bluuebunny/crossref_metadata_2025 huggingface dataset:
Monsoon oscillations regulate fertility of the Red Sea
Authors: Raitsos Dionysios E. , Yi Xing , Platt Trevor , Racault Marie‐Fanny , Brewin Robert J. W. , Pradhan Yaswant , Papadopoulos Vassilis P. , Sathyendranath Shubha , Hoteit Ibrahim
Published: January 2015

Tropical ocean ecosystems are predicted to become warmer, more saline, and less fertile in a future Earth. The Red Sea, one of the warmest and most saline environments in the world, may afford insights into the function of the tropical ocean ecosystem in a changing planet. We show that the concentration of chlorophyll and the duration of the phytoplankton growing season in the Red Sea are controlled by the strength of the winter Arabian monsoon (through horizontal advection of fertile waters from the Indian Ocean). Furthermore, and contrary to expectation, in the last decade (1998–2010) the winter Red Sea phytoplankton biomass has increased by 75% during prolonged positive phases of the Multivariate El Niño–Southern Oscillation Index. A new mechanism is reported, revealing the synergy of monsoon and climate in regulating Red Sea greenness.
Systematic averaging interval effects on solar wind statistics
Authors: Isaacs J. J. , Tessein J. A. , Matthaeus W. H.
Published: January 2015

The choice of interval of averaging in computing statistics of solar wind fluctuations is known to be a sensitive issue in which the need for adequate sampling statistics must be balanced with the complications of establishing an ensemble, given that the solar wind admits inhomogeneity, structure, and variability at its sources. Here we examine the quantitative dependence of interval of averaging (sample size) on estimates of basic statistics such as means, variances, and anisotropies of the measured interplanetary magnetic field.
Case studies of nonorographic gravity waves over the Southern Ocean emphasize the role of moisture
Authors: Plougonven Riwal , Hertzog Albert , Alexander M. Joan
Published: January 2015

Two case studies of nonorographic gravity waves are carried out for wave events that occurred over the Southern Ocean in November 2005. Mesoscale simulations were carried out with the Weather and Research Forecast model. The simulated waves were compared to observations from superpressure balloons of the Vorcore campaign and from the High Resolution Dynamic Limb Sounder satellite. Satisfactory agreement is found, giving confidence in the estimations of wave parameters and amplitudes. For the amplitudes, both the model and observations provide a lower bound, for different reasons. Waves are found in the lower stratosphere with horizontal wavelengths of the order of 150–200 km in the horizontal, 5–8 km in the vertical, corresponding to intrinsic frequencies between 5 and 10 f, where f is the Coriolis parameter. Although the tropospheric flow is very different between the two cases, there are features which are common and appear significant for the gravity waves: these include intense localized updrafts associated with convection in the troposphere and a displaced polar vortex inducing strong winds in the stratosphere above the frontal region. Relative to theoretical expectations, the simulations emphasize the role of moisture. Intrinsic frequencies are significantly higher than those expected for waves produced by dry spontaneous generation from jets. To quantify the contribution of moisture, dry simulations were carried out, yielding momentum fluxes over oceanic regions that were 2.5 times weaker. Identification of the generation mechanisms in these complex flows calls for further study, and these should include moisture and a realistic stratospheric jet.
Monitoring a convective winter episode of the Iberian Peninsula using a multichannel microwave radiometer
Authors: Gascón E. , Sánchez J. L. , Fernández‐González S. , Hermida L. , López L. , García‐Ortega E. , Merino A.
Published: January 2015

On 4 March 2011, a heavy snowfall episode affected the central Iberian Peninsula. Under the TECOAGUA Project (aimed at the study of winter cloud masses that produce snow in the Guadarrama Mountains near Madrid), measurements using a ground‐based multichannel microwave radiometer (MMWR) with vertical range 10 km recorded this episode of winter convection embedded within stratiform precipitation. In contrast to radiosondes, data retrieval from the MMWR has a clear advantage for identifying hazardous weather phenomena of short duration, such as winter convective episodes. From these continuous measurements, we analyzed the behavior of variables such as temperature, surface pressure, relative humidity, liquid water content, liquid water path, water vapor content, and integrated water vapor throughout the day. The continuous measurements also permitted construction of skew‐T log‐P profiles every 15 min during the convective episode, indicating vertical evolution of an event with an appearance similar to a “zipper” in which temperature and dew point temperature profiles are “closed” from the surface to 400 hPa and “reopen” at the end of the event. Finally, we selected six indices of stability most suitable for the study of winter convection, namely, the Showalter index, low‐topped convection index, most unstable lifted index, most unstable convective available potential energy (MUCAPE), convective inhibition, and MUCAPE level of free convection. Each of these indices has been evaluated for their capacity to warn of meteorological conditions leading to a convective heavy snowfall event.
The evolution of deep‐ocean flow speeds and δ13C under large changes in the Atlantic overturning circulation: Toward a more direct model‐data comparison
Authors: Bakker Pepijn , Govin Aline , Thornalley David J. R. , Roche Didier M. , Renssen Hans
Published: January 2015

To investigate the dynamics of the Atlantic meridional overturning circulation (AMOC) on timescales longer than the observational records, model‐data comparisons of past AMOC variability are imperative. However, this remains challenging because of dissimilarities between different proxy‐based AMOC tracers and the difficulty of comparing these to model output. We present an iLOVECLIM simulation with tuned AMOC evolution and focus on AMOC tracers that are directly comparable to reconstructions: flow speeds and δ13C. We deduce their driving factors and show that they yield different but complementary information about AMOC changes. Simulated flow speed changes are only linked to AMOC changes in regions bathed by North Atlantic Deep Water; however, in those regions they do provide details on vertical migration and thickness changes of the water masses. Simulated δ13C changes in the North Atlantic Deep Water region are again related to AMOC changes. Yet in regions bathed by Antarctic Bottom Water or Antarctic Intermediate Water, the δ13C evolution is driven by Southern Hemisphere source water δ13C changes, while in the Nordic Seas and the two major overflow regions it is driven by Northern Hemisphere source water δ13C changes. This shows that AMOC changes are not necessarily recorded by δ13C and stresses the need for combining both tracers in paleoclimate studies. A preliminary model‐data comparison for Last Interglacial flow speeds and δ13C changes in the Deep Western Boundary Current shows that this integrated approach is far from straightforward and currently inconclusive on the Last Interglacial AMOC evolution. Nonetheless, the approach yields potential for more direct and in‐depth model‐data comparisons of past AMOC changes.
Mammalian Embryo: Establishment of the Embryonic Axes
Authors: Srinivas Shankar
Published: January 2015

Owing to implantation and the requirement for extraembryonic tissues during mammalian embryogenesis, the development of the foetal axes is a relatively late event. Consequently, the definitive body axes of the organism are established in the founder tissue of the foetus well after polarised asymmetries have arisen in the conceptus. The anterior–posterior polarity of the organism has its origin in an extraembryonic tissue, the visceral endoderm, and there is evidence that the axes of the conceptus directly influence the orientation of the definitive body axes. Directional cell movements in the visceral endoderm help position the primitive streak, a structure that plays a key role in establishing the pattern of the primary body axis. Subsequently, asymmetries along the left–right axis are generated. As these are fundamental events that the remainder of embryonic development is predicated on, defects in these processes generally lead to embryos that fail to develop further.

Key Concepts

The mammalian embryo first generates structures and tissues that contribute to the placenta; therefore, there are various axes of asymmetry in the early conceptus that are not present in the final foetus.

There is a progressive increase in the degree of asymmetry in the pre‐implantation conceptus from an approximately spherically symmetrical zygote to radially symmetrical early blastocyst and finally bilaterally symmetrical late blastocyst.

The epiblast, which gives rise to the foetus, does not appear to have intrinsic axial information but receives axial patterning information from an extraembryonic tissue called the anterior visceral endoderm.

The anterior visceral endoderm defines the site of gastrulation by restricting the formation of the primitive streak in the epiblast.

The migratory movement of the anterior visceral endoderm is crucial to the proper orientation of the anterior–posterior axis.

A specialised structure called the node, located at the rostral end of the primitive streak, plays a central role not only in the organisation of the primary body axis but also in generating left–right asymmetries.
Anatomy and Morphology of Seed Plants
Authors: Barclay Gregor Fraser
Published: January 2015

Seed plants, the most successful and diverse group of higher plants, are distinguished from other plants by the presence of a testa (seed coat) that protects the embryo. Plant anatomy describes the structure and organisation of the cells, tissues and organs of plants, whereas plant morphology describes the external form and structure of plants. The origin of these fundamental botanical sciences is outlined, and illustrations and descriptions are given of the main anatomical and morphological features of plants, largely from a functional perspective. Meristematic, dermal, support and vascular tissues are described. Also, the fundamental organs, root, stem and leaf, as well as some of their notable modifications are described. Special attention is given to the flower and its modifications. Seed structure and dispersal mechanisms are described, and a key to identifying the common types of fruits is provided.

Key Concepts:

Seed plants are distinguished by the presence of a testa (seed coat) that encloses the embryo.

The morphology of a plant is largely unrelated to its anatomy.

Seed plants differ greatly in size and appearance, yet all are constructed of a few basic cell types, tissues and organs.

Plant organs can be modified to perform different functions.

Flowers are advertisements for attracting pollinators.
Muscle Strength and Changes in Physical Function in Women With Systemic Lupus Erythematosus
Authors: Andrews James S. , Trupin Laura , Schmajuk Gabriela , Barton Jennifer , Margaretten Mary , Yazdany Jinoos , Yelin Edward H. , Katz Patricia P.
Published: January 2015

Objective

Cross‐sectional studies have observed that muscle weakness is associated with worse physical function among women with systemic lupus erythematosus (SLE). The present study examines whether reduced upper and lower extremity muscle strength predict declines in function over time among adult women with SLE.

Methods

One hundred forty‐six women from a longitudinal SLE cohort participated in the study. All measures were collected during in‐person research visits approximately 2 years apart. Upper extremity muscle strength was assessed by grip strength. Lower extremity muscle strength was assessed by peak knee torque of extension and flexion. Physical function was assessed using the Short Physical Performance Battery (SPPB). Regression analyses modeled associations of baseline upper and lower extremity muscle strength with followup SPPB scores controlling for baseline SPPB, age, SLE duration, SLE disease activity (Systemic Lupus Activity Questionnaire), physical activity level, prednisone use, body composition, and depression. Secondary analyses tested whether associations of baseline muscle strength with followup in SPPB scores differed between intervals of varying baseline muscle strength.

Results

Lower extremity muscle strength strongly predicted changes over 2 years in physical function even when controlling for covariates. The association of reduced lower extremity muscle strength with reduced physical function in the future was greatest among the weakest women.

Conclusion

Reduced lower extremity muscle strength predicted clinically significant declines in physical function, especially among the weakest women. Future studies should test whether therapies that promote preservation of lower extremity muscle strength may prevent declines in function among women with SLE.
The Effect of Protein Fusions on the Production and Mechanical Properties of Protein‐Based Materials
Authors: Tsai Shang‐Pu , Howell David W. , Huang Zhao , Hsiao Hao‐Ching , Lu Yang , Matthews Kathleen S. , Lou Jun , Bondos Sarah E.
Published: January 2015

Proteins implement most of the vital molecular functions of living organisms, including structural support, energy generation, biomolecule sensing, and chemical catalysis, storage, and degradation. While capturing proteins in materials could create devices that mimic these functions, this process is challenging due to the sensitivity of protein structure to the chemical environment. Using recombinant DNA methods, specific functions can be incorporated by fusing the gene encoding a self‐assembling protein and the desired functional protein, to produce a single polypeptide that self‐assembles into functionalized materials. However, the functional protein has the potential to disrupt protein production, protein assembly, and/or the structure and mechanical properties of the resulting materials. 24 fusion proteins are created based on Ultrabithorax, a Drosophila transcription factor that self‐assembles into materials in vitro. The appended proteins dictate the solubility and purification yield of the corresponding protein fusions. Any loss of solubility and yield can be mitigated by fusing a third protein that is highly soluble. All protein fusions self‐assemble equally well to produce materials with similar morphologies. Fusing enhanced green fluorescent protein to Ultrabithorax influences mechanical properties of the resulting fibers. It is concluded that a far wider range of proteins can be successfully incorporated into elastomeric protein‐based materials than originally anticipated.
Conjugated Polymer Nanoparticles as Nano Floating Gate Electrets for High Performance Nonvolatile Organic Transistor Memory Devices
Authors: Shih Chien‐Chung , Chiu Yu‐Cheng , Lee Wen‐Ya , Chen Jung‐Yao , Chen Wen‐Chang
Published: January 2015

A molecular nano‐floating gate (NFG) of pentacene‐based transistor memory devices is developed using conjugated polymer nanoparticles (CPN) as the discrete trapping sites embedded in an insulating polymer, poly (methacrylic acid) (PMAA). The nanoparticles of polyfluorene (PF) and poly(fluorene‐alt‐benzo[2,1,3]thiadiazole (PFBT) with average diameters of around 50–70 nm are used as charge‐trapping sites, while hydrophilic PMAA serves as a matrix and a tunneling layer. By inserting PF nanoparticles as the floating gate, the transistor memory device reveals a controllable threshold voltage shift, indicating effectively electron‐trapping by the PF CPN. The electron‐storage capability can be further improved using the PFBT‐based NFG since their lower unoccupied molecular orbital level is beneficial for stabilization of the trapped charges, leading a large memory window (35 V), retention time longer than 104 s with a high ON/OFF ratio of >104. In addition, the memory device performance using conjugated polymer nanoparticle NFG is much higher than that of the corresponding polymer blend thin films of PF/polystyrene. It suggests that the discrete polymer nanoparticles can be effectively covered by the tunneling layer, PMAA, to achieve the superior memory characteristics.
Nanomaterial‐Enabled Stretchable Conductors: Strategies, Materials and Devices
Authors: Yao Shanshan , Zhu Yong
Published: January 2015

Stretchable electronics are attracting intensive attention due to their promising applications in many areas where electronic devices undergo large deformation and/or form intimate contact with curvilinear surfaces. On the other hand, a plethora of nanomaterials with outstanding properties have emerged over the past decades. The understanding of nanoscale phenomena, materials, and devices has progressed to a point where substantial strides in nanomaterial‐enabled applications become realistic. This review summarizes recent advances in one such application, nanomaterial‐enabled stretchable conductors (one of the most important components for stretchable electronics) and related stretchable devices (e.g., capacitive sensors, supercapacitors and electroactive polymer actuators), over the past five years. Focusing on bottom‐up synthesized carbon nanomaterials (e.g., carbon nanotubes and graphene) and metal nanomaterials (e.g., metal nanowires and nanoparticles), this review provides fundamental insights into the strategies for developing nanomaterial‐enabled highly conductive and stretchable conductors. Finally, some of the challenges and important directions in the area of nanomaterial‐enabled stretchable conductors and devices are discussed.
Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations
Authors: Baulac Stéphanie , Ishida Saeko , Marsan Elise , Miquel Catherine , Biraben Arnaud , Nguyen Dang Khoa , Nordli Doug , Cossette Patrick , Nguyen Sylvie , Lambrecq Virginie , Vlaicu Mihaela , Daniau Maïlys , Bielle Franck , Andermann Eva , Andermann Frederick , Leguern Eric , Chassoux Francine , Picard Fabienne
Published: January 2015

Objective

The DEPDC5 (DEP domain‐containing protein 5) gene, encoding a repressor of the mTORC1 signaling pathway, has recently emerged as a major gene mutated in familial focal epilepsies. We aimed to further extend the role of DEPDC5 to focal cortical dysplasias (FCDs).

Methods

Seven patients from 4 families with DEPDC5 mutations and focal epilepsy associated with FCD were recruited and investigated at the clinical, neuroimaging, and histopathological levels. The DEPDC5 gene was sequenced from genomic blood and brain DNA.

Results

All patients had drug‐resistant focal epilepsy, 5 of them underwent surgery, and 1 had a brain biopsy. Electroclinical phenotypes were compatible with FCD II, although magnetic resonance imaging (MRI) was typical in only 4 cases. Histopathology confirmed FCD IIa in 2 patients (including 1 MRI‐negative case) and showed FCD I in 2 other patients, and remained inconclusive in the last 2 patients. Three patients were seizure‐free postsurgically, and 1 had a worthwhile improvement. Sequencing of blood DNA revealed truncating DEPDC5 mutations in all 4 families; 1 mutation was found to be mosaic in an asymptomatic father. A brain somatic DEPDC5 mutation was identified in 1 patient in addition to the germline mutation.

Interpretation

Germline, germline mosaic, and brain somatic DEPDC5 mutations may cause epilepsy associated with FCD, reinforcing the link between mTORC1 pathway and FCDs. Similarly to other mTORopathies, a “2‐hit” mutational model could be responsible for cortical lesions. Our study also indicates that epilepsy surgery is a valuable alternative in the treatment of drug‐resistant DEPDC5‐positive focal epilepsies, even if the MRI is unremarkable. Ann Neurol 2015;77:675–683
APOEε2 is associated with milder clinical and pathological Alzheimer disease
Authors: Serrano‐Pozo Alberto , Qian Jing , Monsell Sarah E. , Betensky Rebecca A. , Hyman Bradley T.
Published: January 2015

Objective

The Alzheimer disease (AD) APOEε4 risk allele associates with an earlier age at onset and increased amyloid‐β deposition, whereas the protective APOEε2 allele delays the onset and appears to prevent amyloid‐β deposition. Yet the clinical and pathological effects of APOEε2 remain uncertain because of its relative rarity. We investigated the effects of APOEε2 and ε4 alleles on AD pathology and cognition in a large US data set of well‐characterized AD patients.

Methods

We studied individuals from the National Alzheimer's Coordinating Center autopsy cohort across the entire clinicopathological continuum of AD. Multivariate models were built to examine the associations between APOE alleles and AD neuropathological changes, using the APOEε3/ε3 group as comparator. Mediation analysis was used to estimate the direct and indirect effects of APOE alleles on AD pathology and cognition (Clinical Dementia Rating Sum of Boxes and Mini‐Mental State Examination).

Results

Compared to APOEε3/ε3, APOEε2 is independently associated with lower Braak neurofibrillary tangle (NFT) stages and possibly fewer neuritic plaques, but has no direct effect on cerebral amyloid angiopathy (CAA) severity, whereas APOEε4 is associated with more neuritic plaques and CAA, but has no independent effect on Braak NFT stage. Unadjusted analyses showed marked differences among APOE genotypes with respect to cognitive performance (ε2 > ε3 > ε4). Mediation analysis suggests that this is largely explained through effects on pathology.

Interpretation

Even when adjusted for age at onset, symptom duration, and other demographic variables, APOEε2 is associated with milder AD pathology and less severe antemortem cognitive impairment compared to APOEε3 and ε4 alleles, suggesting a relative neuroprotective effect of APOEε2 in AD. Ann Neurol 2015;77:917–929
Strokes in Sneddon syndrome without antiphospholipid antibodies
Authors: Bottin Laure , Francès Camille , de Zuttere Dominique , Boëlle Pierre‐Yves , Muresan Ioan‐Paul , Alamowitch Sonia
Published: January 2015

Objective

Sneddon syndrome (SS) is characterized by the association of a livedo reticularis with stroke. Clinicoradiological features of its neurological manifestations, its prognosis, and the frequency of associated cardiac valvulopathy remain poorly known, particularly in the absence of antiphospholipid antibodies (APL). The objectives were to assess the clinicoradiological pattern of SS without APL (SSAPL−) and its midterm prognosis.

Methods

Clinical data, transthoracic echocardiograms, and brain imaging of 53 consecutive patients (83% women) with SSAPL−, followed up at our institution between 1991 and 2011, were reviewed.

Results

Seventy‐four strokes were reported; 76% were ischemic strokes (IS), 15% transient ischemic attacks, and 9% hemorrhagic strokes. Heart valve lesions were found in 50% of the cases. Brain imaging showed 177 IS of 3 different types: large territorial (43%), small distal corticosubcortical (14%), and small deep (23%) IS. No significant association was found between the valve involvement and the presence of territorial IS. After a mean follow‐up of 7.4 years, 82% of patients had a modified Rankin Scale score ≤ 2. The ischemic event recurrence rate was 20%, with a similar annual rate in the antiplatelet group (3%) compared to the anticoagulation group (2.7%).

Interpretation

SSAPL− is not only a neurocutaneous disorder, but is frequently associated with heart valve involvement. The latter does not influence the IS type, which suggests that strokes are caused by vasculopathy of the small and medium‐size cerebral arteries. Our results show no progression toward a serious disability in the majority of the cases and a moderate recurrence rate under antiplatelet therapy. Ann Neurol 2015;77:817–829
Structures and conformation of a benzo‐12‐crown‐4 containing dipeptide
Authors: Tripathi Garima , Ramanathan Gurunath
Published: January 2015

Crystal structures of the dipeptide Boc‐12‐Crown‐4‐l‐DOPA‐Gly‐OMe (chi) and Boc‐12‐Crown‐4‐d/l‐DOPA‐Gly‐OMe (rac) were solved by single crystal X‐ray diffraction. Analysis of the packing differences in the crystal reveals that the presence of a water molecule inchienables intermolecular contacts with the solvent that result in a different conformation of the dipeptide backbone itself. An uncommon NH…N interaction stabilizes the peptide in its solid state. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 104: 148–155, 2015.
Impact of surgical innovation on tissue repair in the surgical patient
Authors: Tevlin R , Atashroo D , Duscher D , Mc Ardle A , Gurtner G C , Wan D C , Longaker M T
Published: January 2015

Background

Throughout history, surgeons have been prolific innovators, which is hardly surprising as most surgeons innovate daily, tailoring their intervention to the intrinsic uniqueness of each operation, each patient and each disease. Innovation can be defined as the application of better solutions that meet new requirements, unarticulated needs or existing market needs. In the past two decades, surgical innovation has significantly improved patient outcomes, complication rates and length of hospital stay. There is one key area that has great potential to change the face of surgical practice and which is still in its infancy: the realm of regenerative medicine and tissue engineering.

Methods

A literature review was performed using PubMed; peer-reviewed publications were screened for relevance in order to identify key surgical innovations influencing regenerative medicine, with a focus on osseous, cutaneous and soft tissue reconstruction.

Results

This review describes recent advances in regenerative medicine, documenting key innovations in osseous, cutaneous and soft tissue regeneration that have brought regenerative medicine to the forefront of the surgical imagination.

Conclusion

Surgical innovation in the emerging field of regenerative medicine has the ability to make a major impact on surgery on a daily basis.
Quantitative analysis of technological innovation in minimally invasive surgery
Authors: Hughes-Hallett A , Mayer E K , Pratt P J , Vale J A , Darzi A W
Published: January 2015

Background

In the past 30 years surgical practice has changed considerably owing to the advent of minimally invasive surgery (MIS). This paper investigates the changing surgical landscape chronologically and quantitatively, examining the technologies that have played, and are forecast to play, the largest part in this shift in surgical practice.

Methods

Electronic patent and publication databases were searched over the interval 1980–2011 for (‘minimally invasive’ OR laparoscopic OR laparoscopy OR ‘minimal access’ OR ‘key hole’) AND (surgery OR surgical OR surgeon). The resulting patent codes were allocated into technology clusters. Technology clusters referred to repeatedly in the contemporary surgical literature were also included in the analysis. Growth curves of patents and publications for the resulting technology clusters were then plotted.

Results

The initial search revealed 27 920 patents and 95 420 publications meeting the search criteria. The clusters meeting the criteria for in-depth analysis were: instruments, image guidance, surgical robotics, sutures, single-incision laparoscopic surgery (SILS) and natural-orifice transluminal endoscopic surgery (NOTES). Three patterns of growth were observed among these technology clusters: an S-shape (instruments and sutures), a gradual exponential rise (surgical robotics and image guidance), and a rapid contemporaneous exponential rise (NOTES and SILS).

Conclusion

Technological innovation in MIS has been largely stagnant since its initial inception nearly 30 years ago, with few novel technologies emerging. The present study adds objective data to the previous claims that SILS, a surgical technique currently adopted by very few, represents an important part of the future of MIS.
The rise of big clinical databases
Authors: Cook J A , Collins G S
Published: January 2015

Background

The routine collection of large amounts of clinical data, ‘big data’, is becoming more common, as are research studies that make use of these data source. The aim of this paper is to provide an overview of the uses of data from large multi-institution clinical databases for research.

Methods

This article considers the potential benefits, the types of data source, and the use to which the data is put. Additionally, the main challenges associated with using these data sources for research purposes are considered.

Results

Common uses of the data include: providing population characteristics; identifying risk factors and developing prediction (diagnostic or prognostic) models; observational studies comparing different interventions; exploring variation between healthcare providers; and as a supplementary source of data for another study. The main advantages of using such big data sources are their comprehensive nature, the relatively large number of patients they comprise, and the ability to compare healthcare providers. The main challenges are demonstrating data quality and confidently applying a causal interpretation to the study findings.

Conclusion

Large clinical database research studies are becoming ubiquitous and offer a number of potential benefits. However, the limitations of such data sources must not be overlooked; each research study needs to be considered carefully in its own right, together with the justification for using the data for that specific purpose.
Surgical innovation
Authors: Dejong C H C , Earnshaw J J
Published: January 2015

More necessary than ever
Of Stewards and Stakeholders: Getting the Government Ownership Question Right
Authors: Buckwalter Neal
Published: January 2015

Neal Buckwalter, PhD, assistant professor in the School of Public, Nonprofit & Health Administration at Grand Valley State University (Grand Rapids, MI, USA) shares with us some of the insights from his research on examining the interplay between administrative and democratic institutions, including the impacts of administrative decisions on public perceptions of governance structures.
Clinical outcomes associated with evolving treatment modalities and radiation techniques for base‐of‐tongue carcinoma: thirty years of institutional experience
Authors: Chen Leechuan Andy , Anker Christopher J. , Hunt Jason P. , Buchmann Luke O. , Grossmann Kenneth F. , Boucher Kenneth , Fang Li‐Ming Christine , Shrieve Dennis C. , Hitchcock Ying J.
Published: January 2015

Curative treatment for base‐of‐tongue squamous cell carcinoma (BOT SCC) has evolved over time; however, comparative outcomes analysis for various treatment strategies is lacking. The authors reviewed the evolution of treatment modality and radiotherapy (RT) technique for 231 consecutive BOT SCC patients at our institution between 1981 and 2011. Treatment modalities included definitive chemoradiotherapy (chemoRT) (42%), definitive RT (33%), surgery followed by RT (20%), and surgery alone (5%). RT techniques included external beam plus interstitial brachytherapy (EBRT + IB) (37%), conventional EBRT (29%), intensity‐modulated radiation therapy ± simultaneous integrated boost (IMRT ± SIB) (34%). Clinical characteristics and outcomes were stratified by modality or RT technique. Treatment modality evolved from definitive RT (1980s–1990s) to definitive chemoRT (1990s–2000s). RT technique evolved from EBRT + IB (1980s–1990s) to conventional EBRT (1990s–2000s) to IMRT + SIB (2000s). With median alive follow‐up of 6 years (0.3–28 years), the 5‐year LC, LRC, and OS rates were 80%, 73%, and 51%. There was no difference in distribution of gender, age, stage among treatment modalities. Definitive chemoRT had improved LRC (HR 1.6) and OS (HR 1.7) compared to definitive RT. IMRT + SIB had improved LRC (HR 3.2), DFS (HR 3.4), and OS (HR 3.0) compared to conventional EBRT. Over the past 30 years, BOT SCC treatment has undergone major paradigm shifts that incorporate nonsurgical functional preservation, concurrent chemotherapy, and advanced RT techniques. Excellent locoregional control and survival outcomes are associated with accelerated IMRT with chemotherapy.
Differences in IGF‐axis protein expression and survival among multiethnic breast cancer patients
Authors: Hernandez Brenda Y. , Wilkens Lynne R. , Le Marchand Loïc , Horio David , Chong Clayton D. , Loo Lenora W. M.
Published: January 2015

There is limited knowledge about the biological basis of racial/ethnic disparities in breast cancer outcomes. Aberrations in IGF signaling induced by obesity and other factors may contribute to these disparities. This study examines the expression profiles of the insulin‐like growth factor (IGF)‐axis proteins and the association with breast cancer survival across a multiethnic population. We examined the expression profiles of the IGF1, IGF1R, IGFBP2 (IGF‐binding proteins), and IGFBP3 proteins in breast tumor tissue and their relationships with all‐cause and breast cancer‐specific survival up to 17 years postdiagnosis in a multiethnic series of 358 patients in Hawaii, USA. Native Hawaiians, Caucasians, and Japanese were compared. Covariates included demographic and clinical factors and ER/PR/HER2 (estrogen receptor/progesterone receptor/human epidermal growth factor receptor‐2) status. In Native Hawaiian patients, IGFBP2 and IGFBP3 expression were each independently associated with overall and breast cancer mortality (IGFB2: HRmort = 10.96, 95% CI: 2.18–55.19 and HRmort = 35.75, 95% CI: 3.64–350.95, respectively; IGFBP3: HRmort = 5.16, 95% CI: 1.27–20.94 and HRmort = 8.60, 95% CI: 1.84–40.15, respectively). IGF1R expression was also positively associated with all‐cause mortality in Native Hawaiians. No association of IGF‐axis protein expression and survival was observed in Japanese or Caucasian patients. The interaction of race/ethnicity and IGFBP3 expression on mortality risk was significant. IGF‐axis proteins may have variable influence on breast cancer progression across different racial/ethnic groups. Expression of binding proteins and receptors in breast tumors may influence survival in breast cancer patients by inducing aberrations in IGF signaling and/or through IGF‐independent mechanisms. Additional studies to evaluate the role of the IGF‐axis in breast cancer are critical to improve targeted breast cancer treatment strategies.
Development and validation of the functional assessment of cancer therapy–antiangiogenesis subscale
Authors: Kaiser Karen , Beaumont Jennifer L. , Webster Kimberly , Yount Susan E. , Wagner Lynne I. , Kuzel Timothy M. , Cella David
Published: January 2015

The Functional Assessment of Cancer Therapy (FACT)–Antiangiogenesis (AntiA) Subscale was developed and validated to enhance treatment decision‐making and side effect management for patients receiving anti‐angiogenesis therapies. Side effects related to anti‐angiogenesis therapies were identified from the literature, clinician input, and patient input. Fifty‐nine possible patient expressions of side effects were generated. Patient and clinician ratings of the importance of these expressions led us to develop a 24‐item questionnaire with clinical and research potential. To assess the scale's reliability and validity, 167 patients completed the AntiA Subscale, the Functional Assessment of Cancer Therapy‐general (FACT‐G), the FACT‐Kidney Symptom Index (FKSI), the FACIT‐Fatigue Subscale, the Global Rating of Change Scale (GRC), and the PROMIS Global Health Scale. Patient responses to the AntiA were analyzed for internal consistency, test–retest reliability, convergent and discriminant validity, and responsiveness to change in clinical status. All tested scales were found to have good internal consistency reliability (Cronbach's alpha 0.70–0.92). Test–retest reliability was also good (0.72–0.88) for total and subscale scores and lower for individual items. The total score, subscale scores, and all single items (except nosebleeds) significantly differentiated between groups defined by level of side effect bother. Evaluation of responsiveness to change in this study was not conclusive, suggesting an area for further research. The AntiA is a reliable and valid measure of side effects from anti‐angiogenesis therapy.
S‐adenosylmethionine blocks osteosarcoma cells proliferation and invasion in vitro and tumor metastasis in vivo: therapeutic and diagnostic clinical applications
Authors: Parashar Surabhi , Cheishvili David , Arakelian Ani , Hussain Zahid , Tanvir Imrana , Khan Haseeb Ahmed , Szyf Moshe , Rabbani Shafaat A.
Published: January 2015

Osteosarcoma (OS) is an aggressive and highly metastatic form of primary bone cancer affecting young children and adults. Previous studies have shown that hypomethylation of critical genes is driving metastasis. Here, we examine whether hypermethylation treatment can block OS growth and pulmonary metastasis. Human OS cells LM‐7 and MG‐63 were treated with the ubiquitous methyl donor S‐adenosylmethionine (SAM) or its inactive analog S‐adenosylhomocystine (SAH) as control. Treatment with SAM resulted in a dose‐dependent inhibition of tumor cell proliferation, invasion, cell migration, and cell cycle characteristics. Inoculation of cells treated with 150 μmol/L SAM for 6 days into tibia or via intravenous route into Fox Chase severe combined immune deficient (SCID) mice resulted in the development of significantly smaller skeletal lesions and a marked reduction in pulmonary metastasis as compared to control groups. Epigenome wide association studies (EWAS) showed differential methylation of several genes involved in OS progression and prominent signaling pathways implicated in bone formation, wound healing, and tumor progression in SAM‐treated LM‐7 cells. Real‐time polymerase chain reaction (qPCR) analysis confirmed that SAM treatment blocked the expression of several prometastatic genes and additional genes identified by EWAS analysis. Immunohistochemical analysis of normal human bone and tissue array from OS patients showed significantly high levels of expression of one of the identified gene platelet‐derived growth factor alpha (PDGFA). These studies provide a possible mechanism for the role of DNA demethylation in the development and metastasis of OS to provide a rationale for the use of hypermethylation therapy for OS patients and identify new targets for monitoring OS development and progression.
Using topical imiquimod for the management of positive in situ margins after melanoma resection
Authors: Pandit Amrita S. , Geiger Erik J. , Ariyan Stephan , Narayan Deepak , Choi Jennifer Nam
Published: January 2015

The treatment of melanoma in situ (MIS) is controversial with current standard of care being surgical excision with clear margins. Alternative topical therapy with imiquimod has been proposed in recent studies as a possible treatment for MIS. This study aimed to evaluate the use of topical 5% imiquimod as an alternative approach for the treatment of residual melanoma in situ after surgical resection of the primary lesion. A retrospective chart review of all patients treated with topical 5% imiquimod for residual MIS following standard resection with 5–10 mm margins at Yale‐New Haven Hospital from 2008 through 2013 was performed. The pre‐ and posttreatment results were confirmed by diagnostic tissue biopsy. Twenty‐two patients were included in the study. One of these 22 patients was lost to follow up. Twenty patients (95%) had complete resolution of their residual MIS and 1 patient did not respond to imiquimod (5%). No reports of recurrences were noted at the treatment sites. For patients with residual melanoma in situ after the initial excision, topical 5% imiquimod appears to be a reasonable alternative treatment with good clinical and histopathologic success rates.
Sonic hedgehog from pharyngeal arch 1 epithelium is necessary for early mandibular arch cell survival and later cartilage condensation differentiation
Authors: Billmyre Katherine Kretovich , Klingensmith John
Published: January 2015

Background: Morphogenesis of vertebrate craniofacial skeletal elements is dependent on a key cell population, the cranial neural crest cells (NCC). Cranial NCC are formed dorsally in the cranial neural tube and migrate ventrally to form craniofacial skeletal elements as well as other tissues. Multiple extracellular signaling pathways regulate the migration, survival, proliferation, and differentiation of NCC. Results: In this study, we demonstrate that Shh expression in the oral ectoderm and pharyngeal endoderm is essential for mandibular development. We show that a loss of Shh in these domains results in increased mesenchymal cell death in pharyngeal arch 1 (PA1) after NCC migration. This increased cell death can be rescued in utero by pharmacological inhibition of p53. Furthermore, we show that epithelial SHH is necessary for the early differentiation of mandibular cartilage condensations and, therefore, the subsequent development of Meckel's cartilage, around which the dentary bone forms. Nonetheless, a rescue of the cell death phenotype does not rescue the defect in cartilage condensation formation. Conclusions: Our results show that SHH produced by the PA1 epithelium is necessary for the survival of post‐migratory NCC, and suggests a key role in the subsequent differentiation of chondrocytes to form Meckel's cartilage. Developmental Dynamics 244:564–576, 2015. © 2015 Wiley Periodicals, Inc.
Morphological Awareness and Its Role in Compensation in Adults with Dyslexia
Authors: Law Jeremy M. , Wouters Jan , Ghesquière Pol
Published: January 2015

This study examines the role of morphological awareness (MA) in literacy achievement and compensation in word reading of adults with dyslexia through an exploration of three questions: (1) Do adult dyslexics demonstrate a deficit in MA, and how is this potential deficit related to phonological awareness (PA)? (2) Does MA contribute independently to literacy skills equally in dyslexics and control readers? and (3) Do MA and PA skills differ in compensated and noncompensated dyslexics?

A group of dyslexic and normal reading university students matched for age, education and IQ participated in this study. Group analysis demonstrated an MA deficit in dyslexics; as well, MA was found to significantly predict a greater proportion of word reading and spelling within the dyslexic group compared with the controls. Compensated dyslexics were also found to perform significantly better on the morphological task than noncompensated dyslexics. Additionally, no statistical difference was observed in MA between the normal reading controls and the compensated group (independent of PA and vocabulary).

Results suggest that intact and strong MA skills contribute to the achieved compensation of this group of adults with dyslexia. Implications for MA based intervention strategies for people with dyslexia are discussed. Copyright © 2015 John Wiley & Sons, Ltd.
Phylogenetic and morphological relationships between nonvolant small mammals reveal assembly processes at different spatial scales
Authors: Luza André Luís , Gonçalves Gislene Lopes , Hartz Sandra Maria
Published: January 2015

The relative roles of historical processes, environmental filtering, and ecological interactions in the organization of species assemblages vary depending on the spatial scale. We evaluated the phylogenetic and morphological relationships between species and individuals (i.e., inter‐ and intraspecific variability) of Neotropical nonvolant small mammals coexisting in grassland‐forest ecotones, in landscapes and in regions, that is, three different scales. We used a phylogenetic tree to infer evolutionary relationships, and morphological traits as indicators of performance and niche similarities between species and individuals. Subsequently, we applied phylogenetic and morphologic indexes of diversity and distance between species to evaluate small mammal assemblage structures on the three scales. The results indicated a repulsion pattern near forest edges, showing that phylogenetically similar species coexisted less often than expected by chance. The strategies for niche differentiation might explain the phylogenetic repulsion observed at the edge. Phylogenetic and morphological clustering in the grassland and at the forest interior indicated the coexistence of closely related and ecologically similar species and individuals. Coexistence patterns were similar whether species‐trait values or individual values were used. At the landscape and regional scales, assemblages showed a predominant pattern of phylogenetic and morphological clustering. Environmental filters influenced the coexistence patterns at three scales, showing the importance of phylogenetically conserved ecological tolerances in enabling taxa co‐occurrence. Evidence of phylogenetic repulsion in one region indicated that other processes beyond environmental filtering are important for community assembly at broad scales. Finally, ecological interactions and environmental filtering seemed important at the local scale, while environmental filtering and historical colonization seemed important for community assembly at broader scales.
Thymocyte‐derived BDNF influences T‐cell maturation at the DN3/DN4 transition stage
Authors: Linker Ralf A. , Lee De‐Hyung , Flach Anne‐Christine , Litke Tanja , van den Brandt Jens , Reichardt Holger M. , Lingner Thomas , Bommhardt Ursula , Sendtner Michael , Gold Ralf , Flügel Alexander , Lühder Fred
Published: January 2015

Brain‐derived neurotrophic factor (BDNF) promotes neuronal survival, regeneration, and plasticity. Emerging evidence also indicates an essential role for BDNF outside the nervous system, for instance in immune cells. We therefore investigated the impact of BDNF on T cells using BDNF knockout (KO) mice and conditional KO mice lacking BDNF specifically in this lymphoid subset. In both settings, we observed diminished T‐cell cellularity in peripheral lymphoid organs and an increase in CD4+CD44+ memory T cells. Analysis of thymocyte development revealed diminished total thymocyte numbers, accompanied by a significant increase in CD4/CD8 double‐negative (DN) thymocytes due to a partial block in the transition from the DN3 to the DN4 stage. This was neither due to increased thymocyte apoptosis nor defects in the expression of the TCR‐β chain or the pre‐TCR. In contrast, pERK but not pAKT levels were diminished in DN3 BDNF‐deficient thymocytes. BDNF deficiency in T cells did not result in gross deficits in peripheral acute immune responses nor in changes of the homeostatic proliferation of peripheral T cells. Taken together, our data reveal a critical autocrine and/or paracrine role of T‐cell‐derived BDNF in thymocyte maturation involving ERK‐mediated TCR signaling pathways.
Copper‐Catalysed Alkylarylation of Activated Alkenes Using AIBN and Beyond: An Access to Cyano‐Containing Oxindoles
Authors: Zhou Dong , Li Zi‐Hao , Li Jie , Li Shu‐Hua , Wang Ming‐Wei , Luo Xiao‐Ling , Ding Guo‐Liang , Sheng Rui‐Long , Fu Mei‐Jun , Tang Shi
Published: January 2015

A practical copper‐catalysed oxidative radical alkylarylation of activated alkenes using AIBN (azobisisobutyronitrile) and related reagents has been developed. This has allowed the general incorporation of nitrile moieties into oxindoles by a cascade addition/C(sp2)–H cyclization process. This protocol demonstrates for the first time that DIAD (diisopropyl azodicarboxylate) can act as a new activator for the C(sp3)–H functionalization of acetonitrile instead of the usual Ag salts. The use of an inexpensive copper salt as the catalyst, the general access to primary and tertiary nitriles, as well as the air‐ and moisture‐tolerant reaction conditions make this protocol a highly attractive approach to cyano‐containing oxindoles.