bluuebunny/crossref_metadata_2025 huggingface dataset:
New insights into survival trend analyses in cancer population-based studies: the SUDCAN methodology
Authors: Uhry Zoé , Bossard Nadine , Remontet Laurent , Iwaz Jean , Roche Laurent
Published: December 2016

The main objective of the SUDCAN study was to compare, for 15 cancer sites, the trends in net survival and excess mortality rates from cancer 5 years after diagnosis between six European Latin countries (Belgium, France, Italy, Portugal, Spain and Switzerland). The data were extracted from the EUROCARE-5 database. The study period ranged from 6 (Portugal, 2000–2005) to 18 years (Switzerland, 1989–2007). Trend analyses were carried out separately for each country and cancer site; the number of cases ranged from 1500 to 104 000 cases. We developed an original flexible excess rate modelling strategy that accounts for the continuous effects of age, year of diagnosis, time since diagnosis and their interactions. Nineteen models were constructed; they differed in the modelling of the effect of the year of diagnosis in terms of linearity, proportionality and interaction with age. The final model was chosen according to the Akaike Information Criterion. The fit was assessed graphically by comparing model estimates versus nonparametric (Pohar-Perme) net survival estimates. Out of the 90 analyses carried out, the effect of the year of diagnosis on the excess mortality rate depended on age in 61 and was nonproportional in 64; it was nonlinear in 27 out of the 75 analyses where this effect was considered. The model fit was overall satisfactory. We analysed successfully 15 cancer sites in six countries. The refined methodology proved necessary for detailed trend analyses. It is hoped that three-dimensional parametric modelling will be used more widely in net survival trend studies as it has major advantages over stratified analyses.
Trends in net survival from ovarian cancer in six European Latin countries: results from the SUDCAN population-based study
Authors: Chirlaque María-Dolores , Uhry Zoé , Salmerón Diego , Sánchez-Zapata María-Isabel , Zannoni Gian Franco , Navarro Carmen
Published: December 2016

European Latin countries have some similarities in their health systems. It is thus interesting to look at their differences in cancer survival (here, ovarian cancer) through monitoring of specific indicators of quality care. The aim of this SUDCAN collaborative study was to compare the trends in 1 and 5-year net survival from ovarian cancer and the trends in the excess mortality rates between six European Latin countries (Belgium, France, Italy, Portugal, Spain and Switzerland). The data were extracted from the EUROCARE-5 database. First, the net survival was studied over the 2000–2004 period using the Pohar-Perme estimator. For trend analyses, the study period was specific to each country. The results are reported from 1992 to 2004 in France, Italy, Spain and Switzerland, and from 2000 to 2004 in Belgium and Portugal. The analyses were carried out using a flexible excess rate modelling. Over the period 2000–2004, there were slight differences in the 5-year age-standardized net survivals from ovarian cancer; they ranged from 36% in Spain to 42% in Belgium. Net survival was much higher in young than in old age groups, but this difference was more marked in Spain and less marked in France. Between 1992 and 2004, the net survival increased in all countries, mainly in young and middle-aged women. However, the differences in 5-year net survival between these countries were larger in 2004 than in 1992. Slight differences were observed in survival from ovarian cancer between the six European Latin countries. A considerable improvement in survival was observed in all countries, especially in young and middle-aged women. This study highlights the need for further monitoring of ovarian cancer outcomes.
Trends in net survival from skin malignant melanoma in six European Latin countries: results from the SUDCAN population-based study
Authors: Galceran Jaume , Uhry Zoé , Marcos-Gragera Rafael , Borràs Joan
Published: December 2016

In Europe as a whole, survival from skin malignant melanoma (SMM) has increased constantly since the 1980s. The aim of the SUDCAN collaborative study was to compare the trends in the 5-year net survival from SMM and in related excess mortality rate between six European Latin countries (Belgium, France, Italy, Portugal, Spain, and Switzerland). The data were extracted from the EUROCARE-5 database (end of follow-up: 01 January 2009). First, the net survival was studied over the 2000–2004 period using the Pohar-Perme estimator. For trend analyses, the study period was specific to each country. The results are reported from 1992 to 2004 in France, Italy, Spain, and Switzerland and from 2000 to 2004 in Belgium and Portugal. The analyses were carried out using a flexible excess rate modeling. Over the 2000–2004 period, the 5-year net survival from SMM ranged from 79 (Portugal) to 90% (Switzerland). In all countries, net survival was higher in women versus men and in young versus old age groups. From 1992 to 2004, the 5-year net survival increased the most in the countries with the lowest survivals in 1992 (+9% in Italy and Spain vs. +2% in Switzerland or +4% in France). The differences between countries decreased between 1992 and 2004. Although survival increased to a lower or higher extent in all countries during the period studied, significant differences in net survival from SMM persisted among the six countries studied. Health policies should mainly enhance early diagnosis by increasing public awareness and with screening campaigns. Furthermore, new immunotherapies, which will be approved soon hopefully, should also be used to improve the outcomes of SMM treatment.
Trends in net survival from esophageal cancer in six European Latin countries: results from the SUDCAN population-based study
Authors: Launoy Guy , Bossard Nadine , Castro Clara , Manfredi Sylvain
Published: December 2016

Esophageal cancer represents a major clinical challenge because of its poor prognosis. The aim of the SUDCAN collaborative study was to compare the net survival from esophageal cancer between six European Latin countries (Belgium, France, Italy, Portugal, Spain, and Switzerland) and report the trends in net survival and the dynamics of excess mortality rates (EMRs) up to 5 years after diagnosis. The data were extracted from the EUROCARE-5 database. First, net survival was studied over the period 2000–2004 using the Pohar-Perme estimator. For trend analyses, the study period was specific to each country. The results were reported from 1992 to 2004 in France, Italy, Spain, and Switzerland and from 2000 to 2004 in Belgium and Portugal. These trend analyses were carried out using a flexible excess rate modeling strategy. There were some differences between countries in age-standardized net survival (2000–2004). The 5-year net survival ranged between 9 (Spain) and 21% (Belgium). The small increase in net survival from 1992 and 2004 was mostly observed at ages 55 and 65, but was less marked at age 75. There was a slight decrease in EMR between 1992 and 2004 until ∼24 months after diagnosis. Beyond this period, the decrease in the EMR was moderate and the same in all countries irrespective of the year of diagnosis. Some improvement in the 5-year net survival was observed in all countries limited to the 24 months after diagnosis. However, survival differences between countries persisted. Further improvement is expected from innovative treatments.
Spontaneous Activation of Antigen-presenting Cells by Genes Encoding Truncated Homo-Oligomerizing Derivatives of CD40
Authors: Levin Noam , Pato Aviad , Cafri Gal , Eisenberg Galit , Peretz Tamar , Margalit Alon , Lotem Michal , Gross Gideon
Published: December 2016

The interaction between the CD40 receptor on antigen-presenting cells (APCs) and its trimeric ligand on CD4 T cells is essential for the initiation and progression of the adaptive immune response. Here we undertook to endow CD40 with the capacity to trigger spontaneous APC activation through ligand-independent oligomerization. To this end we exploited the GCN4 yeast transcriptional activator, which contains a leucine zipper DNA-binding motif that induces homophilic interactions. We incorporated GCN4 variants forming homodimers, trimers, or tetramers at the intracellular domain of human and mouse CD40 and replaced the extracellular portion with peptide-β2m or other peptide tags. In parallel we examined similarly truncated CD40 monomers lacking a GCN4 motif. The oligomeric products appeared to arrange in high–molecular-weight aggregates and were considerably superior to the monomer in their ability to trigger nuclear factor kB signaling, substantiating the anticipated constitutively active (ca) phenotype. Cumulative results in human and mouse APC lines transfected with caCD40 mRNA revealed spontaneous upregulation of CD80, IL-1β, TNFα, IL-6, and IL-12, which could be further enhanced by caTLR4 mRNA. In mouse bone-marrow–derived dendritic cells caCD40 upregulated CD80, CD86, MHC-II, and IL-12 and in human monocyte–derived dendritic cells it elevated surface CD80, CD83 CD86, CCR7, and HLA-DR. Oligomeric products carrying the peptide-β2m extracellular portion could support MHC-I presentation of the linked peptide up to 4 days post-mRNA transfection. These findings demonstrate that the expression of a single caCD40 derivative in APCs can exert multiple immunostimulatory effects, offering a new powerful tool in the design of gene-based cancer vaccines.
Soluble Epoxide Hydrolase Inhibition and Epoxyeicosatrienoic Acid Treatment Improve Vascularization of Engineered Skin Substitutes
Authors: Supp Dorothy M. , Hahn Jennifer M. , McFarland Kevin L. , Combs Kelly A. , Lee Kin Sing Stephen , Inceoglu Bora , Wan Debin , Boyce Steven T. , Hammock Bruce D.
Published: December 2016

Background:

Autologous engineered skin substitutes comprised of keratinocytes, fibroblasts, and biopolymers can serve as an adjunctive treatment for excised burns. However, engineered skin lacks a vascular plexus at the time of grafting, leading to slower vascularization and reduced rates of engraftment compared with autograft. Hypothetically, vascularization of engineered skin grafts can be improved by treatment with proangiogenic agents at the time of grafting. Epoxyeicosatrienoic acids (EETs) are cytochrome P450 metabolites of arachidonic acid that are inactivated by soluble epoxide hydrolase (sEH). EETs have multiple biological activities and have been shown to promote angiogenesis. Inhibitors of sEH (sEHIs) represent attractive therapeutic agents because they increase endogenous EET levels. We investigated sEHI administration, alone or combined with EET treatment, for improved vascularization of engineered skin after grafting to mice.

Methods:

Engineered skin substitutes, prepared using primary human fibroblasts and keratinocytes, were grafted to full-thickness surgical wounds in immunodeficient mice. Mice were treated with the sEHI 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), which was administered in drinking water throughout the study period, with or without topical EET treatment, and were compared with vehicle-treated controls. Vascularization was quantified by image analysis of CD31-positive areas in tissue sections.

Results:

At 2 weeks after grafting, significantly increased vascularization was observed in the TPPU and TPPU + EET groups compared with controls, with no evidence of toxicity.

Conclusions:

The results suggest that sEH inhibition can increase vascularization of engineered skin grafts after transplantation, which may contribute to enhanced engraftment and improved treatment of full-thickness wounds.
Chronic Hypertension in Pregnancy: Diagnosis, Management, and Outcomes
Authors: ANKUMAH NANA-AMA E. , SIBAI BAHA M.
Published: December 2016

Chronic hypertension affects up to 5% of pregnancies. Women can be stratified into low-risk or high-risk chronic hypertension based on baseline laboratory and diagnostic work-up, comorbid conditions, and outcomes in prior pregnancies. Pregnancies complicated by chronic hypertension are at risk for increased adverse maternal and neonatal outcomes including superimposed preeclampsia, fetal growth restriction, placental abruption, and perinatal death. Mainstays of management include blood pressure control, close monitoring for development of superimposed preeclampsia, serial ultrasound assessment of fetal growth, and antenatal testing after 32 weeks.
Imaging of Adnexal Masses
Authors: THAKUR MILI , TIMMERMAN DIRK
Published: December 2016

We review and emphasize the importance of gynecologic ultrasound scan for the preoperative evaluation of adnexal masses. Transvaginal ultrasound performed by a trained clinician has a good sensitivity and specificity for discriminating benign and malignant adnexal masses. In conjunction with a carefully obtained history, assessment of risk factors, a focused physical examination and serum markers, the information obtained by a gynecologic ultrasound evaluation can assist the clinician in the diagnosis and treatment of adnexal masses.
Tubal Disease and Impersonators/Masqueraders
Authors: KHOURI OLIVIA R. , MONTEAGUDO ANA , TIMOR-TRITSCH ILAN E.
Published: December 2016

Ultrasound is considered the first-line imaging modality in the evaluation of the fallopian tubes. This chapter reviews both the physiologic and pathologic sonographic findings of the fallopian tubes and how to recognize characteristic entities. Specifically, it describes how to use ultrasound techniques to distinguish between pathologic processes including chronic versus acute pelvic inflammatory disease, as well as infertility, torsion, and malignancy. It also describes how to employ modern ultrasound techniques, such as color Doppler, three-dimensional imaging, and salpingocentesis in clinical practice.
EFFICACY OF INTRAVITREAL AFLIBERCEPT IN MACULAR TELANGIECTASIA TYPE 1 IS LINKED TO THE OCULAR ANGIOGENIC PROFILE
Authors: Kowalczuk Laura , Matet Alexandre , Dirani Ali , Daruich Alejandra , Ambresin Aude , Mantel Irmela , Spaide Richard F. , Turck Natacha , Behar-Cohen Francine
Published: December 2016

Purpose:

To evaluate intravitreal aflibercept in macular telangiectasia Type 1 (MacTel 1) patients and measure their ocular angiogenic profile.

Methods:

Eight subjects with MacTel 1 refractory to bevacizumab, ranibizumab, or laser therapy and switched to aflibercept were included. Best-corrected visual acuity, central macular thickness, and cystic areas quantified on optical coherence tomography B-scans were assessed during 12 months. Perifoveal capillary densities were measured on optical coherence tomography angiography. Aqueous humor was sampled from six patients and eight control subjects undergoing cataract extraction. Growth factors were quantified using a multiarray immunoassay.

Results:

Over 12 months, patients received 6.6 ± 1.4 (range, 5–8) intravitreal aflibercept injections. Twelve months after switching to aflibercept, best-corrected visual acuity increased by ≥5 letters in 5 of 8 patients, compared with preaflibercept levels. Mean best-corrected visual acuity improved from 79.6 (∼20/50) to 88.0 (∼20/35) Early Treatment Diabetic Retinopathy Study letters (P = 0.042), and central macular thickness decreased from 434 ± 98 μm to 293 ± 59 μm (P = 0.014). Compared with control subjects, the profile of angiogenic factors in MacTel 1 eyes revealed no difference in vascular endothelial growth factor-A levels but significantly higher levels of placental growth factor (P = 0.029), soluble vascular endothelial growth factor receptor-1 (sFlt-1; P = 0.013), vascular endothelial growth factor-D (P = 0.050), and Tie-2 (P = 0.019). Placental growth factor levels inversely correlated with both superficial and deep capillary plexus densities on optical coherence tomography angiography (P = 0.03).

Conclusion:

The clinical response to aflibercept coupled to the angiogenic profile of MacTel 1 eyes support the implication of the placental growth factor/Flt-1 pathway in MacTel 1.
Techniques for Learning Descemet Membrane Endothelial Keratoplasty for Eyes of Asian Patients With Shallow Anterior Chamber
Authors: Hayashi Takahiko , Oyakawa Itaru , Kato Naoko
Published: December 2016

Purpose:

To describe several essential surgical techniques that overcome difficulties in performing Descemet membrane endothelial keratoplasty (DMEK) for inexperienced surgeons, especially those who perform DMEK on eyes of Asian patients.

Methods:

Nine eyes of 9 Asian patients with bullous keratopathy who underwent DMEK were analyzed retrospectively. All patients were given a diuretic such as d-mannitol or acetazolamide shortly before surgery, with retrobulbar anesthesia and a Nadbath facial nerve block. Core vitrectomy before DMEK was performed in several cases in which a high vitreous pressure during surgery was predicted. The donor graft was stained with trypan blue, and a 25-G anterior chamber maintenance cannula was used to maintain the anterior chamber depth during graft insertion in all eyes.

Results:

The cornea became clear in all eyes. The best spectacle-corrected visual acuity had improved significantly 6 months after the surgery compared with preoperative values (P = 0.026). The corneal endothelial cell density was 1371 cells per square millimeter at postoperative 6 months.

Conclusions:

Although DMEK is technically difficult, especially for inexperienced surgeons who operate on eyes of Asian patients, controlling anterior chamber pressure using various manipulations may help to prevent iatrogenic primary graft failure and lead to successful DMEK.
Treatment of Pseudomonas Keratitis by Continuous Infusion of Topical Antibiotics With the Morgan Lens
Authors: Wang Mingwu , Smith Whitney A. , Duncan Joshua K. , Miller Joseph M.
Published: December 2016

Purpose:

Despite following standard treatment, Pseudomonas keratitis can continue to progress and result in loss of vision or of the eye. Our cases demonstrate that the Morgan Lens can be an effective topical antibiotic delivery vehicle in advanced keratitis.

Methods:

Two patients (3 eyes) with Pseudomonas keratitis were included in this report after failing to respond to intense inpatient topical treatment. Because loss of the eyes was imminent, the Morgan Lenses were used for continuous lavage with ceftazidime (50 mg/mL), in conjunction with other conventional treatment.

Results:

Three days after lavage, corneal cultures became negative in all eyes. Infusion was continued for at least a week to ensure sterilization of the infection before switching to standard topical therapy. The infection in both cases was promptly eradicated and the eyes were rescued.

Conclusions:

The Morgan Lens can be a viable alternative in treating severe and aggressive infectious keratitis or sclerokeratitis. Application of the Morgan Lens is noninvasive and requires minimal training. Intravenous tubing connectors allow for easy swapping between medications, simultaneous administration of multiple medications, and titration of dosing. Additionally, it is cost-effective as the low demand for nursing care essentially eliminates the need for intensive care unit admission.
Extracorporeal Liver Support Systems in Paediatric Liver Failure
Authors: Jain Vandana , Dhawan Anil
Published: December 2016

Extracorporeal liver support systems (ELSS), encompassing artificial and bioartificial devices, have been used for decades, with the aim of supporting patients with acute liver failure and acute‐on chronic liver failure, as a bridge to recovery (acute liver failure only) or liver transplantation, in an era of organ donation shortage. Although biochemical efficacy has been consistently demonstrated by these devices, translation into clinical and survival benefits has been unclear, due to study limitations and lack of reliable prognostic scoring in liver failure. Consequently, extracorporeal devices are not widely accepted as routine therapy in adult liver failure. Recent large multicentre trials using artificial liver systems have not revealed beneficial outcomes associated with albumin dialysis but plasma exchange practices have shown some potential. In paediatric liver failure, data on extracorporeal systems is scarce, comprising few reports on albumin dialysis (namely, Molecular Adsorbent Recirculating System; MARS) and plasma exchange. When extrapolating data from adult studies differences in disease presentation, aetiology, prognosis and the suitability, and safety of such devices in children must be considered. The aim of this review is to critically appraise current practices of extracorporeal liver support systems to help determine efficacy in paediatric liver failure.
The Mental Stress Ischemia Prognosis Study: Objectives, Study Design, and Prevalence of Inducible Ischemia
Authors: Hammadah Muhammad , Al Mheid Ibhar , Wilmot Kobina , Ramadan Ronnie , Shah Amit J. , Sun Yan , Pearce Brad , Garcia Ernest V. , Kutner Michael , Bremner J. Douglas , Esteves Fabio , Raggi Paolo , Sheps David S. , Vaccarino Viola , Quyyumi Arshed A.
Published: December 2016

Objective

Mental stress–induced myocardial ischemia (MSIMI) is a common phenomenon in patients with coronary artery disease (CAD), but contemporary studies of its prognostic significance and its underlying pathophysiology are limited.

Methods

We prospectively enrolled patients with confirmed CAD in the Mental Stress Ischemia Prognosis Study (MIPS) between 2011 and 2014. All patients underwent mental stress testing using a standardized public speaking task, and ischemia was detected by 99mTc-sestamibi myocardial perfusion imaging. Patients also underwent conventional stress testing for myocardial ischemia (CSIMI) using exercise or pharmacological stress testing. Furthermore, digital microvascular flow, endothelial function, arterial stiffness, and blood sample collections were performed before, during, and after mental stress. Two-year adverse clinical outcomes are being assessed.

Results

Six-hundred ninety-five patients completed baseline enrollment in the MIPS. Their mean (standard deviation) age was 62.9 (9.1) years, 72% were men, 30% were African American, and 32% had a history myocardial infarction. The prevalence of MSIMI and CSIMI is 16.1% and 34.7%, respectively. A total of 151 patients (22.9%) had only CSIMI, 28 (4.2%) had only MSIMI, and 78 (11.8%) had both MSIMI and CSIMI. Patients with ischemia had a lower ejection fraction and higher prevalence of previous coronary artery bypass grafting compared with those without inducible ischemia (p < .050). The prevalence of obstructive CAD was not statistically different between patients with and without MSIMI (p = .426); in contrast, it was higher in patients with CSIMI (p < .001).

Conclusions

The MIPS data will provide useful information to assess the prognostic significance and underlying mechanisms of MSIMI.
Prevalence and Predictors of Hospitalizations Among HIV-Infected and At-Risk HIV-Uninfected Women
Authors: Hotton Anna L. , Weber Kathleen M. , Hershow Ronald C. , Anastos Kathryn , Bacchetti Peter , Golub Elizabeth T. , Gustafson Deborah , Levine Alexandra M. , Young Mary , Cohen Mardge H.
Published: December 2016

Objectives:

We evaluated the Veterans Aging Cohort Study (VACS) Index score, an index composed of age, CD4 count, viral load, hemoglobin, Hepatitis C coinfection, Fibrosis Index-4, and estimated glomerular filtration rate, and psychosocial and clinical risk factors for all-cause hospitalization among HIV-infected women on highly active antiretroviral therapy and HIV-uninfected women.

Methods:

Data were collected from 2008 to 2014 from 1585 highly active antiretroviral therapy-experienced HIV infected and 692 uninfected women. Cox proportional hazards regression evaluated predictors of first hospitalization over 2 years.

Results:

Among HIV-infected women, VACS Index score (per 5 points) [adjusted hazard ratio (aHR) 1.08; 95% confidence interval (CI): 1.06 to 1.11], Centers for Epidemiologic Studies-Depression (CESD) scores ≥16 (aHR 1.61; 95% CI: 1.30 to 1.99), smoking (aHR 1.26; 95% CI: 1.02 to 1.55), abuse history (aHR 1.52; 95% CI: 1.20 to 1.93), diabetes (aHR 1.63; 95% CI: 1.31 to 2.04), and black race (aHR 1.28; 95% CI: 1.03 to 1.59) increased risk of hospitalization. Among HIV-uninfected women, VACS Index score (aHR 1.08; 95% CI: 1.03 to 1.13), CESD scores ≥16 (aHR 1.38; 95% CI: 1.02 to 1.86), diabetes (aHR 2.15; 95% CI: 1.57 to 2.95), and black race (aHR 1.61; 95% CI: 1.15 to 2.24) predicted subsequent hospitalization.

Conclusions:

Psychosocial and clinical factors were associated with risk of hospitalization independently of the VACS Index score. Additional research on contextual and psychosocial influences on health outcomes among women is needed.
Higher temperature exacerbates the impact of sediments on embryo performances in a salmonid
Authors: Mari Lisandrina , Garaud Laura , Evanno Guillaume , Lasne Emilien
Published: December 2016

In a warming climate, higher temperatures are likely to modulate positively or negatively the effect of other environmental factors on biota, although such interactions are poorly documented. Here, we explore under controlled conditions the combined effects of two common stressors in freshwater ecosystems, higher temperature and sediment load, on the embryonic development of arctic charr (
Salvelinus alpinus
L.). In the warm treatment, embryos had a lower survival, a longer incubation period and a smaller body size with a bigger yolk sac volume. Our data show a significant interaction between temperature and sediment load with temperature increasing dramatically the negative effects of sediment load on fitness-related traits. In the climate change context, these findings highlight the importance of taking into account different thermal scenarios when examining the effect of environmental or anthropogenic stressors.
Patterns of migrating soaring migrants indicate attraction to marine wind farms
Authors: Skov Henrik , Desholm Mark , Heinänen Stefan , Kahlert Johnny A. , Laubek Bjarke , Jensen Niels Einar , Žydelis Ramūnas , Jensen Bo Præstegaard
Published: December 2016

Monitoring of bird migration at marine wind farms has a short history, and unsurprisingly most studies have focused on the potential for collisions. Risk for population impacts may exist to soaring migrants such as raptors with
K
-strategic life-history characteristics. Soaring migrants display strong dependence on thermals and updrafts and an affinity to land areas and islands during their migration, a behaviour that creates corridors where raptors move across narrow straits and sounds and are attracted to islands. Several migration corridors for soaring birds overlap with the development regions for marine wind farms in NW Europe. However, no empirical data have yet been available on avoidance or attraction rates and behavioural reactions of soaring migrants to marine wind farms. Based on a post-construction monitoring study, we show that all raptor species displayed a significant attraction behaviour towards a wind farm. The modified migratory behaviour was also significantly different from the behaviour at nearby reference sites. The attraction was inversely related to distance to the wind farm and was primarily recorded during periods of adverse wind conditions. The attraction behaviour suggests that migrating raptor species are far more at risk of colliding with wind turbines at sea than hitherto assessed.
Using wire shaping techniques and holographic optics to optimize deposition characteristics in wire-based laser cladding
Authors: Goffin N. J. , Higginson R. L. , Tyrer J. R.
Published: December 2016

In laser cladding, the potential benefits of wire feeding are considerable. Typical problems with the use of powder, such as gas entrapment, sub-100% material density and low deposition rate are all avoided with the use of wire. However, the use of a powder-based source material is the industry standard, with wire-based deposition generally regarded as an academic curiosity. This is because, although wire-based methods have been shown to be capable of superior quality results, the wire-based process is more difficult to control. In this work, the potential for wire shaping techniques, combined with existing holographic optical element knowledge, is investigated in order to further improve the processing characteristics. Experiments with pre-placed wire showed the ability of shaped wire to provide uniformity of wire melting compared with standard round wire, giving reduced power density requirements and superior control of clad track dilution. When feeding with flat wire, the resulting clad tracks showed a greater level of quality consistency and became less sensitive to alterations in processing conditions. In addition, a 22% increase in deposition rate was achieved. Stacking of multiple layers demonstrated the ability to create fully dense, three-dimensional structures, with directional metallurgical grain growth and uniform chemical structure.
Two-zone tumor tolerance can arise from a simple immunological feedforward motif that estimates tumor growth rates
Authors: Sontag Eduardo D.
Published: December 2016

Since the early 1990s, many authors have independently suggested that self/nonself recognition by the immune system might be modulated by the rates of change of antigen challenges. This paper introduces an extremely simple and purely conceptual mathematical model that allows dynamic discrimination of immune challenges. The main component of the model is a motif which is ubiquitous in systems biology, the incoherent feedforward loop, which endows the system with the capability to estimate exponential growth exponents, a prediction which is consistent with experimental work showing that exponentially increasing antigen stimulation is a determinant of immune reactivity. Combined with a bistable system and a simple feedback repression mechanism, an interesting phenomenon emerges as a tumor growth rate increases: elimination, tolerance (tumor growth), again elimination, and finally a second zone of tolerance (tumor escape). This prediction from our model is analogous to the “two-zone tumor tolerance” phenomenon experimentally validated since the mid 1970s. Moreover, we provide a plausible biological instantiation of our circuit using combinations of regulatory and effector T cells.
Umap and Bismap: quantifying genome and methylome mappability
Authors: Karimzadeh Mehran , Ernst Carl , Kundaje Anshul , Hoffman Michael M.
Published: December 2016

Motivation

Short-read sequencing enables assessment of genetic and biochemical traits of individual genomic regions, such as the location of genetic variation, protein binding, and chemical modifications. Every region in a genome assembly has a property calledmappabilitywhich measures the extent to which it can be uniquely mapped by sequence reads. In regions of lower mappability, estimates of genomic and epigenomic characteristics from sequencing assays are less reliable. At best, sequencing assays will produce misleadingly low numbers of reads in these regions. At worst, these regions have increased susceptibility to spurious mapping from reads from other regions of the genome with sequencing errors or unexpected genetic variation. Bisulfite sequencing approaches used to identify DNA methylation exacerbate these problems by introducing large numbers of reads that map to multiple regions. While many tools consider mappability during the read mapping process, subsequent analysis often loses this information. Both to correct assumptions of uniformity in downstream analysis, and to identify regions where the analysis is less reliable, it is necessary to know the mappability of both ordinary and bisulfite-converted genomes.

Results

We introduce the Umap software for identifying uniquely mappable regions of any genome. Its Bismap extension identifies mappability of the bisulfite-converted genome. With a read length of 24 bp, 18.7% of the unmodified genome and 33.5% of the bisulfite-converted genome is not uniquely mappable. This complicates interpretation of functional genomics experiments using short-read sequencing, especially in regulatory regions. For example, 81% of human CpG islands overlap with regions that are not uniquely mappable. Similarly, in some ENCODE ChIP-seq datasets, up to 50% of peaks overlap with regions that are not uniquely mappable. We also explored differentially methylated regions from a case-control study and identified regions that were not uniquely mappable. In the widely used 450K methylation array, 4,230 probes are not uniquely mappable. Genome mappability is higher with longer sequencing reads, but most publicly available ChIP-seq and reduced representation bisulfite sequencing datasets have shorter reads. Therefore, uneven and low mappability remains a concern in a majority of existing data.

Availability

A Umap and Bismap track hub for human genome assemblies GRCh37/hg19 and GRCh38/hg38, and mouse assemblies GRCm37/mm9 and GRCm38/mm10 is available athttp://bismap.hoffmanlab.orgfor use with the UCSC and Ensembl genome browsers. We have deposited in Zenodo the current version of our software (https://doi.org/10.5281/zenodo.800648) and the mappability data used in this project (https://doi.org/10.5281/zenodo.800645). In addition, the software (https://bitbucket.org/hoffmanlab/umap) is freely available under the GNU General Public License, version 3 (GPLv3).

Contact

michael.hoffman@utoronto.ca
Whole genome sequence accuracy is improved by replication in a population of mutagenized sorghum
Authors: Addo-Quaye Charles , Tuinstra Mitch , Carraro Nicola , Weil Clifford , Dilkes Brian P.
Published: December 2016

The accurate detection of induced mutations is critical for both forward and reverse genetics studies. Experimental chemical mutagenesis induces relatively few single base changes per individual. In a complex eukaryotic genome, false positive detection of mutations can occur at or above this mutagenesis rate. We demonstrate here, using a population of ethyl methanesulfonate (EMS) treatedSorghum bicolorBTx623 individuals, that using replication to detect false positive induced variants in next-generation sequencing data permits higher throughput variant detection with greater accuracy. We used a lower sequence coverage depth (average of 7X) from 586 independently mutagenized individuals and detected 5,399,493 homozygous SNPs. Of these, 76% originated from only 57,872 genomic positions prone to false positive variant calling. These positions are characterized by high copy number paralogs where the error-prone SNP positions are at copies containing a variant at the SNP position. The ability of short stretches of homology to generate these error prone positions suggests that incompletely assembled or poorly mapped repeated sequences are one driver of these error prone positions. Removal of these false positives left 1,275,872 homozygous and 477,531 heterozygous EMS-induced SNPs which, congruent with the mutagenic mechanism of EMS, were greater than 98% G:C to A:T transitions. Through this analysis we generated a database of sequence indexed mutants of Sorghum. This collection contains 4,035 high impact homozygous mutations in 3,637 genes and 56,514 homozygous missense mutations in 23,227 genes. Each line contains, on average, 2,177 annotated homozygous SNPs per genome, including seven likely gene knockouts and 96 missense mutations. The number of mutations in a transcript was linearly correlated with the transcript length and also the G+C count, but not with the GC/AT ratio. Analysis of the detected mutagenized positions identified CG-rich patches, and flanking sequences strongly influenced EMS-induced mutation rates. Our method for detecting false-positive induced mutations is generally applicable to any organism, is independent of the choice ofin silicovariant-calling algorithm, and is most valuable when the true mutation rate is likely to be low, such as in laboratory induced mutations or somatic mutation detection in medicine.
Gene fractionation and function in the ancient subgenomes of maize
Authors: Renny-Byfield Simon , Rodgers-Melnick Eli , Ross-Ibarra Jeffrey
Published: December 2016

The maize genome experienced an ancient whole genome duplication approximately 10 million years ago and the duplicate subgenomes have since experienced reciprocal gene loss (fractionation) such that many genes have returned to single-copy status. This process has not affected the subgenomes equally; reduced gene expression in one of the subgenomes mitigates the consequences of mutations and gene deletions and is thought to drive higher rates of fractionation. Here we take advantage of published genome-wide SNP and phenotype association data to show that, in accordance with predictions of this model, paralogs with greater expression contribute more to phenotypic variation compared to their lowly expressed counterparts. Furthermore, paralogous genes in the least-fractionated subgenome account for a greater degree of phenotypic diversity than those resident on the more-fractionated subgenome. We also show that the two subgenomes of maize are distinct in epigenetic characteristics. Intriguingly, analysis of singleton genes reveals that these differences persist even after fractionation is complete.
Myotome adaptability confers developmental robustness to somitic myogenesis in response to fibre number alteration
Authors: Roy Shukolpa D. , Williams Victoria C. , Pipalia Tapan G. , Li Kuoyu , Hammond Christina L. , Knappe Stefanie , Knight Robert D. , Hughes Simon M.
Published: December 2016

Summary Statement

Homeostatic interactions between muscle stem cells and fibres during myogenesis ensure the correct muscle size is formed independent of fibre number in zebrafish

Balancing the number of stem cells and their progeny is crucial for tissue development and repair. Here we examine how muscle stem/precursor cell (MPC) numbers are tightly regulated during zebrafish somitic muscle development. MPCs expressing Pax7 are initially located in the dermomyotome (DM) external cell layer, adopt a highly stereotypical distribution and thereafter a proportion of MPCs migrate into the myotome. Regional variations in the proliferation and terminal differentiation of MPCs contribute to growth of the myotome. To probe the robustness of spatiotemporal regulation of MPCs, we compared the behaviour of wild type (wt) MPCs with those in mutant zebrafish that lack the muscle regulatory factor Myod.Myodfh261mutants form one third fewer multinucleate fast muscle fibres than wt and show a significant expansion of the Pax7+MPC population in the DM. Subsequently,myodfh261mutant fibres generate more cytoplasm per nucleus, leading to recovery of muscle bulk. In addition, relative to wt siblings, there is an increased number of MPCs inmyodfh261mutants and these migrate prematurely into the myotome, differentiate and contribute to the hypertrophy of existing fibres. Thus, homeostatic reduction of the excess MPCs returns their number to normal levels, but fibre numbers remain low. The GSK3 antagonist BIO prevents MPC migration into the deep myotome, suggesting that canonical Wnt pathway activation maintains the DM in zebrafish, as in amniotes. BIO does not, however, block recovery of themyodfh261mutant myotome, indicating that homeostasis acts on fibre intrinsic growth to maintain muscle bulk. The findings suggest the existence of a critical window for early fast fibre formation followed by a period in which homeostatic mechanisms regulate myotome growth by controlling fibre size.
When null hypothesis significance testing is unsuitable for research: a reassessment
Authors: Szucs Denes , Ioannidis John PA
Published: December 2016

Null hypothesis significance testing (NHST) has several shortcomings that are likely contributing factors behind the widely debated replication crisis of psychology, cognitive neuroscience and biomedical science in general. We review these shortcomings and suggest that, after about 60 years of negative experience, NHST should no longer be the default, dominant statistical practice of all biomedical and psychological research. Different inferential methods (NHST, likelihood estimation, Bayesian methods, false-discovery rate control) may be most suitable for different types of research questions. Whenever researchers use NHST they should justify its use, and publish pre-study power calculations and effect sizes, including negative findings. Studies should optimally be pre-registered and raw data published. The current statistics lite educational approach for students that has sustained the widespread, spurious use of NHST should be phased out. Instead, we should encourage either more in-depth statistical training of more researchers and/or more widespread involvement of professional statisticians in all research.
Mitochondrial-nuclear interactions maintain geographic separation of deeply diverged mitochondrial lineages in the face of nuclear gene flow
Authors: Morales Hernán E. , Pavlova Alexandra , Amos Nevil , Major Richard , Kilian Andrzej , Greening Chris , Sunnucks Paul
Published: December 2016

Metabolic processes in eukaryotic cells depend on interactions between mitochondrial and nuclear gene products (mitonuclear interactions). These interactions could play a direct role in population divergence. We studied the evolution of mitonuclear interactions in a widespread passerine that experienced population divergence followed by bi-directional mitochondrial introgression into different nuclear backgrounds. Using >60,000 SNPs, we quantified patterns of nuclear genetic differentiation between populations that occupy different climates and harbour deeply divergent mitolineages despite ongoing nuclear gene flow. Analyses were performed independently for two sampling transects intersecting mitochondrial divergence in different nuclear backgrounds. In both transects, low genome-wide nuclear differentiation was accompanied by strong differentiation at a ~15.4 Mb region of chromosome 1A. This region is enriched for genes performing mitochondrial functions. Molecular signatures of selective sweeps in this region alongside those in the mitochondrial genome suggest a history of adaptive mitonuclear co-introgression. The chromosome 1A region has elevated linkage disequilibrium, suggesting that selection on genomic architecture may favour low recombination among nuclear-encoded genes with mitochondrial functions. In this system, mitonuclear interactions appear to maintain the geographic separation of two mitolineages in the face of nuclear gene flow, supporting mitonuclear co-evolution as an important vehicle for climatic adaptation and population divergence.
Partitioned Learning of Deep Boltzmann Machines for SNP Data
Authors: Hess Moritz , Lenz Stefan , Blätte Tamara J , Bullinger Lars , Binder Harald
Published: December 2016

Learning the joint distributions of measurements, and in particular identification of an appropriate low-dimensional manifold, has been found to be a powerful ingredient of deep leaning approaches. Yet, such approaches have hardly been applied to single nucleotide polymorphism (SNP) data, probably due to the high number of features typically exceeding the number of studied individuals. After a brief overview of how deep Boltzmann machines (DBMs), a deep learning approach, can be adapted to SNP data in principle, we specifically present a way to alleviate the dimensionality problem by partitioned learning. We propose a sparse regression approach to coarsely screen the joint distribution of SNPs, followed by training several DBMs on SNP partitions that were identified by the screening. Aggregate features representing SNP patterns and the corresponding SNPs are extracted from the DBMs by a combination of statistical tests and sparse regression. In simulated case-control data, we show how this can uncover complex SNP patterns and augment results from univariate approaches, while maintaining type 1 error control. Time-to-event endpoints are considered in an application with acute myeloid lymphoma patients, where SNP patterns are modeled after a pre-screening based on gene expression data. The proposed approach identified three SNPs that seem to jointly influence survival in a validation data set. This indicates the added value of jointly investigating SNPs compared to standard univariate analyses and makes partitioned learning of DBMs an interesting complementary approach when analyzing SNP data.
Population dynamics of synthetic Terraformation motifs
Authors: Solé Ricard V. , Montañez Raúl , Duran Nebreda Salvador , Rodriguez-Amor Daniel , Vidiella Blai , Sardanyés Josep
Published: December 2016

Ecosystems are complex systems, currently experiencing several threats associated with global warming, intensive exploitation, and human-driven habitat degradation. Such threats are pushing ecosystems to the brink of collapse. Because of a general presence of multiple stable states, including states involving population extinction, and due to intrinsic nonlinearities associated with feedback loops, collapse can occur in a catastrophic manner. Such catastrophic shifts have been suggested to pervade many of the future transitions affecting ecosystems at many different scales. Many studies have tried to delineate potential warning signals predicting such ongoing shifts but little is known about how such transitions might be effectively prevented. It has been recently suggested that a potential path to prevent or modify the outcome of these transitions would involve designing synthetic organisms and synthetic ecological interactions that could push these endangered systems out of the critical boundaries. Four classes of such ecological engineering designs orTerraformation motifshave been defined in a qualitative way. Here we develop the simplest mathematical models associated with these motifs, defining the expected stability conditions and domains where the motifs shall properly work.
Adversarial Deep Structural Networks for Mammographic Mass Segmentation
Authors: Zhu Wentao , Xie Xiaohui
Published: December 2016

Mass segmentation is an important task in mammogram analysis, providing effective morphological features and regions of interest (ROI) for mass detection and classification. Inspired by the success of using deep convolutional features for natural image analysis and conditional random fields (CRF) for structural learning, we propose an end-to-end network for mammographic mass segmentation. The network employs a fully convolutional network (FCN) to model potential function, followed by a CRF to perform structural learning. Because the mass distribution varies greatly with pixel position, the FCN is combined with position priori for the task. Due to the small size of mammogram datasets, we use adversarial training to control over-fitting. Four models with different convolutional kernels are further fused to improve the segmentation results. Experimental results on two public datasets, INbreast and DDSM-BCRP, show that our end-to-end network combined with adversarial training achieves the-state-of-the-art results.
AI-BL1.0: a program for automatic on-line beamline optimization using the evolutionary algorithm
Authors: Xi Shibo , Borgna Lucas Santiago , Zheng Lirong , Du Yonghua , Hu Tiandou
Published: December 2016

In this report, AI-BL1.0, an open-source Labview-based program for automatic on-line beamline optimization, is presented. The optimization algorithms used in the program are Genetic Algorithm and Differential Evolution. Efficiency was improved by use of a strategy known as Observer Mode for Evolutionary Algorithm. The program was constructed and validated at the XAFCA beamline of the Singapore Synchrotron Light Source and 1W1B beamline of the Beijing Synchrotron Radiation Facility.