhibitors are commonly used for treating small cell lung cancer (SCLC). Tyrosyl-DNA phosphodiesterase (TDP1) repairs DNA damage caused by this class of drugs and may therefore influence treatment outcome. In this study, we investigated whether common TDP1 single nucleotide polymorphisms (SNPs) are associated with overall survival among SCLC patients. Experimental Design: Two TDP1 SNPs (rs942190 and rs2401863) were analyzed in 890 patients from 10 studies in the International Lung Cancer Consortium (ILCCO). The Kaplan-Meier method and Cox regression analyses were used to evaluate genotype associations with overall mortality at 36 months post-diagnosis, adjusting for age, sex, race, and tumor stage. Results: Patients homozygous for the minor allele (GG) of rs942190 had poorer survival compared to those carrying AA alleles, with a hazard ratio (HR) of 1.36 (95% confidence interval (CI): 1.08-1.72, p-value=0.01), but no association with survival was observed for patients carrying the AG genotype (HR=1.04, 95% CI:0.84-1.29, p-value=0.72). For rs2401863, patients homozygous for the minor allele (CC) tended to have better survival than patients carrying AA alleles (HR=0.79, 95% CI: 0.61-1.02, p-value=0.07). Results from the Genotype Tissue Expression (GTEx) Project, the Encyclopedia of DNA Elements (ENCODE), and the ePOSSUM web application support the potential function of rs942190. Conclusions: We found the rs942190 GG genotype to be associated with relatively poor survival among SCLC patients. Further investigation is needed to confirm the result and to determine whether this genotype may be a predictive marker for treatment efficacy of DNA topoisomerase inhibitors.

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A molecularly annotated model of patient-derived colon cancer stem-like cells to assess genetic and non-genetic mechanisms of resistance to anti-EGFR therapy

Purpose Patient-derived xenografts ("xenopatients") of colorectal cancer metastases have been essential to identify genetic determinants of resistance to the anti-EGF Receptor (EGFR) antibody cetuximab, and to explore new therapeutic strategies. From xenopatients, a genetically annotated collection of stem-like cultures ("xenospheres") was generated and characterized for response to targeted therapies. Experimental Design. Xenospheres underwent exome-sequencing analysis, gene expression profile and in vitro targeted treatments to assess genetic, biological and pharmacological correspondence with xenopatients, and to investigate non-genetic biomarkers of therapeutic resistance. The outcome of EGFR family inhibition was tested in an NRG1-expressing in vivo model. Results. Xenospheres faithfully retained the genetic make-up of their matched xenopatients over in vitro and in vivo passages. Frequent and rare genetic lesions triggering primary resistance to cetuximab through constitutive activation of the RAS signaling pathway were conserved, as well as the vulnerability to their respective targeted treatments. Xenospheres lacking such alterations (RASwt) were highly sensitive to cetuximab, but were protected by ligands activating the EGFR family, mostly NRG1. Upon reconstitution of NRG1 expression, xenospheres displayed increased tumorigenic potential in vivo, generated tumors completely resistant to cetuximab, and sensitive only to comprehensive EGFR family inhibition. Conclusions. Xenospheres are a reliable model to identify both genetic and non-genetic mechanisms of response and resistance to targeted therapies in colorectal cancer. In the absence of RAS pathway mutations, NRG1 and other EGFR ligands can play a major role in conferring primary cetuximab resistance, indicating that comprehensive inhibition of the EGFR family is required to achieve a significant therapeutic response.

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Modulation of Navitoclax Sensitivity by Dihydroartemisinin-Mediated MCL-1 Repression in BCR-ABL+ B-Lineage Acute Lymphoblastic Leukemia

Purpose: BCR-ABL+ B-ALL leukemic cells are highly dependent on the expression of endogenous anti-apoptotic MCL-1 to promote viability and are resistant to BH3-mimetic agents such as navitoclax (ABT-263) that targets BCL-2, BCL-XL, and BCL-W. However, the survival of most normal blood cells and other cell types are also dependent on Mcl-1. Despite the requirement for MCL-1 in these cell types, initial reports of MCL-1-specific BH3-mimetics have not described any overt toxicities associated with single-agent use, but these agents are still early in clinical development. Therefore, we sought to identify FDA-approved drugs that could sensitize leukemic cells to ABT-263. Experimental Design: A screen identified dihydroartemisinin (DHA), a water-soluble metabolite of the anti-malarial artemisinin. Using mouse and human leukemic cell lines, and primary patient-derived xenografts, the effect of DHA on survival was tested and mechanistic studies were carried out to discover how DHA functions. We further tested in vitro and in vivo whether combining DHA with ABT-263 could enhance the response of leukemic cells to combination therapy. Results: DHA causes the down-modulation of MCL-1 expression by triggering a cellular stress response that represses translation. The repression of MCL-1 renders leukemic cells highly sensitive to synergistic cell death induced by ABT-263 in a mouse model of BCR-ABL+ B-ALL both in vitro and in vivo. Furthermore, DHA synergizes with ABT-263 in human Ph+ ALL cell lines, and primary patient derived xenografts of Ph+ ALL in culture. Conclusions: Our findings suggest that combining DHA with ABT-263 can improve therapeutic response in BCR-ABL+ B-ALL.

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The HRD decision--which PARP inhibitor to use for whom and when

Rucaparib, a polyADPribose polymerase (PARP) inhibitor, was approved recently for use in women with high grade serous ovarian cancer (HGSOC). It is now one of 3 approved PARPi for use in recurrent ovarian cancer, a family of agents that has changed the HGSOC treatment landscape and outcome.

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Selective Androgen Receptor Modulator RAD140 Inhibits the Growth of Androgen/Estrogen Receptor Positive Breast Cancer Models with a Distinct Mechanism of Action

Purpose: Steroidal androgens suppress androgen receptor and estrogen receptor positive (AR/ER+) breast cancer cells and were used to treat breast cancer eliciting favorable response. The present study evaluates the activity and efficacy of the oral selective AR modulator (SARM) RAD140 in in vivo and in vitro models of AR/ER+ breast cancer. Experimental Design: A series of in vitro assays were used to determine the affinity of RAD140 to 4 nuclear receptors and evaluate its tissue-selective AR activity. The efficacy and pharmacodynamics of RAD140 as monotherapy or in combination with palbociclib were evaluated in AR/ER+ breast cancer xenograft models. Results: RAD140 bound AR with high affinity and specificity and activated AR in breast cancer but not prostate cancer cells. Oral administration of RAD140 substantially inhibited the growth of AR/ER+ breast cancer patient-derived xenografts (PDXs). Activation of AR and suppression of ER pathway, including the ESR1 gene, were seen with RAD140-treatment. Co-administration of RAD140 and palbociclib showed improved efficacy in the AR/ER+ PDX models. In line with efficacy, a subset of AR-repressed genes associated with DNA replication were suppressed with RAD140-treatment, an effect apparently enhanced by concurrent administration of palbociclib. Conclusions: RAD140 is a potent AR agonist in breast cancer cells with a distinct mechanism of action including the AR-mediated repression of ESR1. It inhibits the growth of multiple AR/ER+ breast cancer PDX models as a single agent, and in combination with palbociclib. The preclinical data presented here supports further clinical investigation of RAD140 in AR/ER+ breast cancer patients.

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William Paske 12 June 1948 to 24 December 2016

Publication date: Available online 3 October 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Peter Bell, Giorgio M. Biasi, Jose Fernandes e Fernandes, Christos Liapis




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Immediate completion lymph node dissection in stage IIIA melanoma does not provide significant additional staging information beyond EORTC SN tumour burden criteria

Publication date: Available online 3 October 2017
Source:European Journal of Cancer
Author(s): Max F. Madu, Viola Franke, Maarten M. Bruin, Danique M.S. Berger, Carolien Bierman, Katarzyna Jóźwiak, Willem M.C. Klop, Michel W.J.M. Wouters, Alexander C.J. van Akkooi, Bart A. Van de Wiel




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Metformin and insulin impact on clinical outcome in patients with advanced hepatocellular carcinoma receiving sorafenib: Validation study and biological rationale

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Andrea Casadei Gardini, Luca Faloppi, Serena De Matteis, Francesco Giuseppe Foschi, Nicola Silvestris, Francesco Tovoli, Vincenzo Palmieri, Giorgia Marisi, Oronzo Brunetti, Umberto Vespasiani-Gentilucci, Giuseppe Perrone, Martina Valgiusti, Anna Maria Granato, Giorgio Ercolani, Giulia Negrini, Emiliano Tamburini, Giuseppe Aprile, Alessandro Passardi, Daniele Santini, Stefano Cascinu, Giovanni Luca Frassineti, Mario Scartozzi
PurposeIn 2015, we published a study on a small series of patients with hepatocellular carcinoma (HCC) treated chronically with metformin for type II diabetes mellitus (DM2) who showed a poorer response to sorafenib. The aim of the present study was to validate the prognostic significance of metformin in HCC patients treated with sorafenib, providing a biological rationale for the mechanism of resistance to sorafenib in patients on chronic metformin therapy, and to clarify the role of sirtuin-3 (SIRT-3), a protein involved in metabolic diseases and acknowledged as a tumour suppressor in HCC, in this resistance.Patients and methodsWe analysed 279 patients consecutively treated with sorafenib for the clinical analysis. Of the 86 (30%) patients with DM2, 52 (19%) were on chronic treatment with metformin and 34 (12%) with insulin. We included 43 patients with HCC for the biological study: 19 (44.1%) were diabetic and 14 (73.7%) of these received metformin for DM2. SIRT-3 expression was investigated by immunohistochemistry (IHC) in formalin-fixed and paraffin-embedded (FFPE) samples.ResultsIn HCC patients undergoing chronic treatment with metformin, the use of sorafenib was associated with poor progression-free survival (PFS) and overall survival (OS) (1.9 and 6.6 months, respectively) compared to 3.7 months and 10.8 months, respectively, for patients without DM2 and 8.4 months and 16.6 months, respectively, for patients on insulin (P < .0001). We also observed that SIRT-3 protein expression was significantly higher in patients treated with metformin than in those not taking this medication (65% versus 25%, respectively) (P = .013).ConclusionsOur findings could be attributed to increased tumour aggressiveness and resistance to sorafenib caused by chronic treatment with metformin.



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‘Corrigendum to “Severe hepatitis under combined immunotherapy: Resolution under corticosteroids plus anti-thymocyte immunoglobulins” [Eur J Cancer 81 (August 2017) 203–205]’

Publication date: Available online 3 October 2017
Source:European Journal of Cancer
Author(s): Iris Spänkuch, Maximilian Gassenmaier, Ioanna Tampouri, Seema Noor, Andrea Forschner, Claus Garbe, Teresa Amaral




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Quantitative assessment of orbital fractures in Asian patients: CT measurement of orbital volume

Publication date: Available online 3 October 2017
Source:Journal of Cranio-Maxillofacial Surgery
Author(s): Kensuke Sugiura, Harumoto Yamada, Takayuki Okumoto, Yoshikazu Inoue, Satoko Onishi
Enophthalmos is caused by an increase of orbital volume after blowout fracture and is one of the most critical complications of such fractures, but is often masked by swelling soon after injury. If surgery is performed after swelling resolves, it becomes more difficult to treat enophthalmos because of atrophy and fibrosis. Accordingly, it is important to estimate the severity of enophthalmos soon after injury. We developed a new criterion for determining whether orbital fractures are indicated for surgery in Asian patients using analysis of orbital volume.We retrospectively calculated the orbital volume of patients treated surgically or conservatively and analyzed the correlation between changes of orbital volume and the severity of enophthalmos.Regression analysis of the correlation between enophthalmos and increased orbital volume (y = 0.8x + 0.2; correlation coefficient: 0.92) showed that enophthalmos of 2.0 mm corresponded to an increase in orbital volume of 2.25 cm³. This result is similar to data reported previously for Caucasian patients — enophthalmos of 2.0 mm is a common surgical indication worldwide. Our results suggest that an increase of orbital volume of >2.25 cm³ could be a new criterion for surgical treatment of blowout fractures in Asians.



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Orthognathic surgery “again” to correct aesthetic failure of primary surgery: Report on outcomes and patient satisfaction in 70 consecutive cases

Publication date: Available online 3 October 2017
Source:Journal of Cranio-Maxillofacial Surgery
Author(s): Mirco Raffaini, Claudia Pisani, Marco Conti
PurposeAn increasing number of patients complain about unsatisfactory aesthetic outcomes of orthognathic surgery, desiring reoperation to improve facial aesthetics. The aims of this article are to present a wide range of aesthetic reasons to justify a secondary orthognathic surgery and to report aesthetic outcomes and patient satisfaction after reoperation.Material and MethodsThis research covers 70 consecutive patients who underwent a secondary bimaxillary orthognathic surgery with simultaneous facial lipofilling procedures between January 2006 and December 2015. The screening criteria are described for patient selection, the diagnostic process, surgical procedures, and outcomes. Pre- and postoperative facial appearances are compared. Postoperatively, patients were asked to state the improvements perceived in their facial appearance and their satisfaction with the aesthetic outcomes.ResultsAfter reoperation, all patients showed a full Class I occlusion. Major complications did not occur. According to the clinicians' evaluation, a postoperative evident aesthetic improvement was achieved in 65 patients (92.9%), and 64 patients (91.4%) were satisfied with the aesthetic outcomes achieved.ConclusionSecondary orthognathic surgery performed in conjunction with facial lipofilling procedures in most cases led to satisfactory aesthetic outcomes. A very accurate selection of patients, a meticulous three-dimensional diagnostic process and planning, and appropriate intra-operative maneuvers are required.



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Is Subcranial Le Fort III Plus Le Fort I Osteotomy Stable?

Publication date: Available online 3 October 2017
Source:Journal of Cranio-Maxillofacial Surgery
Author(s): Fernanda Brasil Daura Jorge Boos Lima, Eduardo Hochuli Vieira, Philipp Juergens, Sergio Monteiro Lima Junior
The purpose of this study was to test whether associated subcranial Le Fort III (sLF III) and Le Fort I (LF I) osteotomies are stable after large advancements of the middle third of the face and maxilla. The authors designed a retrospective study and enrolled a sample of consecutive patients with midface hypoplasia treated with associated sLF III and LF I osteotomies in this IRB-approved study between September 2013 and February 2015. To test whether the long-term stability was satisfactory, the authors compared cephalometric changes from immediately after surgery to 18 months after surgery taken from multi-slice computed tomography using two different third-party imaging software programs. Statistical significance was set as P ≤ 0.05. The sample comprised 11 patients (mean age 23.84±4.17 yr; 54% men). The mean advancement of the upper incisor immediately after surgery was 10.03±1.6 mm. After 18 months, the position of the upper incisor did not vary significantly (10.18±2.35 mm). All other cephalometric landmarks did not present statistically significant differences between immediately after and 18 months after surgery, with horizontal and vertical variations of less than one milimeter. This study supports that sLF III and LF I osteotomies are effective in maintaining stable horizontal and vertical skeletal positioning after surgery.



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Evaluation and management of heavy menstrual bleeding in adolescents

Purpose of review: Heavy menstrual bleeding (HMB) is a common condition in women of reproductive age; however, adolescents with this issue present unique challenges in both diagnosis and management. Much of the research into this topic focuses on the adult population, with variable applicability to adolescents. There are currently no standard guidelines for the work up and treatment of adolescents with HMB. Recent findings: Current research into this topic has explored the utilization of standardized protocols in the evaluation of HMB in adolescents, the efficacy of various hormonal, nonhormonal, and surgical treatment modalities, and the benefits of a multidisciplinary approach. Recent literature has focused on adolescents found to have an underlying bleeding disorder, recommending more comprehensive bleeding disorder work up to identify these patients in a timely manner and initiate effective treatment plans. Summary: Providers in the primary care setting should be aware of the definitions for normal menses, and be able to recognize abnormal bleeding and HMB. Early recognition of HMB in adolescents can then lead to appropriate diagnosis of underlying disorders, and current research has proposed standard protocols to assist with the evaluation, ultimately leading to effective long-term management into adulthood. Video abstract: http://ift.tt/2hL92DC

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Endometriosis in adolescents

Purpose of review: The current article addresses recent literature regarding the diagnosis and management of endometriosis in adolescents. Recent findings: An increasing body of literature suggests that advanced-stage endometriosis (revised scoring system of the American Society for Reproductive Medicine Stage III or IV) and deeply invasive endometriosis are relatively common in adolescents. There remains limited data on the efficacy of postoperative hormonal management of endometriosis in the adolescent population. Summary: Strong consideration should be made for surgical diagnosis of endometriosis in adolescents with pelvic pain, including noncyclic pain, with a concurrent family history of endometriosis and personal history of atopic disease. More research is needed regarding the benefits of the routine use of hypoestrogenic and other hormonal agents in the prevention of disease progression and long-term sequela in adolescents with endometriosis.

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Current review of prepubertal vaginal bleeding

Purpose of review: Prepubertal vaginal bleeding raises many concerns and evaluation and diagnosis may prove difficult for many providers. We aim to provide a comprehensive review and recent updates for those practitioners who care for these patients. Recent findings: Prompt management in the case of prepubertal vaginal bleeding is indicated, especially to rule out malignancy or abuse. If a child is reluctant to undergo examination, or if the extent of injury or source of bleeding cannot be determined, examination under anesthesia and vaginoscopy is recommended. Use of vaginoscopy allows for clear visualization of the vagina and cervix without distorting hymenal anatomy, as well as diagnosis and removal of a foreign body and evaluation of mucosal damage caused. In the case of sexual abuse, providers specifically trained in pediatrics need to be present, and safety of the patient should always be ensured. Summary: Careful history taking and targeted examination may lead to diagnosis in the case of prepubertal vaginal bleeding. However, in more difficult cases, practitioners should not hesitate to examine a patient in the operating room using general anesthesia to elicit the cause. Although sexual abuse and malignancy are always on the differential, most causes of bleeding are benign and easily treated.

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The use of pulsed CO2 lasers for the treatment of vulvovaginal atrophy: Erratum

No abstract available

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Perinatal outcomes after oocyte donation and in-vitro fertilization

Purpose of review: To critically appraise the existing literature on perinatal outcomes following oocyte donation (OD) pregnancies and compare it with autologous in-vitro fertilization (IVF) pregnancies. Recent findings: OD pregnancies are at higher risk of developing hypertensive disorders compared with autologous IVF. The risk of preterm birth and low birth weight is higher with singleton and multiple OD compared with autologous IVF pregnancies. There is no increased risk of congenital malformations following OD compared with autologous IVF births. Summary: OD pregnancies are at higher risk of developing hypertensive disorders and adverse perinatal outcomes compared with autologous IVF.

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Dual ovarian stimulation and random start in assisted reproductive technologies: from ovarian biology to clinical application

Purpose of review: The opportunity to use gonadotropins to stimulate the growth of antral follicles coming from different follicular waves available in different moment of the menstrual cycle allowed the implementation of innovative protocols in assisted reproductive technologies. The purpose of this review is to explore the possible advantages related to these new controlled ovarian stimulation (COS) strategies. Recent findings: Women exhibit major and minor wave patterns of ovarian follicular development during the menstrual cycle, as it is in animal species. These observations led to the introduction of two new strategies for COS: the random start and the double ovarian stimulation within a single menstrual cycle. Summary: The use of gonadotropin-releasing hormone antagonist COS protocols, started randomly at any day of the menstrual cycle, is today a standard procedure in those cases where obtaining oocytes is an urgent task, such as in case of fertility preservation for malignant diseases or other medical indications. On the other hand, in poor prognosis patients, double ovarian stimulation has been suggested with the aim of maximizing the number of oocytes retrieved within a single menstrual cycle and, in turn increasing the chance to obtain a reproductively competent embryo. Randomized control trials are necessary to confirm these preliminary findings.

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Should we forget about embryos till day 5?

Purpose of review: To find the way of having more and better blastocyst is essential. How to culture embryos up to blastocyst stage remains critical. Recent findings: Several studies show how a blastocyst score can predict the implantation potential. If that score is enough to choose the best blastocyst, as culture conditions would not be affected in these days, we would not need to check early cleavage embryos, even it could be better for the embryo development. Summary: The item that should be discussed is if it is better to evaluate or not embryos at early cleavage stages. If we do not check embryos on days 2 and 3, we should change our way to work and how to culture those embryos. First step would be to perform all embryo transfers on day 5 or 6. If we let embryos grow to blastocyst without any morphology evaluation, we should adapt several steps in our laboratory, for example we should move to a single-step culture medium or we should not do assisted hatching on day 3 embryos.

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A universal freeze all strategy: why it is not warranted

Purpose of review: There's some preclinical evidence of an adverse effect of multifollicular growth on endometrial function in assisted reproductive technology cycles. Universal elective frozen embryo transfer (eFET) in an unstimulated cycle is being promoted as a panacea, regardless of patient, and cycle characteristics. We review the clinical evidence on the effectiveness and safety of eFETs. Recent findings: Randomized controlled trials (RCTs) comparing fresh and eFET yield contradictory results in terms of live birth rates. RCTs mainly involve women with an excessive response to ovarian stimulation. Studies including women with a normal or low ovarian response are either patient/physician preference or retrospective studies, prone to bias. Yet, they yield contradictory results as well. Overall, eFET seems to have limited potential to improve effectiveness of assisted reproductive technology, which could be limited to hyper-responders. Other suggested advantages of eFET include better obstetric and perinatal outcome. However, recent studies show that frozen embryo transfers can be associated with serious complications including hypertensive disorders during pregnancy, placenta accreta, or increased perinatal mortality. Summary: The evidence behind advantages of eFET is of low quality. As such, switching to a universal eFET strategy does not seem justified. New RCTs including women from different strata of ovarian response are needed.

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Preimplantation embryonic mosaicism: origin, consequences and the reliability of comprehensive chromosome screening

Purpose of review: Embryonic mosaicism represents an ongoing challenge for contemporary comprehensive chromosome screening platforms due to the unknown reproductive potential of mosaic embryos and technical difficulties of its detection from a single embryo biopsy. Recent findings: Mosaicism in preimplantation embryos is a product of mitotic errors arising primarily from anaphase lag and chromosome nondisjunction. To date, there is high variability among estimations of prevalence of mosaicism in blastocysts, the most recent ranging from 3.3 to 83%. It has been reported that alleged mosaic embryos can develop into healthy babies, although the proper study evaluating this question remains to be completed. Technical artefacts from comprehensive chromosome screening platforms may also hinder correct classification of embryos as genuine mosaics. Summary: Although complex, embryonic mosaicism is a phenomenon that deserves further investigation. Many embryos classified as mosaic may have actual reproductive potential. The predictive value of intermediate chromosome copy number assignments for the remaining embryo and for ongoing reproductive potential needs more careful consideration. In addition, recent advancements in extended embryo culture raise the possibility of investigating whether preferential segregation, selective advantage of normal cells or surveillance of abnormal chromosome numbers occur at postimplantation stages.

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Endometrial microbiome

Purpose of review: There have been great improvements in assisted reproduction in the recent decade; however, there are still a significant number of chromosomally normal blastocysts that fail to produce live births. The human microbiome is the totality of the microbes and their genomes that exist in and on the host. The understanding of its impact on health and human disease, particularly in human reproduction, is evolving. Recent findings: New technologies have empowered metagenomic sample analysis that allows for more fully characterizing the reproductive tract microbiome. With these technologies, we have determined not only that sites previously thought to be sterile in fact have robust microbiomes, but also have better characterized the normal and abnormal vaginal and endometrial microbiome. Summary: The understanding of the microbiome in health and human disease, in particular in relation to human reproduction, is in its infancy. As the reproductive tract dysbiosis are better characterized and understood, we may be better equipped to manipulate it more expertly.

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Reduced upper obstructions in N3 and increased lower obstructions in REM sleep stage detected with manometry

Abstract

In obstructive sleep apnea (OSA), airway obstruction occurs at different anatomic levels. The frequency and location of obstructions play a crucial role in the planning of surgical treatment. The aim of this study was to evaluate the pharyngeal obstruction levels in different sleep stages with manometry in OSA patients. In addition, the manometry results were compared with drug-induced sleep endoscopy (DISE). Forty-one patients with OSA received manometry measurements during one night of sleep. All patients were simultaneously evaluated with polysomnography. The frequency of obstructions in different sleep stages was assessed. Twenty patients were additionally studied with DISE. Obstruction levels detected with manometry were compared with DISE. The frequency of upper and to a lesser extent lower obstructions decreased in sleep stage N3. In rapid eye movement (REM) sleep, lower obstructions increased. The overall proportion of upper and lower obstructions detected with manometry corresponded with DISE in 13 of 20 cases. A significant change in the obstruction levels was detected with manometry in N3 and REM sleep. The reduction of both upper and to a lesser extent lower obstructions in N3 suggests more stable airways in slow-wave sleep. Relevant lower obstructions were not detected in DISE compared to manometry in 5 out of 20 examinations. This could be a potential reason for treatment failure of site-specific surgical OSA treatment when only performing DISE preoperatively. Therefore, manometry could be a useful complementary tool in the preoperative evaluation for OSA.

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Changes in the Soleus H-reflex Test and Correlations between Its Results and Dynamic Magnetic Resonance Imaging Abnormalities in Patients with Hirayama Disease

Hirayama disease (HD) was first reported by the Japanese scholar Keizo Hirayama in 1959 (Hirayama et al., 1959). The aetiology of HD remains controversial. Currently, the main implicated mechanism is chronic cervical spinal cord ischaemia caused by microcirculatory disturbances in the territory of the anterior spinal artery during neck flexion (Hirayama, 2000; Hirayama, 2008). Because anterior horn cells are extremely vulnerable to ischaemia and a previous autopsy case of HD revealed confined necrosis in both the cervical anterior horn and ventral nerve root areas (Hirayama et al., 1987), HD is considered a neurological disease that involves only lower motor neurons (LMN) (e.g., anterior horn cells and ventral nerve roots) (Hirayama, 2008).

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Rhythmic EEG patterns in extremely preterm infants: classification and association with brain injury and outcome

In many units, neuro-monitoring with electroencephalography (EEG) during the first postnatal days has become part of standard care. Brain protection has become one of the main aims of neonatal intensive care, since the survival rate of extremely preterm infants (born <28 weeks gestational age) has increased due to major advances in perinatal care. (Costeloe et al., 2012; Zegers et al., 2016)

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Mechanisms regulating T-cell infiltration and activity in solid tumors

Abstract

T-lymphocytes play a critical role in cancer immunity as evidenced by their presence in resected tumor samples derived from long-surviving patients, and impressive clinical responses to various immunotherapies that reinvigorate them. Indeed, tumors can upregulate a wide array of defense mechanisms, both direct and indirect, to suppress the ability of Tcells to reach the tumor bed and mount curative responses upon infiltration. In addition, patient and tumor genetics, previous antigenic experience, and the microbiome, are all important factors in shaping the T-cell repertoire and sensitivity to immunotherapy. Here, we review the mechanisms that regulate T-cell homing, infiltration, and activity within the solid tumor bed. Finally, we summarize different immunotherapies and combinatorial treatment strategies that enable the immune system to overcome barriers for enhanced tumor control and improved patient outcome.

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Risk of advanced colorectal neoplasm by the proposed combined United States and United Kingdom risk stratification guidelines

/Aims: The United Kingdom (U.K.) guidelines for risk stratification after colon polypectomy differ from the United States (U.S.) guidelines in 2 ways: the U.K. guidelines consider ≥5 adenomas as high risk and do not consider histology (villous or high-grade dysplasia [HGD]) in assessment. Thus, we aimed to investigate the risk of advanced colorectal neoplasm (CRN) by categorized risk groups, considering both ≥5 adenomas and histology.

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Long-term Patient and Graft Survival of Kidney Transplant Recipients with Hepatitis C Virus Infection in the United States.

Background: Hepatitis C virus (HCV) infection is common among kidney transplant (KTx) recipients. However, the impact of HCV infection on long-term graft and recipient survival after KTx from the large-scale data remains to be determined. Methods: We used the Organ Procurement and Transplantation Network (OPTN) database to identify all adults undergoing KTx in 2004-2006 in the United States. A propensity score (PS) was created to match each HCV-positive recipient with a HCV-negative control for unbiased comparisons. Survival analysis was conducted to evaluate recipient and death-censored graft survival. Results: Out of 33,357 adult primary KTx recipients, 1470 (4.4%) were HCV-positive. 1,364 HCV-positive and -negative pairs were selected based on PS-matching. Based on the multivariable regression models, HCV is associated with a higher risk of death (hazard ratio [HR]=1.50, 95% confidence interval [95% CI=1.28-1.75) and graft failure (HR=1.26, 95% CI=1.08-1.47). Infection was a more common cause of death in HCV-positive patients than in HCV-negative recipients (HR=1.64, 95% CI=1.12-2.42). The incidence of death due to liver failure was 0.23% per year among HCV-positive recipients, whereas no HCV-negative recipients died from liver failure. Graft failure due to recurrent disease was higher in HCV-positive than in HCV-negative recipients (HR=2.00; 95% CI=1.06-3.78). Conclusion: HCV infection is associated with decreased long-term recipient and graft survival. Future studies are needed to examine whether recently available, safe and effective antiviral therapy improves the long-term clinical outcome in these patients. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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In response to the commentary of Dr. Lou on treatment of laryngopharyngeal reflux using a sleep positioning device: A prospective cohort study

The authors of the paper "Treatment of Laryngopharyngeal Reflux Using a Sleep Positioning Device: A Prospective Cohort Study [1]," would like to begin by thanking Dr. Lou and our scientific community for interest in this work. We further appreciate the commentary of Dr. Lou and the opportunity to further discuss this work in the American Journal of Otolaryngology. The principle critique of this commentary is that our study may overestimate treatment effect due to misdiagnosis or concurrent diagnosis of GERD.

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Phase II study of cabozantinib in patients with progressive glioblastoma: subset analysis of patients with prior antiangiogenic therapy

Abstract

Background

Cabozantinib is a potent, multi-target inhibitor of hepatocyte growth factor receptor (MET) and vascular endothelial growth factor receptor-2 (VEGFR2). This open-label, phase II trial evaluated cabozantinib in patients with recurrent or progressive glioblastoma (GBM; NCT00704288).

Methods

Patients were initially enrolled to a starting cabozantinib dose of 140 mg/day, but the starting dose was amended to 100 mg/day because of safety concerns. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate, assessed by an independent radiology facility using modified Response Assessment in Neuro-Oncology (RANO) criteria. Additional endpoints included duration of response, 6-month and median progression-free survival (PFS), overall survival (OS), glucocorticoid use, and safety.

Results

Among 222 patients enrolled, 70 patients had received prior antiangiogenic therapy. Herein, we report results in this subset of 70 patients. The objective response rate was 4.3%, and the median duration of response was 4.2 months. The proportion of patients alive and progression-free at 6 months was 8.5%. Median PFS was 2.3 months, and median OS was 4.6 months. The most common adverse events (AEs) reported in all patients, regardless of dose group, included fatigue (74.3%), diarrhea (47.1%), increased alanine aminotransferase (37.1%), headache (35.7%), hypertension (35.7%), and nausea (35.7%); overall, 34 (48.6%) patients experienced AEs that resulted in dose reductions.

Conclusions

Cabozantinib treatment appeared to have modest clinical activity with a 4.3% response rate in patients who had received prior antiangiogenic therapy for GBM.

Clinical Trials Registration Number

NCT00704288 (http://ift.tt/2vWrPPz)

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The Elderly Left Behind – Changes in Survival Trends of Primary Central Nervous System Lymphoma Over The Past Four Decades

Abstract

Background

There has been significant improvement in treatment outcomes of Primary Central Nervous System Lymphoma (PCNSL) at specialized centers over the past several decades; however, it is unclear if these changes have translated to benefits in the general population.

Methods

In this study, we utilized two national databases to examine survival trends over time for PCNSL (Central Brain Tumor Registry of the United States (CBTRUS, 2000 – 2013) and 18 Surveillance, Epidemiology, and End Results (SEER, 1973 – 2013) registries).

Results

The annual incidence of PCNSL in 2013 was 0.4 per 100,000 population (CBTRUS/SEER). Incidence increased from 0.1 per 100,000 in the 1970s to 0.4 per 100,000 in the 1980s, correlating with an increase in the diagnosis of patients ≥70 years (1973:0.2 vs 2013:2.1 – SEER). Incidence rates differed greatly between young and elderly patients (age 20–29 years: 0.08 vs 70–79: 4.32 – CBTRUS). Even though the median overall survival of all patients doubled from 12.5 months in the 1970s to 26 in the 2010s, this survival benefit was limited to patients age <70. Survival in the elderly population did not change in the last 40 years (6 months in the 1970s vs 7 in the 2010s, p-value = 0.1).

Conclusion

The poor outcome seen in the particularly vulnerable elderly patient population highlights the need for clinical trials targeting the elderly in hopes of improving treatment strategies and survival.

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Processing of haptic texture information over sequential exploration movements

Abstract

Where textures are defined by repetitive small spatial structures, exploration covering a greater extent will lead to signal repetition. We investigated how sensory estimates derived from these signals are integrated. In Experiment 1, participants stroked with the index finger one to eight times across two virtual gratings. Half of the participants discriminated according to ridge amplitude, the other half according to ridge spatial period. In both tasks, just noticeable differences (JNDs) decreased with an increasing number of strokes. Those gains from additional exploration were more than three times smaller than predicted for optimal observers who have access to equally reliable, and therefore equally weighted, estimates for the entire exploration. We assume that the sequential nature of the exploration leads to memory decay of sensory estimates. Thus, participants compare an overall estimate of the first stimulus, which is affected by memory decay, to stroke-specific estimates during the exploration of the second stimulus. This was tested in Experiments 2 and 3. The spatial period of one stroke across either the first or second of two sequentially presented gratings was slightly discrepant from periods in all other strokes. This allowed calculating weights of stroke-specific estimates in the overall percept. As predicted, weights were approximately equal for all strokes in the first stimulus, while weights decreased during the exploration of the second stimulus. A quantitative Kalman filter model of our assumptions was consistent with the data. Hence, our results support an optimal integration model for sequential information given that memory decay affects comparison processes.

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Contingency proportion systematically influences contingency learning

Abstract

In the color-word contingency learning paradigm, each word appears more often in one color (high contingency) than in the other colors (low contingency). Shortly after beginning the task, color identification responses become faster on the high-contingency trials than on the low-contingency trials—the contingency learning effect. Across five groups, we varied the high-contingency proportion in 10% steps, from 80% to 40%. The size of the contingency learning effect was positively related to high-contingency proportion, with the effect disappearing when high contingency was reduced to 40%. At the two highest contingency proportions, the magnitude of the effect increased over trials, the pattern suggesting that there was an increasing cost for the low-contingency trials rather than an increasing benefit for the high-contingency trials. Overall, the results fit a modified version of Schmidt's (2013, Acta Psychologica, 142, 119–126) parallel episodic processing account in which prior trial instances are routinely retrieved from memory and influence current trial performance.

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Sound specificity effects in spoken word recognition: The effect of integrality between words and sounds

Abstract

Recent evidence has shown that nonlinguistic sounds co-occurring with spoken words may be retained in memory and affect later retrieval of the words. This sound-specificity effect shares many characteristics with the classic voice-specificity effect. In this study, we argue that the sound-specificity effect is conditional upon the context in which the word and sound coexist. Specifically, we argue that, besides co-occurrence, integrality between words and sounds is a crucial factor in the emergence of the effect. In two recognition-memory experiments, we compared the emergence of voice and sound specificity effects. In Experiment 1 , we examined two conditions where integrality is high. Namely, the classic voice-specificity effect (Exp. 1a) was compared with a condition in which the intensity envelope of a background sound was modulated along the intensity envelope of the accompanying spoken word (Exp. 1b). Results revealed a robust voice-specificity effect and, critically, a comparable sound-specificity effect: A change in the paired sound from exposure to test led to a decrease in word-recognition performance. In the second experiment, we sought to disentangle the contribution of integrality from a mere co-occurrence context effect by removing the intensity modulation. The absence of integrality led to the disappearance of the sound-specificity effect. Taken together, the results suggest that the assimilation of background sounds into memory cannot be reduced to a simple context effect. Rather, it is conditioned by the extent to which words and sounds are perceived as integral as opposed to distinct auditory objects.

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“The importance of surgical maneuvers during treatment of frontal migraines (site I): a prospective, randomized cohort study evaluating foraminotomy/fasciotomy, myectomy, and arterectomy”

The current prospective, blinded, randomized cohort study aims to delineate the relative contribution of different surgical treatments for frontal migraines.

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Antibiotic prophylaxis in breast reduction surgery: a different approach

We read with interest the manuscript entitled Antibiotic Prophylaxis in Breast Reduction Surgery: A Systematic Review and Metaanalysis published by Zapata-Copete and al. in Journal of Plastic, Reconstructive & Aesthetic Surgery in August 2017 (1).

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Preoperative fasting in children

1A012A033J03

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Burnout and resilience in anaesthesia and intensive care medicine

1H022H013J02

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Is Subcranial Le Fort III Plus Le Fort I Osteotomy Stable?

The purpose of this study was to test whether associated subcranial Le Fort III (sLF III) and Le Fort I (LF I) osteotomies are stable after large advancements of the middle third of the face and maxilla. The authors designed a retrospective study and enrolled a sample of consecutive patients with midface hypoplasia treated with associated sLF III and LF I osteotomies in this IRB-approved study between September 2013 and February 2015. To test whether the long-term stability was satisfactory, the authors compared cephalometric changes from immediately after surgery to 18 months after surgery taken from multi-slice computed tomography using two different third-party imaging software programs.

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Orthognathic surgery “again” to correct aesthetic failure of primary surgery: Report on outcomes and patient satisfaction in 70 consecutive cases

An increasing number of patients complain about unsatisfactory aesthetic outcomes of orthognathic surgery, desiring reoperation to improve facial aesthetics. The aims of this article are to present a wide range of aesthetic reasons to justify a secondary orthognathic surgery and to report aesthetic outcomes and patient satisfaction after reoperation.

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Conservative treatment of children with chronic diffuse sclerosing osteomyelitis/tendoperiostitis of the mandible

Chronic diffuse sclerosing osteomyelitis (DSO) of the mandible is a rare disease of unknown etiology. It has been suggested that overuse of the masticatory muscles, tendoperiostitis (TP), is a contributing factor for DSO. Therefore, we tested this hypothesis by treating consecutive children with conservative therapy.All patients were treated with conservative therapy, comprising occlusal splint therapy, physiotherapy, and/or disease counselling. Pain intensity on a visual analogue scale (VAS) and pain frequency in number of days per 3 months were recorded before the start of treatment, and at 3, 6, and 12 months after treatment initiation.

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Quantitative assessment of orbital fractures in Asian patients: CT measurement of orbital volume

Enophthalmos is caused by an increase of orbital volume after blowout fracture and is one of the most critical complications of such fractures, but is often masked by swelling soon after injury. If surgery is performed after swelling resolves, it becomes more difficult to treat enophthalmos because of atrophy and fibrosis. Accordingly, it is important to estimate the severity of enophthalmos soon after injury. We developed a new criterion for determining whether orbital fractures are indicated for surgery in Asian patients using analysis of orbital volume.

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Unraveling Pancreatic Segmentation

Abstract

Background

Limited pancreatic resections are increasingly performed, but the rate of postoperative fistula is higher than after classical resections. Pancreatic segmentation, anatomically and radiologically identifiable, may theoretically help the surgeon removing selected anatomical portions with their own segmental pancreatic duct and thus might decrease the postoperative fistula rate. We aimed at systematically and comprehensively reviewing the previously proposed pancreatic segmentations and discuss their relevance and limitations.

Methods

PubMed database was searched for articles investigating pancreatic segmentation, including human or animal anatomy, and cadaveric or surgical studies.

Results

Overall, 47/99 articles were selected and grouped into 4 main hypotheses of pancreatic segmentation methodology: anatomic, vascular, embryologic and lymphatic. The head, body and tail segments are gross description without distinct borders. The arterial territories defined vascular segments and isolate an isthmic paucivascular area. The embryological theory relied on the fusion plans of the embryological buds. The lymphatic drainage pathways defined the lymphatic segmentation. These theories had differences, but converged toward separating the head and body/tail parts, and the anterior from posterior and inferior parts of the pancreatic head. The rate of postoperative fistula was not decreased when surgical resection was performed following any of these segmentation theories; hence, none of them appeared relevant enough to guide pancreatic transections.

Conclusion

Current pancreatic segmentation theories do not enable defining anatomical–surgical pancreatic segments. Other approaches should be explored, in particular focusing on pancreatic ducts, through pancreatic ducts reconstructions and embryologic 3D modelization.

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The 150 most important questions in cancer research and clinical oncology series: questions 57–66

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

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Correction to: The 3.5-year survival rates of primary molars treated according to three treatment protocols: a controlled clinical trial

Abstract

Mw. M. Mijan will defend her PhD thesis on 15th September 2017. Whilst reviewing her work in preparation to the event, we discovered a few irregularities that prompted a recheck of the database and ditto analyses. These activities have lead to a few textual changes in the publication.

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Correction to: The 3.5-year survival rates of primary molars treated according to three treatment protocols: a controlled clinical trial

Abstract

Mw. M. Mijan will defend her PhD thesis on 15th September 2017. Whilst reviewing her work in preparation to the event, we discovered a few irregularities that prompted a recheck of the database and ditto analyses. These activities have lead to a few textual changes in the publication.

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Prognostic Significance of Pre- to Postoperative Dynamics of the Prognostic Nutritional Index for Patients with Renal Cell Carcinoma Who Underwent Radical Nephrectomy

Abstract

Background

This study aimed to examine the prognostic role of Prognostic Nutritional Index (PNI) dynamics in the pre- and postoperative periods for patients with renal cell carcinoma (RCC) who undergo radical nephrectomy (RN).

Methods

The study analyzed 324 patients with RCC who underwent RN. The overall population was classified into four groups according to four types of pre- to postoperative PNI dynamics as follows: group 1 (low → low PNI), group 2 (low → high PNI), group 3 (high → low PNI), and group 4 (high → high PNI). The level of PNI was calculated using the following formula: 10 × serum albumin level (g/dL) + 0.005 × absolute lymphocyte counts in blood (/mm³). The primary end point was cancer-specific survival (CSS), and the secondary end point was overall survival (OS).

Results

The patients with higher pre- and postoperative PNI (>45) had better survival outcomes than those with lower pre- and postoperative PNI (≤45). Notably, the patients in group 4 showed the best CSS and OS rates, whereas the patients in group 1 had the worst survival outcomes. Furthermore, PNI dynamics were identified as an independent predictor of CSS and OS outcomes, in addition to pre- and postoperative PNI, tumor size, and pathologic T (pT) stage. The patients with localized RCC (≤pT2) showed significant differences in both CSS and OS estimates, whereas the patients with advanced pT stage (≥pT3) demonstrated a difference only in OS outcomes, according to PNI dynamics.

Conclusions

This study is the first to provide the independent prognostic importance of dynamics of nutritional status for patients with RCC.

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Outcome with Primary En-bloc Esophagectomy for Submucosal Esophageal Adenocarcinoma

Abstract

Background

Intramucosal esophageal adenocarcinoma can be reliably treated endoscopically. Controversy exists about the use of endotherapy versus esophagectomy for submucosal tumors. Increasingly endotherapy is considered for submucosal tumors in part because of the presumed high mortality with esophagectomy and the perceived poor prognosis in patients with nodal disease. This study was designed to assess survival following primary en bloc esophagectomy (EBE) in patients with submucosal esophageal adenocarcinoma (EAC).

Methods

This is a retrospective review of all patients who underwent EBE for submucosal EAC between 1998 and 2015. No patient had neoadjuvant therapy.

Results

There were 32 patients (28M/4F; median age 64 years). The median tumor size was 1.5 cm (0.4–8.0), and the median number of resected nodes was 48 (23–85). There was one perioperative death. Lymph node metastases were present in 7 patients (22%). There was one involved node in four patients and 2, 3, and 31 nodes in one patient each. The one N3 patient received adjuvant therapy. The median follow-up was 87 months. Overall survival at 5 and 10 years was 84 and 70% respectively. Disease-specific survival at 10 years was 90%. Eight patients died, but only three deaths (9%) were related to EAC. Disease-specific survival at 10 years in node-positive patients was 71%.

Conclusions

Survival after primary en bloc esophagectomy for submucosal adenocarcinoma was excellent even in node-positive patients. Mortality with esophagectomy was low and far less than the 22% risk of node metastases in patients with submucosal tumor invasion. Esophagectomy should remain the preferred treatment for T1b esophageal adenocarcinoma.

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Prognostic Significance of Pre- to Postoperative Dynamics of the Prognostic Nutritional Index for Patients with Renal Cell Carcinoma Who Underwent Radical Nephrectomy

Abstract

Background

This study aimed to examine the prognostic role of Prognostic Nutritional Index (PNI) dynamics in the pre- and postoperative periods for patients with renal cell carcinoma (RCC) who undergo radical nephrectomy (RN).

Methods

The study analyzed 324 patients with RCC who underwent RN. The overall population was classified into four groups according to four types of pre- to postoperative PNI dynamics as follows: group 1 (low → low PNI), group 2 (low → high PNI), group 3 (high → low PNI), and group 4 (high → high PNI). The level of PNI was calculated using the following formula: 10 × serum albumin level (g/dL) + 0.005 × absolute lymphocyte counts in blood (/mm³). The primary end point was cancer-specific survival (CSS), and the secondary end point was overall survival (OS).

Results

The patients with higher pre- and postoperative PNI (>45) had better survival outcomes than those with lower pre- and postoperative PNI (≤45). Notably, the patients in group 4 showed the best CSS and OS rates, whereas the patients in group 1 had the worst survival outcomes. Furthermore, PNI dynamics were identified as an independent predictor of CSS and OS outcomes, in addition to pre- and postoperative PNI, tumor size, and pathologic T (pT) stage. The patients with localized RCC (≤pT2) showed significant differences in both CSS and OS estimates, whereas the patients with advanced pT stage (≥pT3) demonstrated a difference only in OS outcomes, according to PNI dynamics.

Conclusions

This study is the first to provide the independent prognostic importance of dynamics of nutritional status for patients with RCC.

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Multiple rapidly growing desmoid tumors that were difficult to distinguish from recurrence of rectal cancer

Abstract

Background

Intra-abdominal desmoid tumors are usually slow growing and solitary, but multifocal desmoid tumors develop on rare occasions. Diagnosing desmoid tumors before histological examination of a surgical biopsy is often difficult. In particular, if a patient has a prior history of malignancy, it may be difficult to differentiate between these lesions and disease recurrence or metastasis.

Case presentation

We present a rare case of multiple rapidly growing intra-abdominal desmoid tumors after surgical trauma, without familial adenomatous polyposis. A 51-year-old male underwent abdominal perineal resection with lateral lymph node dissection after neoadjuvant chemotherapy for lower rectal cancer. Follow-up computed tomography (CT), performed 6 months after primary surgery, showed a 20-mm solitary mass in the pelvic mesentery. Another CT scan, performed 3 months later, revealed that the mass had grown to 35 mm in size and that two new masses had formed. Based on imaging studies and his medical history, it was difficult to distinguish the desmoid tumors from recurrence of rectal cancer. Curative resection was chosen for therapeutic diagnosis. The pathological diagnosis was multiple mesenteric desmoid tumors.

Conclusions

Desmoid tumors should not be excluded as a differential diagnosis for intra-abdominal masses after intra-abdominal surgery, even in cases of rapidly growing multiple masses.

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Salvage re-irradiation for recurrent high-grade glioma and comparison to bevacizumab alone

Abstract

While salvage re-irradiation is often used for recurrent high-grade glioma (HGG), there have been few comparisons between various re-radiation dose/fractionation schedules or with bevacizumab alone. We analyzed patients with recurrent HGG who received re-irradiation at Dana-Farber Cancer Institute and Brigham and Women's Hospital from 2010 to 2014 (n = 67), as well as those who received bevacizumab alone (n = 177). Cox proportional hazards modeling was used to examine factors associated with overall survival (OS). Propensity score modeling was used to compare survival after re-irradiation vs. bevacizumab alone. Median time from initial diagnosis to re-irradiation was 31.4 months. The most common re-irradiation dose/fractionations used were 6 Gy × 5 (36%), 3.5 Gy × 10 (21%), 2.67 Gy × 15 (15%), and 18–20 Gy × 1 (15%). No early or late toxicities >grade 2 were observed. Median PFS and OS after re-irradiation were 4.8 and 10.7 months, respectively. Number of progressions prior to re-irradiation (adjusted hazard ratio [AHR] 1.6; 95% CI, 1.1–2.3; p = .007), and recurrence in a new brain location (vs. local-only; AHR 7.4; 95% CI, 2.4–23.1; p < .001) were associated with OS; dose/fractionation was not. Compared with bevacizumab alone, re-irradiated patients had a non-significant increase in OS (HR 0.80; 95% CI, 0.53–1.23; P = .31). Among patients with a local-only recurrence, there was a trend towards longer median OS after re-irradiation compared to bevacizumab alone (12.4 vs. 8.0 months; p = .12). Survival after re-irradiation for recurrent HGG appears independent of dose/fractionation and compares favorably with bevacizumab alone.

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The Case of an Ugly Truth

  The great tragedy of Science — the slaying of a beautiful hypothesis by an ugly fact.                                                                             […]

EMCrit by Rory Spiegel.

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P 26 Evaluation of clinical, electrophysiological, sonographic and MRI characteristics of the CIDP spectrum disorder

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease with a wide spectrum of clinical presentation and treatment response. Electrophysiological studies constitute the gold standard used to characterise CIDP patients and contribute to treatment decisions. However, mostly at late stages electrophysiological methods show a pronounced axonal damage and are not able to distinguish CIDP subtypes. Therefore, therapeutic decisions have to be based solely on the clinical course.

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P 27 Beyond binary parcellation of the vestibular cortex

A binary approach to resting-state functional connectivity based parcellation (fCBP) provides useful insights into human brain organization, but also entails oversimplifications (Glasser, 2016). This is especially true for multisensory and higher-level associative brain areas, such as the bilateral vestibular cortical network with its multiple multisensory areas (Dieterich and Brandt, 2015). This study aimed to identify subunits of the vestibular cortex whilst accounting for a possible affiliation of voxel to different sensory systems using a multivariate fCBP within a vestibular region of interest (ROI) including known cortical areas of the vestibular network, i.e.

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RE: “THE HIDDEN EPIDEMIC OF FIREARM INJURY: INCREASING FIREARM INJURY RATES DURING 2001–2013”

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THREE AUTHORS REPLY

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Lessons Learned From Past Gene-Environment Interaction Successes

Abstract

Genetic and environmental factors are both known to contribute to susceptibility to complex diseases. Therefore, the study of gene-environment interaction (G×E) has been a focus of research for several years. In this article, select examples of G×E from the literature are described to highlight different approaches and underlying principles related to the success of these studies. These examples can be broadly categorized as studies of single metabolism genes, genes in complex metabolism pathways, ranges of exposure levels, functional approaches and model systems, and pharmacogenomics. Some studies illustrated the success of studying exposure metabolism for which candidate genes can be identified. Moreover, some G×E successes depended on the availability of high-quality exposure assessment and longitudinal measures, study populations with a wide range of exposure levels, and the inclusion of ethnically and geographically diverse populations. In several examples, large population sizes were required to detect G×Es. Other examples illustrated the impact of accurately defining scale of the interactions (i.e., additive or multiplicative). Last, model systems and functional approaches provided insights into G×E in several examples. Future studies may benefit from these lessons learned.

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Residential Proximity to Major Roadways, Fine Particulate Matter, and Hepatic Steatosis The Framingham Heart Study

Abstract

We examined associations between ambient air pollution and hepatic steatosis among 2,513 participants from the Framingham (Massachusetts) Offspring Study and Third Generation Cohort who underwent a computed tomography scan (2002–2005), after excluding men who reported >21 drinks/week and women who reported >14 drinks/week. We calculated each participant's residential-based distance to a major roadway and used a spatiotemporal model to estimate the annual mean concentrations of fine particulate matter. Liver attenuation was measured by computed tomography, and liver-to-phantom ratio (LPR) was calculated. Lower values of LPR represent more liver fat. We estimated differences in continuous LPR using linear regression models and prevalence ratios for presence of hepatic steatosis (LPR ≤ 0.33) using generalized linear models, adjusting for demographics, individual and area-level measures of socioeconomic position, and clinical and lifestyle factors. Participants who lived 58 m (25th percentile) from major roadways had lower LPR (β = −0.003, 95% confidence interval: −0.006, −0.001) and higher prevalence of hepatic steatosis (prevalence ratio = 1.16, 95% confidence interval: 1.05, 1.28) than those who lived 416 m (75th percentile) away. The 2003 annual average fine particulate matter concentration was not associated with liver-fat measurements. Our findings suggest that living closer to major roadways was associated with more liver fat.

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Meat, Dietary Heme Iron, and Risk of Type 2 Diabetes Mellitus The Singapore Chinese Health Study

Abstract

We evaluated the relationships of red meat, poultry, fish, and shellfish intakes, as well as heme iron intake, with the risk of type 2 diabetes mellitus (T2D).The Singapore Chinese Health Study is a population-based cohort study that recruited 63,257 Chinese adults aged 45–74 years from 1993 to 1998. Usual diet was evaluated using a validated 165-item semiquantitative food frequency questionnaire at recruitment. Physician-diagnosed T2D was self-reported during 2 follow-up interviews in 1999–2004 and 2006–2010. During a mean follow-up of 10.9 years, 5,207 incident cases of T2D were reported. When comparing persons in the highest intake quartiles with those in the lowest, the multivariate-adjusted hazard ratio for T2D was 1.23 (95% confidence interval (CI): 1.14, 1.33) for red meat intake (P for trend < 0.001), 1.15 (95% CI: 1.06, 1.24) for poultry intake (P for trend = 0.004), and 1.07 (95% CI: 0.99, 1.16) for fish/shellfish intake (P for trend = 0.12). After additional adjustment for heme iron, only red meat intake remained significantly associated with T2D risk (multivariate-adjusted hazard ratio = 1.13, 95% CI: 1.01, 1.25; P for trend = 0.02). Heme iron was associated with a higher risk of T2D even after additional adjustment for red meat intake (multivariate-adjusted hazard ratio = 1.14, 95% CI: 1.02, 1.28; P for trend = 0.03). In conclusion, red meat and poultry intakes were associated with a higher risk of T2D. These associations were mediated completely for poultry and partially for red meat by heme iron intake.

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Geographic Patterns of Autism Spectrum Disorder Among Children of Participants in Nurses’ Health Study II

Abstract

Data indicate that the prevalence of autism spectrum disorder (ASD) may be increasing and that it varies geographically. We investigated associations between residential location and ASD in the children of Nurses' Health Study II (United States) participants in order to generate hypotheses about social and environmental factors related to etiology or diagnosis. Analyses included data on 13,507 children born during 1989–1999 (486 with ASD). We explored relationships between ASD and residential location both at birth and at age 6 years (i.e., closer to average age at diagnosis). Generalized additive models were used to predict ASD odds across the United States. Children born in New England were 50% more likely to be diagnosed with ASD compared with children born elsewhere in the United States. Patterns were not explained by geographic variation in maternal age, birth year, child's sex, community income, or prenatal exposure to hazardous air pollutants, indicating that spatial variation is not attributable to these factors. Using the residential address at age 6 years produced similar results; however, areas of significantly decreased ASD odds were observed in the Southeast, where children were half as likely to have ASD. These results may indicate that diagnostic factors are driving spatial patterns; however, we cannot rule out the possibility that other environmental factors are influencing distributions.

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