bluuebunny/crossref_metadata_2025 huggingface dataset:
The Social Impact of Trade and Migration
Authors: Boozer Anna Lucille
Published: December 2015

Egypt’s Western Desert is located on the fringes of Egypt proper. Despite its remote location, the Western Desert inhabitants connected with people in the Nile Valley and more distant locations. These connections are visible in the form of trade, technology, and migration. In order to understand the impact of this connection with other regions upon local oasites, this article offers a critique of current theories on migration and consumption before reviewing the evidence of such connections chronologically. The available evidence suggests that the Old Kingdom, the New Kingdom, the Perisan Period, and the Roman Period may have been particularly prominent periods of connectivity for the Western Desert. This evidence also suggests strong connections to Thebes throughout most of the history of the Western Desert. Since formal research in the Western Desert is relatively recent, it is anticipated that the current image of Western Desert connections will change in future years.
Ihahamuka
Authors: Taylor Christopher C.
Published: December 2015

One of the core metaphors in Rwandan traditional medicine concerns the flow of bodily fluids. This metaphor is a recursive one, extending into other domains of Rwandan symbolic thought, including notions of the person, ritual, and myth. Stated briefly, this metaphor opposes states of orderly flows to disorderly ones, including blocked flows and excessive flows. The healthy body is characterized by sufficient but not excessive or inadequate bodily flows. Unhealthy or afflicted bodies are often characterized by disorders in “flow” states. After the genocide, many Tutsi victims experienced post-traumatic stress in the form of a specifically Rwandan symptom that they termed ihahamuka. This symptom, as described by Rwandans, involves the blockage of breath in the lungs. Many Rwandans who had suffered extreme trauma during the genocide, but had managed to survive, complained of ihahamuka. Many were highly “Westernized” in terms of their education and religion but were experiencing a disorder that can only be fully understood via traditional Rwandan medicine, a medicine in which they expressed very little credence.
Valuing Wild Nature
Authors: Cafaro Philip
Published: December 2015

Preserving wild nature has been an important goal of the conservation and environmental movements throughout their existence. The reasons given for preserving wild species and wild places sometimes focus on the benefits to human beings and sometimes on the intrinsic value of wild things themselves. In either case, more or less emphasis may be given to wildness per se as a direct value-conferring property. Though nature lovers have won many battles, overall we are losing the war to preserve the wild. Little wild nature will remain a century from now unless humanity consciously and forcefully commits to limiting our numbers and our economic demands on the biosphere. For those who place a high value on wild nature, creating societies that preserve wildness on the landscape remains a key, ineliminable component of a proper environmentalism.
A History of Environmental Ethics
Authors: Kawall Jason
Published: December 2015

This chapter presents a history of environmental ethics as a distinct academic field, from its early origins in the 1960s to recent, contemporary work. It focuses on the key movements and theories that have shaped—and continue to shape—the development of the field, while noting how these have changed and evolved over time. In addition, while tracing the history of these movements, the chapter attempts to present some of the central issues and topics that have garnered particular attention within the field. Finally, it closes with some tentative thoughts on promising paths for environmental ethicists to explore as our field continues to develop and mature.
Anthropocentrism
Authors: Thompson Allen
Published: December 2015

Exclusive moral concern for human beings is often thought to be the ideological source of many contemporary environmental problems. So the development of a non-anthropocentric theory of intrinsic moral value, according to which at least some parts of the non-human world are morally considerable for their own sake, is often thought to be a defining characteristic of a satisfying environmental ethic. This chapter unpacks three distinct forms of anthropocentrism, outlines three versions of ethical nonanthropocentrism, and sketches some of the debate between anthropocentrists and nonanthropocentrists before concluding that a virtue-theoretic approach to human natural goodness exemplifies one form of anthropocentrism that may continue to play a vital role in developing an environmental ethic suitable to the Anthropocene.
In Pursuit of Meaningful Use of Learning Goals in Residency: A Qualitative Study of Pediatric Residents
Authors: Lockspeiser Tai M. , Li Su-Ting T. , Burke Ann E. , Rosenberg Adam A. , Dunbar Alston E. , Gifford Kimberly A. , Gorman Gregory H. , Mahan John D. , McKenna Michael P. , Reed Suzanne , Schwartz Alan , Harris Ilene , Hanson Janice L.
Published: December 2015

Purpose

Medical education aims to equip physicians for lifelong learning, an objective supported by the conceptual framework of self-regulated learning (SRL). Learning goals have been used to develop SRL skills in learners across the medical education continuum. This study’s purpose was to elicit residents’ perspectives on learning goal use and to develop explanations suggesting how aspects of the learning environment may facilitate or hinder the meaningful use of learning goals in residency.

Method

Resident focus groups and program director interviews were conducted in 2012–2013, audio-recorded, and transcribed. Programs were selected to maximize diversity of size, geographic location, type of program, and current use of learning goals. Data were analyzed using the constant comparative method associated with grounded theory. Further analysis compared themes frequently occurring together to strengthen the understanding of relationships between the themes. Through iterative discussions, investigators built a grounded theory.

Results

Ninety-five third-year residents and 12 program directors at 12 pediatric residency programs participated. The analysis identified 21 subthemes grouped into 5 themes: program support, faculty roles, goal characteristics and purposes, resident attributes, and accountability and goal follow-through. Review of relationships between the themes revealed a pyramid of support with program support as the foundation that facilitates the layers above it, leading to goal follow-through.

Conclusions

Program support facilitates each step of the SRL process that leads to meaningful use of learning goals in residency. A strong foundation of program support should include attention to aspects of the implicit curriculum as well as the explicit curriculum.
Everyday Executive Functioning in Chronic Pain
Authors: Baker Katharine S. , Gibson Stephen , Georgiou-Karistianis Nellie , Roth Robert M. , Giummarra Melita J.
Published: December 2015

Objectives:

People with chronic pain may experience impairments in high-level cognitive skills, particularly executive functions. Such impairments are not adequately measured in most clinical pain management settings yet could be a key influence on everyday functioning. We administered a well-validated, well-normed self-report measure to determine which aspects of executive functioning are compromised in the daily experience of patients with chronic pain, and whether these are associated with pain severity, medications, and mood.

Materials and Methods:

Sixty-three patients attending a multidisciplinary pain management clinic, and 66 pain-free age-matched and sex-matched controls, completed the Behavior Rating Inventory of Executive Function, Adult version (BRIEF-A). The BRIEF-A measures 9 aspects of executive function: Inhibit, Shift, Emotional Control, Initiate, Self-Monitor, Working Memory, Plan/Organize, Task Monitor, and Organization of Materials. Patients completed a battery of mood and pain-related measures.

Results:

Profile analysis revealed that patients with chronic pain reported significantly greater overall executive function impairments than controls. The patients showed greatest impairments on Working Memory and Emotional Control subscales, with more than half scoring in the clinically elevated range. A significant proportion of the variance in these scores was explained by total medication detriment (but not opioids alone), negative emotional states, and pain interference. Pain intensity and duration were not strong predictors of reported executive dysfunction.

Discussion:

Multiple factors impact on self-reported executive problems in this population. Specific deficits in Working Memory and Emotional Control have implications for patient engagement with treatment, and retention of information provided in therapy. A screening tool like the BRIEF-A may be useful in pain management settings.
The Fibromyalgia Survey Score Correlates With Preoperative Pain Phenotypes But Does Not Predict Pain Outcomes After Shoulder Arthroscopy
Authors: Cheng Jennifer , Kahn Richard L. , YaDeau Jacques T. , Tsodikov Alexander , Goytizolo Enrique A. , Guheen Carrie R. , Haskins Stephen C. , Oxendine Joseph A. , Allen Answorth A. , Gulotta Lawrence V. , Dines David M. , Brummett Chad M.
Published: December 2015

Objectives:

Fibromyalgia (FM) characteristics can be evaluated using a simple, self-reported measure that correlates with postoperative opioid consumption after lower-extremity joint arthroplasty. The purpose of this study was to determine whether preoperative pain history and the FM survey score can predict postoperative outcomes after shoulder arthroscopy, which may cause moderate to severe pain.

Materials and Methods:

In this prospective study, 100 shoulder arthroscopy patients completed preoperative validated self-report measures to assess baseline quality of recovery score, physical functioning, depression, anxiety, and neuropathic pain. FM characteristics were evaluated using a validated measure of widespread pain and comorbid symptoms on a 0 to 31 scale. Outcomes were assessed on postoperative day 2 (opioid consumption [primary], pain, physical functioning, quality of recovery score), and day 14 (opioid consumption, pain).

Results:

FM survey scores ranged from 0 to 13. The cohort was divided into tertiles for univariate analyses. Preoperative depression and anxiety (P<0.001) and neuropathic pain (P=0.008) were higher, and physical functioning was lower (P<0.001), in higher FM survey score groups. The fibromyalgia survey score was not associated with postoperative pain or opioid consumption; however, it was independently associated with poorer quality of recovery scores (P=0.001). The only independent predictor of postoperative opioid use was preoperative opioid use (P=0.038).

Discussion:

FM survey scores were lower than those in a previous study of joint arthroplasty. Although they distinguished a negative preoperative pain phenotype, FM scores were not independently associated with postoperative opioid consumption. Further research is needed to elucidate the impact of a FM-like phenotype on postoperative analgesic outcomes.
Disengagement of general practitioners in cervical cancer screening
Authors: Poncet Lorraine , Rigal Laurent , Panjo Henri , Gautier Arnaud , Chauvin Pierre , Menvielle Gwenn , Cadot Emmanuelle , Ringa Virginie
Published: December 2015

In the absence of organized cervical cancer screening (CCS) programs, gynecologists remain principal actors in obtaining a Pap smear, followed by general practitioners (GPs). In France, with the growing scarcity of gynecologists and social inequalities in access to opportunistic screening, GPs are valuable resources for women’s gynecologic follow-up. We aimed to investigate the characteristics of GPs who do not perform CCS, analyzing the effect of GPs’ sex and their evolution over time. On the basis of data from three cross-sectional surveys conducted among representative samples of French GPs in 1998, 2002, and 2009 (n=5199), we constructed univariate and multivariate logistic mixed models (level 2: county, level 1: GP) with random intercept stratified on GPs’ sex to investigate the characteristics of the GPs associated with no practice of CCS ever. Almost one-third of all GPs did not perform CCS ever and it increased with time. Male GPs were always more likely not to perform it (odds ratio=0.50, 95% confidence interval=0.42–0.59). The percentage of GPs not performing CCS increased more markedly among male than among female GPs, and increased more among the youngest age group. Increasingly fewer GPs engage in CCS when the growing scarcity of medical gynecologists calls for more participation. Female GPs remain significantly more active in CCS than male GPs. The participation in CCS is determined differently according to the practitioner’s sex.
Resilience As a Life Practice
Authors: Leslie Jamie L. , Wray Janet N. , Lonneman William
Published: December 2015

One method for developing personal resilience is to listen to the stories of others who developed resilience. This article highlights the elements of spiritual practice, relationships, and education, as experienced by the first American saint, Elizabeth Ann Seton. Seton worked through immense suffering, demonstrating integration, adjustment, and growth. Her life story is an example of resilience as a practice that nurses can learn from today.
A Comparative Study of Immunohistochemical Myoepithelial Cell Markers in Cutaneous Benign Cystic Apocrine Lesions
Authors: Wood Andrew , Houghton Sinatra L. , Biswas Asok
Published: December 2015

The use of immunohistochemical markers for myoepithelial cells (MEC) is a useful tool in the distinction of benign from malignant epithelial neoplasms. Although their use in breast tumors is well recognized, little is known concerning its application in comparable cutaneous lesions. Using benign cutaneous cystic apocrine lesions as a study model, the aim of this study was to compare 5 immunohistochemical markers [calponin, p63, smooth muscle actin (SMA), cytokeratin 14, and CD10] in their effectiveness to highlight MEC. Cases of apocrine hidrocystoma and cystadenoma (n = 44) were reviewed with a particular emphasis on proliferative features and apocrine change. The MEC staining pattern and the intensity and distribution scores in proliferative (n = 29) and nonproliferative (n = 15) lesions were assessed, and the differences between the 2 groups were statistically analyzed using Fisher exact test. Calponin and SMA stained MEC in the most consistent manner. Being a nuclear stain, p63 was easy to interpret but typically showed discontinuous staining. Cytokeratin 14 not only effectively highlighted MEC but also stained some luminal epithelial cells in an unpredictable manner. Because of prominent background dermal fibroblast staining, CD10 was often difficult to interpret. Only SMA and p63 showed a statistically significant difference in MEC staining intensity scores between the proliferative and nonproliferative groups. Our results show that immunohistological staining for MEC in benign cystic apocrine lesions of the skin is variable. The authors recommend that a panel of markers that includes calponin and p63 be used and highlight the need for awareness of specific caveats associated with individual markers.
When the Topic Turns to Sex
Authors: Steinke Elaine E. , Johansen Pernille Palm , Dusenbury Wendy
Published: December 2015

Patients with cardiovascular disease and their partners frequently have concerns about sexual intimacy, and sexual counseling is needed across health care settings to ensure that patients receive information to safely resume sexual activity. The purpose of this review is to provide practical, evidence-based approaches to enable health care providers to discuss sexual counseling, illustrated by several case scenarios. Evidence shows that patients expect health care providers to initiate sexual activity discussions, although providers may be hesitant and often rely on patients to ask questions. Although some providers cite lack of knowledge or confidence in their ability to provide sexual counseling, others mention time pressures in the clinical setting. Although such barriers exist, sexual counseling can be individualized to the cardiac condition of a patient with a few select questions. The representative examples of patients with angina pectoris, myocardial infarction, coronary artery bypass surgery, heart failure, and implantable cardioverter defibrillator are used to illustrate key points and provide a model for sexual counseling in practice.
INTRAVITREAL MELPHALAN AS SALVAGE THERAPY FOR REFRACTORY RETINAL AND SUBRETINAL RETINOBLASTOMA
Authors: Francis Jasmine H. , Marr Brian P. , Brodie Scott E. , Gobin Pierre , Dunkel Ira J. , Abramson David H.
Published: December 2015

Purpose:

This case series highlights the novel use of intravitreal melphalan for nonvitreous retinoblastoma. It assesses the efficacy and toxicity of intravitreal melphalan for nonvitreous retinoblastoma.

Methods:

This observational small case series investigates three patients treated with intravitreal melphalan for nonvitreous retinoblastoma that was refractory to multiple-course ophthalmic artery chemosurgery. Patients' demographics, response to treatment, and toxicity of treatment as clinically evaluated are measured by electroretinogram.

Patients:

Three eyes of three patients received a median of 7 weekly intravitreal melphalan injections (30 μg/0.07 cc) for persistent retinal or subretinal tumors refractory to treatment with multiple-course ophthalmic artery chemosurgery.

Results:

Eyes remain tumor free at a median of 14-month follow-up. One eye was enucleated because of a vitreous hemorrhage that obscured fundus details. One eye had extinguished electroretinogram recordings before injections and two eyes had a decrease in electroretinogram responses over the intravitreal treatment course. The eye with subretinal seeding demonstrated marked retinopathy by ophthalmoscopy and fluorescein angiography and one eye was enucleated because of the development of a vitreous hemorrhage.

Conclusion:

This small case series highlights that nonvitreous disease that is, refractory or persistent despite previous ophthalmic artery chemosurgery can regress with intravitreal melphalan. However, this treatment may result in retinal toxicity.
Misleading Gastrointestinal Symptoms
Authors: Macedo Guilherme , Lopes Susana , Peixoto Armando
Published: December 2015

Inorganic lead intoxication has emerged as an important and challenging clinical problem owing to increased awareness of lead and enhanced surveillance of exposed individuals. However, recognition may not be very difficult when there is an obvious history of exposure. Our interest began a few years ago when we could trace an outbreak, following a patient who was admitted with colickly abdominal pain, convulsions, and coma. After that, 16 more cases were identified and characterized. All patients recovered completely after adequate chelation therapy. Although the clinical picture of lead intoxication is pleomorphic, the increased awareness of gastroenterologists in this subject may possibly bring chronically complaining difficult patients to an earlier, unexpected, and fairly treatable disease.
An Isolated Metastasis From Clear Cell Renal Cell Carcinoma to the Uterus: A Case Report and Review of Literature
Authors: Singh Kamaljeet , DiSilvestro Paul A. , Lawrence W. Dwayne , Quddus M. Ruhul
Published: December 2015

Ovaries are a favored site for metastatic tumors arising in the female genital tract. Other organs of the mullerian system, that is, the uterine corpus as well as the fallopian tubes, cervix, and the vagina are less commonly involved by metastases. If there is no clinical history of a known extramullerian primary tumor, suspicion that a uterine mass represents metastatic disease is low. We report the case of a renal clear cell carcinoma presenting as an isolated uterine mass and morphologically mimicking a primary endometrial clear cell adenocarcinoma. A review of the English literature yielded only a recent abstract describing 3 cases of renal clear cell carcinoma metastasizing to the endometrium.
Cervical Carcinomas With Neuroendocrine Differentiation: A Report of 28 Cases With Immunohistochemical Analysis and Molecular Genetic Evidence of Common Clonal Origin With Coexisting Squamous and Adenocarcinomas
Authors: Emerson Robert E. , Michael Helen , Wang Mingsheng , Zhang Shaobo , Roth Lawrence M. , Cheng Liang
Published: December 2015

Cervical neuroendocrine carcinomas are rare, aggressive tumors and their immunohistochemical features and clonal relationship to coexisting tumors are incompletely described. Twenty-eight cases were identified (17 small cell, 9 large cell, and 2 mixed), 10 of which had an invasive squamous or adenocarcinoma component. Staining for synaptophysin, chromogranin A, TTF1, c-kit, CD44, and p16 was performed. Analyses for loss of heterozygosity (LOH) at 5 polymorphic microsatellite markers (D3S1300, D9S171, D11S914, D13S319, and TP53) and X-chromosome inactivation were performed. Of 17 cases with available blocks, 13 (76%) were synaptophysin+, 8 (47%) were chromogranin A+, 8 (47%) were TTF1+, 7 (41%) were c-kit+, and 6 (35%) were CD44+. Strong patchy or strong diffuse p16 staining was seen in all cases. LOH and X-chromosome inactivation analysis were performed for 17 cases, 8 of which had a coexisting squamous or adenocarcinoma component. Five of the 8 (63%) cases with 2 components showed allelic loss in both components. All 5 of these cases demonstrated identical LOH between the neuroendocrine and squamous or adenocarcinoma components. Nonrandom X-chromosome inactivation was seen in the neuroendocrine and other components in 4 of the 8 cases. In all 4 cases the pattern of inactivation was identical between the 2 components. Cervical neuroendocrine carcinomas have features similar to other extrapulmonary neuroendocrine carcinomas, including expression of TTF1, c-kit, and CD44. Consistent staining for p16 is also seen. Concordant genetic alterations support common clonal origin for neuroendocrine carcinomas with a coexisting squamous or adenocarcinoma component.
Ovarian Tumors in Children and Adolescents: A 10-Yr Histopathologic Review in Korle-Bu Teaching Hospital, Ghana
Authors: Akakpo Patrick K. , Derkyi-Kwarteng Leonard , Quayson Solomon E. , Gyasi Richard K. , Anim Jehoram T.
Published: December 2015

To determine the histopathologic types, frequency of occurrence, age distribution, presenting signs, and symptoms of ovarian tumors in children and adolescents diagnosed at the Korle-Bu Teaching Hospital all histopathology slides and request cards of ovarian tumors diagnosed in subjects aged, 0 to 19 yr over a 10-yr period (2001–2010) were reviewed. Biographical and clinical data of the patients were collected. The results were entered into Epi-info to determine the frequency of various ovarian tumors in different age groups and their association with presenting signs and symptoms. A total of 67 (9.5%) ovarian tumors were diagnosed in patients aged 0 to 19 yr of a total of 706 diagnosed in all age groups during the period. The majority [44 (65.7%)] were germ cell tumors, the commonest being mature cystic teratoma. Burkitt lymphoma was the single most common malignant tumor, comprising 6(9%) of all the tumors, although as a group malignant germ cell tumors were still the most common malignant ovarian tumors in children and adolescents. Although germ cell tumors were the most common tumors in this age group (both benign and malignant), Burkitt lymphoma, a peculiar malignant tumor in this subregion, was the single most common malignant tumor of the ovary.
Clinicopathologic Analysis of Postchemotherapy Gestational Trophoblastic Neoplasia: An Entity Overlapping With Epithelioid Trophoblastic Tumor
Authors: Lu Bingjian , Zhang Xiaofei , Liang Yun
Published: December 2015

Surgery is generally not required for the majority of gestational trophoblastic neoplasias (GTNs) because they are potentially curable by chemotherapy alone. The histologic assessment is rarely available although the identification of a specific subtype of GTN is relevant to clinical intervention and prognostic prediction. In this study, we analyzed the clinicopathologic features of 4 postchemotherapy GTNs. They presented as a persistent uterine (Cases 1, 2, and 3) or pelvic mass (Case 4) with a raised serum β-hCG level after multiple courses of chemotherapy. All patients were alive without evidence of disease at follow-up periods of 58 to 109 mo after surgery and salvage chemotherapy except for Case 4 which had a recurrent pelvic mass. These GTNs had a characteristic histopathologic pattern of extensive necrosis and a rim of scant viable mononucleated tumor cells at the periphery of the lesion. Immunostaining showed that these tumor cells had a lower Ki67 index than choriocarcinoma, and epithelioid trophoblastic cell tumor although they exhibited an epithelioid trophoblastic cell tumor-like immunostaining pattern (CD146−, hPL−, and p63+). A small number of β-hCG-positive multinucleated trophoblastic cells were also present in 3 of the 4 cases. We suggest that these postchemotherapy GTNs may represent a “snap shot” of the hypothetical choriocarcinoma-epithelioid trophoblastic cell tumor transition. Our findings should provide insights into the pathogenesis of GTNs.
p16 Immunostaining Allows for Accurate Subclassification of Vulvar Squamous Cell Carcinoma Into HPV-Associated and HPV-Independent Cases
Authors: Cheng Angela S. , Karnezis Anthony N. , Jordan Suzanne , Singh Naveena , McAlpine Jessica N. , Gilks C. Blake
Published: December 2015

The aim of this study was to compare morphologic assessment and p16 immunohistochemistry (IHC) in the determination of human papilloma virus (HPV) status in vulvar squamous cell carcinoma (VSCC). A total of 201 invasive VSCC cases were classified as “HPV-associated” when warty/basaloid VSCC or high-grade squamous intraepithelial lesion (vulvar intraepithelial neoplasia 2/3) was observed, or “HPV-independent” in the presence of well-differentiated keratinizing invasive SCC or differentiated vulvar intraepithelial neoplasia. For p16 IHC, strong nuclear and cytoplasmic staining of all cells in at least the lowermost third of the epithelium was scored as positive. All cases with discrepant HPV predictions by hematoxylin and eosin morphology versus p16 IHC were further analyzed by polymerase chain reaction for HPV DNA. On the basis of hematoxylin and eosin morphologic assessment, 50/201 tumors showed features suggestive of HPV-associated, and 47 of those showed p16 immunoreactivity (94% concordance). Of the 146 cases considered HPV-independent based on hematoxylin and eosin, 115 (79%) showed negative p16 immunostaining. Thus 83% (162/196) concordance between morphologic assessment and p16 IHC was observed, overall. In 34 cases, where morphologic assessment and p16 IHC did not agree, HPV polymerase chain reaction agreed with p16 IHC in 32/34 (94%). The sensitivity and specificity of p16 IHC in classification of VSCC as HPV-independent or HPV-associated was 100% and 98.4%, respectively. Morphologic assessment and p16 IHC are concordant in classifying VSCC as HPV-independent or HPV-associated in a majority of cases (83%). Most of the discrepant cases are p16-positive well-differentiated keratinizing VSCC, and HPV polymerase chain reaction supports classification of a large majority of these (94%) as HPV-associated. p16 IHC is validated as an accurate surrogate marker for determination of HPV status in VSCC.
Accurate genetic profiling of anthropometric traits using a big data approach
Authors: Canela-Xandri Oriol , Rawlik Konrad , Woolliams John A. , Tenesa Albert
Published: December 2015

Genome-wide association studies (GWAS) promised to translate their findings into clinically beneficial improvements of patient management by tailoring disease management to the individual through the prediction of disease risk1,2. However, the ability to translate genetic findings from GWAS into predictive tools that are of clinical utility and which may inform clinical practice has, so far, been encouraging but limited1,2. Here we propose to use a more powerful statistical approach that enables the prediction of multiple medically relevant phenotypes without the costs associated with developing a genetic test for each of them. As a proof of principle, we used a common panel of 319,038 SNPs to train the prediction models in 114,264 unrelated White-British for height and four obesity related traits (body mass index, basal metabolic rate, body fat percentage, and waist-to-hip ratio). We obtained prediction accuracies that ranged between 46% and 75% of the maximum achievable given their explained heritable component. This represents an improvement of up to 75% over the phenotypic variance explained by the predictors developed through large collaborations3, which used more than twice as many training samples. Across-population predictions in White nonBritish individuals were similar to those of White-British whilst those in Asian and Black individuals were informative but less accurate. The genotyping of circa 500,000 UK Biobank4participants will yield predictions ranging between 66% and 83% of the maximum. We anticipate that our models and a common panel of genetic markers, which can be used across multiple traits and diseases, will be the starting point to tailor disease management to the individual. Ultimately, we will be able to capitalise on whole-genome sequence and environmental risk factors to realise the full potential of genomic medicine.
Phylogenetic and functional substrate specificity for endolithic microbial communities in hyper-arid environments
Authors: Crits-Christoph Alexander , Robinson Courtney K , Ma Bing , Ravel Jacques , Wierzchos Jacek , Ascaso Carmen , Artieda Octavio , Souza-Egipsy Virginia , Cristina Casero M. , DiRuggiero Jocelyne
Published: December 2015

Under extreme water deficit, endolithic (inside rock) microbial ecosystems are considered environmental refuges for life in cold and hot deserts, yet their diversity and functional adaptations remain vastly unexplored. The metagenomic analyses of the communities from two rock substrates, calcite and ignimbrite, revealed that they were dominated by Cyanobacteria, Actinobacteria, and Chloroflexi. The relative distribution of major phyla was significantly different between the two substrates and biodiversity estimates, from 16S rRNA gene sequences and from the metagenome data, all pointed to a higher taxonomic diversity in the calcite community. While both endolithic communities showed adaptations to extreme aridity and to the rock habitat, their functional capabilities revealed significant differences. ABC transporters and pathways for osmoregulation were more diverse in the calcite chasmoendolithic community. In contrast, the ignimbrite cryptoendolithic community was enriched in pathways for secondary metabolites, such as non-ribosomal peptides (NRPS) and polyketides (PKS). Assemblies of the metagenome data produced population genomes for the major phyla found in both communities and revealed a greater diversity of Cyanobacteria population genomes for the calcite substrate. Draft genomes of the dominant Cyanobacteria in each community were constructed with more than 93% estimated completeness. The two annotated proteomes shared 64% amino acid identity and a significantly higher number of genes involved in iron update, and NRPS gene clusters, were found in the draft genomes from the ignimbrite. Both the community-wide and genome-specific differences may be related to higher water availability and the colonization of large fissures and cracks in the calcite in contrast to a harsh competition for colonization space and nutrient resources in the narrow pores of the ignimbrite. Together, these results indicated that the habitable architecture of both lithic substrates- chasmoendolithic versus cryptoendolithic - might be an essential element in determining the colonization and the diversity of the microbial communities in endolithic substrates at the dry limit for life.
Multidimensional Heritability Analysis of Neuroanatomical Shape
Authors: Ge Tian , Reuter Martin , Winkler Anderson M. , Holmes Avram J. , Lee Phil H. , Tirrell Lee S. , Roffman Joshua L. , Buckner Randy L. , Smoller Jordan W. , Sabuncu Mert R.
Published: December 2015

In the dawning era of large-scale biomedical data, multidimensional phenotype vectors will play an increasing role in examining the genetic underpinnings of brain features, behavior and disease. For example, shape measurements derived from brain MRI scans are multidimensional geometric descriptions of brain structure and provide an alternate class of phenotypes that remains largely unexplored in genetic studies. Here we extend the concept of heritability to multidimensional traits, and present the first comprehensive analysis of the heritability of neuroanatomical shape measurements across an ensemble of brain structures based on genome-wide SNP and MRI data from 1,320 unrelated, young and healthy individuals. We replicate our findings in an extended twin sample from the Human Connectome Project (HCP). Our results demonstrate that neuroanatomical shape can be significantly heritable, above and beyond volume, and can serve as a complementary phenotype to study the genetic determinants and clinical relevance of brain structure.
Dynamic changes in histone modifications precede de novo DNA methylation in oocytes
Authors: Stewart Kathleen R. , Veselovska Lenka , Kim Jeesun , Huang Jiahao , Saadeh Heba , Tomizawa Shin-ichi , Smallwood Sébastien A. , Chen Taiping , Kelsey Gavin
Published: December 2015

Erasure and subsequent reinstatement of DNA methylation in the germline, especially at imprinted CpG islands (CGIs), is crucial to embryogenesis in mammals. The mechanisms underlying DNA methylation establishment remain poorly understood, but a number of post-translational modifications of histones are implicated in antagonizing or recruiting the de novo DNA methylation complex. In mouse oogenesis, DNA methylation establishment occurs on a largely unmethylated genome and in nondividing cells, making it a highly informative model for examining how histone modifications can shape the DNA methylome. Using a chromatin immunoprecipitation (ChIP) and genome-wide sequencing (ChIP-seq) protocol optimized for low cell numbers and novel techniques for isolating primary and growing oocytes, profiles were generated for histone modifications implicated in promoting or inhibiting DNA methylation. CGIs destined for DNA methylation show reduced protective H3K4 dimethylation (H3K4me2) and trimethylation (H3K4me3) in both primary and growing oocytes, while permissive H3K36me3 increases specifically at these CGIs in growing oocytes. Methylome profiling of oocytes deficient in H3K4 demethylase KDM1A or KDM1B indicated that removal of H3K4 methylation is necessary for proper methylation establishment at CGIs. This work represents the first systematic study performing ChIP-seq in oocytes and shows that histone remodeling in the mammalian oocyte helps direct de novo DNA methylation events.
The Saccharomyces Genome Database: Advanced Searching Methods and Data Mining
Authors: Cherry J. Michael
Published: December 2015

At the core of the Saccharomyces Genome Database (SGD) are chromosomal features that encode a product. These include protein-coding genes and major noncoding RNA genes, such as tRNA and rRNA genes. The basic entry point into SGD is a gene or open-reading frame name that leads directly to the locus summary information page. A keyword describing function, phenotype, selective condition, or text from abstracts will also provide a door into the SGD. A DNA or protein sequence can be used to identify a gene or a chromosomal region using BLAST. Protein and DNA sequence identifiers, PubMed and NCBI IDs, author names, and function terms are also valid entry points. The information in SGD has been gathered and is maintained by a group of scientific biocurators and software developers who are devoted to providing researchers with up-to-date information from the published literature, connections to all the major research resources, and tools that allow the data to be explored. All the collected information cannot be represented or summarized for every possible question; therefore, it is necessary to be able to search the structured data in the database. This protocol describes the YeastMine tool, which provides an advanced search capability via an interactive tool. The SGD also archives results from microarray expression experiments, and a strategy designed to explore these data using the SPELL (Serial Pattern of Expression Levels Locator) tool is provided.
The Saccharomyces Genome Database: Gene Product Annotation of Function, Process, and Component
Authors: Cherry J. Michael
Published: December 2015

An ontology is a highly structured form of controlled vocabulary. Each entry in the ontology is commonly called a term. These terms are used when talking about an annotation. However, each term has a definition that, like the definition of a word found within a dictionary, provides the complete usage and detailed explanation of the term. It is critical to consult a term’s definition because the distinction between terms can be subtle. The use of ontologies in biology started as a way of unifying communication between scientific communities and to provide a standard dictionary for different topics, including molecular functions, biological processes, mutant phenotypes, chemical properties and structures. The creation of ontology terms and their definitions often requires debate to reach agreement but the result has been a unified descriptive language used to communicate knowledge. In addition to terms and definitions, ontologies require a relationship used to define the type of connection between terms. In an ontology, a term can have more than one parent term, the term above it in an ontology, as well as more than one child, the term below it in the ontology. Many ontologies are used to construct annotations in the Saccharomyces Genome Database (SGD), as in all modern biological databases; however, Gene Ontology (GO), a descriptive system used to categorize gene function, is the most extensively used ontology in SGD annotations. Examples included in this protocol illustrate the structure and features of this ontology.
Recovery of Replication-Competent and G-Gene-Deleted Rabies Viruses from cDNA
Authors: Hagendorf Nadin , Conzelmann Karl-Klaus
Published: December 2015

This protocol describes the recovery of replication-competent rabies viruses (RV) such as SAD L16 or SAD L16-eGFP. It is suggested that at least three parallel transfection experiments are performed to increase the success rate (in three 3.5-cm2 dishes or in three wells in a six-well plate). The entire protocol takes 10 d, and successful rescue can be obtained after 6 d. An additional procedure for the recovery of G-gene-deleted viruses is also included. Please note that appropriate biosafety measures are needed.
Pseudotyping of G-Gene-Deficient Rabies Virus
Authors: Hagendorf Nadin , Conzelmann Karl-Klaus
Published: December 2015

G-deleted fluorescent rabies virus (RV) pseudotyped with RV G proteins, SAD ΔG eGFP (RV CVS-G), can be used as single-round vectors for efficient retrograde labeling of neurons. For these experiments, as well as for monosynaptic tracing, which involves pseudotyping in situ, the use of the CVS strain G is recommended because of its high tropism for neurons. Pseudotype virus stocks generated by transfection of pCAGGS-G (or in MG139-on cells) contain the G protein of the vaccine strain SAD L16, which is broader in its tropism, and infects astrocytes, glia, and oligodendrocytes. We also describe a procedure for pseudotyping with ASLV Env A, which uses a cell-line expressing a version of the EnvA protein that is incorporated efficiently into the RV envelope (EnvARGRGct).
Recombinant Fluorescent Rabies Virus Vectors for Tracing Neurons and Synaptic Connections
Authors: Hagendorf Nadin , Conzelmann Karl-Klaus
Published: December 2015

Recombinant rabies virus (RV) vectors expressing fluorescent proteins allow staining of neurons from many mammalian species and enable the study of neuron morphology. Because viral spread occurs only between neurons that have synaptic connections, these vectors also permit transsynaptic tracing. A recently established system for restriction of transsynaptic tracing to a single transsynaptic jump, dubbed monosynaptic tracing, uses glycoprotein gene-defective, pseudotyped RV. This allows infection of defined cells and transient complementation with the glycoprotein in situ to support a single step of transsynaptic crossing to presynaptic cells. Here, we introduce protocols describing the production of RV vectors, including the recovery of recombinant RV from complementary DNA (cDNA) and virus pseudotyping in vitro. This allows retrograde staining of neurons projecting to the inoculation site.
On the transferability of electron density in binary vanadium borides VB, V3B4and VB2
Authors: Terlan Bürgehan , Akselrud Lev , Baranov Alexey I. , Borrmann Horst , Grin Yuri
Published: December 2015

Binary vanadium borides are suitable model systems for a systematic analysis of the transferability concept in intermetallic compounds due to chemical intergrowth in their crystal structures. In order to underline this structural relationship, topological properties of the electron density in VB, V3B4and VB2reconstructed from high-resolution single-crystal X-ray diffraction data as well as derived from quantum chemical calculations, are analysed in terms of Bader's Quantum Theory of Atoms in Molecules [Bader (1990).Atoms in Molecules: A Quantum Theory, 1st ed. Oxford: Clarendon Press]. The compounds VB, V3B4and VB2are characterized by a charge transfer from the metal to boron together with two predominant atomic interactions, the shared covalent B—B interactions and the polar covalent B—Minteractions. The resembling features of the crystal structures are well reflected by the respective B—B interatomic distances as well as by ρ(r) values at the B—B bond critical points. The latter decrease with an increase in the corresponding interatomic distances. The B—B bonds show transferable electron density properties at bond critical points depending on the respective bond distances.
Microwave-assisted synthesis and electrochemical evaluation of VO2 (B) nanostructures
Authors: Ashton Thomas E. , Hevia Borrás David , Iadecola Antonella , Wiaderek Kamila M. , Chupas Peter J. , Chapman Karena W. , Corr Serena A.
Published: December 2015

Understanding how intercalation materials change during electrochemical operation is paramount to optimizing their behaviour and function and in situ characterization methods allow us to observe these changes without sample destruction. Here we first report the improved intercalation properties of bronze phase vanadium dioxide VO2 (B) prepared by a microwave-assisted route which exhibits a larger electrochemical capacity (232 mAh g−1) compared with VO2 (B) prepared by a solvothermal route (197 mAh g−1). These electrochemical differences have also been followed using in situ X-ray absorption spectroscopy allowing us to follow oxidation state changes as they occur during battery operation.
Composite Measures of Health Care Provider Performance: A Description of Approaches
Authors: SHWARTZ MICHAEL , RESTUCCIA JOSEPH D. , ROSEN AMY K.
Published: December 2015

Policy Points:

Composite measures of health care provider performance aggregate individual performance measures into an overall score, thus providing a useful summary of performance.

Numerous federal, state, and private organizations are adopting composite measures for provider profiling and pay‐for‐performance programs.

This article makes an important contribution to the literature by highlighting the advantages and disadvantages of different approaches to creating composite measures and also by summarizing key issues related to the use of the various methods.

Composite measures are a useful complement to individual measures when profiling and creating incentives for improvement, but because of the sensitivity of results to the methods used to create composite measures, careful analysis is necessary before they are implemented.

Context

Since the Institute of Medicine's 2001 report Crossing the Quality Chasm, there has been a rapid proliferation of quality measures used in quality‐monitoring, provider‐profiling, and pay‐for‐performance (P4P) programs. Although individual performance measures are useful for identifying specific processes and outcomes for improvement and tracking progress, they do not easily provide an accessible overview of performance. Composite measures aggregate individual performance measures into a summary score. By reducing the amount of data that must be processed, they facilitate (1) benchmarking of an organization's performance, encouraging quality improvement initiatives to match performance against high‐performing organizations, and (2) profiling and P4P programs based on an organization's overall performance.

Methods

We describe different approaches to creating composite measures, discuss their advantages and disadvantages, and provide examples of their use.

Findings

The major issues in creating composite measures are (1) whether to aggregate measures at the patient level through all‐or‐none approaches or the facility level, using one of the several possible weighting schemes; (2) when combining measures on different scales, how to rescale measures (using z scores, range percentages, ranks, or 5‐star categorizations); and (3) whether to use shrinkage estimators, which increase precision by smoothing rates from smaller facilities but also decrease transparency.

Conclusions

Because provider rankings and rewards under P4P programs may be sensitive to both context and the data, careful analysis is warranted before deciding to implement a particular method. A better understanding of both when and where to use composite measures and the incentives created by composite measures are likely to be important areas of research as the use of composite measures grows.
TASER® Exposure and Cognitive Impairment
Authors: Kane Robert J. , White Michael D.
Published: December 2015

Research Summary

This study reports findings from a randomized controlled trial that examined the effects of the TASER® (a conducted energy weapon sold by TASER International, Scottsdale, Arizona) on several dimensions of cognitive functioning. The research demonstrated that in a sample of healthy human volunteer participants, TASER exposure led to significant and substantial reductions in (a) short‐term auditory recall and (b) abilities to assimilate new information through auditory processes. The effects lasted up to 1 hour for most subjects, almost all of whom returned to baseline 60 minutes postexposure.

Policy Implications

The study applies the findings of reduced cognitive functioning among healthy participants in a laboratory setting to criminal suspects in field settings and questions the abilities of “average” suspects to waive their Miranda rights knowingly, intelligently, and voluntarily within 60 minutes of a TASER exposure. The study poses the question: What would it cost police to wait 60 minutes after a TASER deployment before engaging suspects in custodial interrogations?