bluuebunny/crossref_metadata_2025 huggingface dataset:
The Catacombs
Authors: Fiocchi Nicolai Vincenzo
Published: January 2019

The Roman catacombs, dated to the early third century, are characterized by regular plans that made the best use of available space. In the late third and fourth centuries, the catacombs grew in number and extent through the establishment of new areas. Beginning in the fifth century, the Roman catacombs ceased to be the usual places of burial and become instead spaces dedicated to the cult of the martyrs. The catacombs of the Italian peninsula and the larger islands of the Mediterranean, Greece, and Roman Africa, dated usually between the fourth and fifth centuries, are fewer and smaller than those in Rome, but are distinct in their plans and adaptation to different environments.
Martyria
Authors: Eastman David L.
Published: January 2019

Martyria served as spatial focal points for numerous practices associated with the early Christian cult of the saints. However, the archaeological study of these martyr shrines is limited by the lack of evidence prior to the fourth century, forcing scholars in many cases to rely on textual evidence for their reconstructions of spaces. This chapter studies the earliest evidence for martyr shrines in Smyrna and Rome, which is textual, in order to establish primitive Christian practices surrounding martyria. It then examines the archaeological evidence from martyria in Rome and Philippi of the fourth century or later. These sites demonstrate the continuing expansion of martyria as cultic centers. The chapter concludes with a caveat concerning the popularity of small, even private, shrines that are invisible to the archaeological record.
Churches
Authors: Stewart Charles Anthony
Published: January 2019

Churches have been the subject of archaeological examination since the sixteenth century. As the most monumental expression of Christianity, they represent complex religious and societal ideologies, rooted in Jewish concepts of the synagogue and messianic kingship. The institution of the church was initially viewed as both a physical local body and a global spiritual kingdom, and these notions eventually became symbolized by architecture. In Christianity’s first three centuries, a variety of buildings could accommodate Christian congregations. During the emperor Constantine’s reign, the basilica became the most prestigious form of church and, by the end of the seventh century, was commonplace in Europe, North Africa, and western Asia. Churches were not just assemblages of various materials; they also housed burials, shrines, artifacts, and artistic programs. Archaeology examines how and when churches were designed, constructed, and changed, and how they contributed to the wider society.
Statistical Methods
Authors: Samuelsson Christer , Štajner Sanja
Published: January 2019

Current mainstream natural language processing tasks rely heavily on the use of statistical methods. This chapter presents statistical methods from their fundamentals to more complex methods, including hidden Markov and maximum entropy models applied in language modelling, and the expectation maximization method used in machine translation. It also introduces robust estimation and the methods for calculating inter-annotator agreement and statistical significance, as well as suggestions for further reading and some mathematical details of the presented statistical methods.
Structuralism
Authors: Stewart Thomas
Published: January 2019

During the twentieth century, much of linguistic research shifted in focus from diachronic to synchronic description. The challenge of expanding the database of languages well beyond Indo-European brought about the need to describe languages on their own terms instead of importing alien preconceptions and expectations. Alongside the growth in language resources, there was also a need among practitioners to establish a coherent and reliable set of analytical concepts and methods for synchronic research. This chapter surveys these developments and highlights the enduring relevance of the work.
Word and Paradigm Morphology
Authors: Blevins James P. , Ackerman Farrell , Malouf Rob
Published: January 2019

There has been a broad resurgence in word-based approaches and the reconceptualization of classical ‘word and paradigm’ (WP) approaches as general models of morphological analysis. WP models are well adapted to the description and analysis of complex morphological patterns, most transparently clear in inflection. Modern WP models demonstrate how morphological organization is fundamentally implicational: the central role of words (and paradigms) reflects their predictive value in a morphological system. Understanding the nature of morphological organization, within and across languages, requires exploration of the fundamental elements of implicational relations. Descriptively this involves identifying the internal structure of words and the ways this structure facilitates an external organization into patterns of relatedness. Theoretically, it is necessary to identify analytic tools appropriate for specifying and quantifying word-internal and word-external organization. This type of analytic approach encourages the investigation of the types of learning theories that may play a role in determining the patterns observed to occur and thereby help to explain their learnability.
Morphological Theory and Typology
Authors: Arkadiev Peter M. , Klamer Marian
Published: January 2019

Morphology, by its very language-specific nature, poses conceptual, methodological, and empirical problems for both linguistic theory and language typology. This chapter offers an overview of major issues in morphological typology, starting with the controversial definitions of basic notions such as ‘wordform’ and ‘lexeme’, and proceeding to the classification of morphological phenomena along the syntagmatic and paradigmatic axes. It is argued that traditional dichotomies such as ‘inflection’ vs. ‘derivation’ or ‘agglutination’ vs. ‘flexion’ are to by replaced by multidimensional classifications based on a broad empirical coverage of morphological phenomena attested in human languages, and that only through a mutually informed fruitful interaction of typologists and morphological theorists can an adequate cross-linguistically valid and analytically sophisticated model of morphology be attained.
Facial Palsy Induced by Checkpoint Blockade: A Single Center Retrospective Study
Authors: Yuen Carlen , Reid Pankti , Zhang Zuoli , Soliven Betty , Luke Jason J. , Rezania Kourosh
Published: January 2019

The augmented immune response caused by immune checkpoint inhibitors leads to the emergence of a class of side effects called immune-related adverse events (irAEs). Facial palsy (FP) is rarely reported as an irAE. In this retrospective study, we reviewed the records of 353 patients treated with immunotherapy in our center from 2015–2018. We identified 4 male patients and 1 female patient with FP. Four had metastatic melanoma and were treated with ipilimumab either as monotherapy or in combination with nivolumab or pembrolizumab. The remaining patient had metastatic bladder cancer, treated with atezolizumab. FP was unilateral and occurred 1–23 weeks after starting immunotherapy. FP was part of a more diffuse neuropathic process in 3 of our patients. Lymphocytic pleocytosis was seen in the cerebrospinal fluid of 3 patients who had lumbar punctures. Magnetic resonance imaging showed enhancement of the intracranial portion of the affected facial nerve in 4 patients. The outcome was favorable in all of the patients noting that 1 patient had incomplete recovery. We conclude that FP, in isolation or as a part of a polyneuropathy, is common among neurological irAEs associated with checkpoint inhibitors and generally has a good prognosis.
Melanoma and autoimmunity: spontaneous regressions as a possible model for new therapeutic approaches
Authors: Motofei Ion G.
Published: January 2019

Until now, malignancy has been considered a cellular problem represented by the perturbed (uncontrolled) division of the cells associated with invasion and metastasis. Contrary to this classical approach, a new perspective suggests that cancerous disease is, in fact, a supracellular problem represented by inadequate evolution of complex supracellular processes (embryogenesis, development, regeneration, etc.). Such complex processes would be disconnected from the real needs of the body, inducing unnecessary or even dangerous events such as an exacerbated rate of the cell division, angiogenesis, immunosuppression (specific to embryogenesis and melanoma), invasion (mediated by trophoblastic/placental factors in melanoma), and migration (specific to neural crest cells, which generate melanocytes – the most common origin for melanoma). As a result, a correct and comprehensive interpretation of cancer (causes, evolution, therapy, and prevention) should be conducted from a supracellular perspective. After presenting the supracellular perspective, this article further investigates the favorable evolution of malignant melanoma in two distinct situations: in patients receiving no therapy and in patients treated with immune-checkpoint inhibitors. In patients receiving no therapy, spontaneous regressions of melanoma could be the result of several autoimmune reactions (inducing not only melanoma regression but also vitiligo, an autoimmune event frequently associated with melanoma). Patients treated with immune-checkpoint inhibitors develop similar autoimmune reactions, which are clearly correlated with better therapeutic results. The best example is vitiligo, which is considered a positive prognostic factor for patients receiving immune-checkpoint inhibitors. This finding indicates that immune-checkpoint inhibitors induce distinct types of autoimmune events, some corresponding to specific favorable autoimmune mechanisms (favoring tumor regression) and others to common unfavorable adverse reactions (which should be avoided or minimized). In conclusion, the spectrum of autoimmune reactions induced by immune-checkpoint inhibitors should be restricted in the near future to only these specific favorable autoimmune mechanisms. In this way, the unnecessary autoimmune reactions/autoaggressions could be avoided (a better quality of life), and treatment specificity and efficiency should increase (a higher response rate for melanoma therapy).
Survival Implications of De Novo Versus Recurrent Metastatic Non–Small Cell Lung Cancer
Authors: Moore Sara , Leung Bonnie , Wu Jonn , Ho Cheryl
Published: January 2019

Objectives:

Metastatic non–small cell lung cancer (NSCLC) has a poor prognosis. Most patients present with stage IV, and many patients treated curatively with stage I to III develop recurrent metastatic disease. It is unknown whether the natural history differs between patients with recurrent versus de novo metastatic NSCLC. We hypothesized that de novo metastatic status is associated with decreased overall survival compared with recurrent metastatic disease.

Materials and Methods:

A retrospective review was completed of all patients with NSCLC referred to BC Cancer from 2005 to 2012. Two cohorts were created; de novo metastatic disease and patients treated with curative intent (surgery or radiotherapy) that developed recurrent, metastatic disease. Information was collected on known prognostic and predictive factors. Overall survival was calculated from the date of diagnosis of metastatic disease.

Results:

A total of 9651 patients were evaluated, 5782 (60%) with de novo stage IV disease, and 3869 (40%) with stage I to III disease. Of the 1658 patients who received curative therapy for stage I to III disease, 757 (46%) developed metastases. Patients in the de novo cohort versus recurrent cohort were more likely male (52% vs. 48%), have poorer performance status (Eastern Cooperative Oncology Group≥2 50% vs. 44%), and receive no palliative systemic therapy (67% vs. 61%). The median overall survival in the de novo cohort was 4.7 versus 6.9 m in the recurrent cohort (P<0.001). De novo status was associated with shorter overall survival and this remained significant in a multivariate model that incorporated known prognostic factors.

Conclusions:

In a large population-based study of NSCLC, de novo metastatic status was independently associated with decreased overall survival from the time of metastatic disease diagnosis.
Extraskeletal Osteosarcomas
Authors: Bishop Andrew J. , Livingston J. Andrew , Araujo Dejka M. , Moon Bryan S. , Patel Shreyaskumar , Wang Wei-Lien , Lazar Alexander J. , Roland Christina L. , Guadagnolo B. Ashleigh
Published: January 2019

Objective:

We evaluated our experience treating patients with extraskeletal osteosarcoma (ESOS) using combined modality local therapy, including surgery and radiation therapy (RT), to investigate local control (LC) and other survival endpoints.

Methods:

We reviewed the records of 21 consecutive patients with nonmetastatic, ESOS treated with RT in combination with surgery at our institution from 1984 to 2015. Postoperative RT was used for 10 patients (48%) to a median dose of 60 Gy (range, 60 to 68 Gy). The other 11 patients (52%) received 50 Gy preoperatively. Seven patients (33%) were treated with neoadjuvant or adjuvant chemotherapy. Among the patients who received chemotherapy, all were treated with doxorubicin and ifosfamide for a median of 6 cycles (range, 4 to 6).

Results:

Median follow-up time was 120 months (range, 6 to 200 mo). Larger tumor size (>5 cm) was associated with chemotherapy use (P=0.046). The 5-year LC, distant metastatic free survival, and disease-specific survival rates were 93%, 53%, and 62%, respectively. Only 1 patient (5%) had a local recurrence at 22 months. Nine patients (43%) developed distant metastases at a median time of 9 months (range, 1 to 30 mo) without any significant factors for reduced distant metastatic free survival. Following disease relapse, there were 2 patients who were ultimately salvaged, both of whom were treated with chemotherapy and surgery.

Conclusions:

RT in combination with surgery provides favorable LC for patients with ESOS. However, patients have a high rate of distant metastases with limited salvage.
Meta-analyses of Current Strategies to Treat Uncomplicated Diverticulitis
Authors: Mege Diane , Yeo Heather
Published: January 2019

BACKGROUND:

Uncomplicated colonic diverticulitis is common. There is no consensus regarding the most appropriate management. Some authors have reported the efficacy and safety of observational management, and others have argued for a more aggressive approach with oral or intravenous antibiotic treatment.

OBJECTIVE:

The purpose of this study was to perform an updated meta-analysis of the different management strategies for uncomplicated diverticulitis with 2 separate meta-analyses.

DATA SOURCES:

MEDLINE, Embase, and Cochrane databases were used.

STUDY SELECTION:

All randomized clinical trials, prospective, and retrospective comparative studies were included.

INTERVENTIONS:

Observational and antibiotics treatment or oral and intravenous antibiotics treatment were included.

MAIN OUTCOME MEASURES:

Successful management (emergency management, recurrence, elective management) was measured.

RESULTS:

After review of 293 identified records, 11 studies fit inclusion criteria: 7 studies compared observational management and antibiotics treatment (2321 patients), and 4 studies compared oral and intravenous antibiotics treatment (355 patients). There was no significant difference between observational management and antibiotics treatment in terms of emergency surgery (0.7% vs 1.4%; p = 0.1) and recurrence (11% vs 12%; p = 0.3). In this part, considering only randomized trials, elective surgery during the follow-up occurred more frequently in the observational group than the antibiotic group (2.5% vs 0.9%; p = 0.04). The second meta-analysis showed that failure and recurrence rates were similar between oral and intravenous antibiotics treatment (6% vs 7% (p = 0.6) and 8% vs 9% (p = 0.8)).

LIMITATIONS:

Inclusion of nonrandomized studies, identification of high risks of bias (selection, performance, and detection bias), and presence of heterogeneity between the studies limited this work.

CONCLUSIONS:

Observational management was not statistically different from antibiotic treatment for the primary outcome of needing to undergo surgery. However, in patients being treated by antibiotics, our studies demonstrated that oral administration was similar to intravenous administration and provided lower costs. Although it may be difficult for physicians to do, there is mounting evidence that not treating uncomplicated colonic diverticulitis with antibiotics is a viable treatment alternative.
Role of Repeat Resection in Patients With Metastatic Colorectal Cancer: A Multicenter Retrospective Study
Authors: Matsumoto Takuya , Hasegawa Suguru , Hida Koya , Kawada Kenji , Sakai Yoshiharu , Sugihara Kenichi
Published: January 2019

BACKGROUND:

Little is known about repeat resection for recurrence exclusive of the liver and lungs and the natural history after the first curative resection in patients with metastatic colorectal cancer.

OBJECTIVE:

This study aimed to investigate the role of repeat resection for recurrence of metastatic colorectal cancer in a Japanese cohort.

DESIGN:

This is a multi-institution retrospective observational study.

SETTING:

This study was conducted at participating tertiary referral hospitals.

PATIENTS:

Patients with metastatic colorectal cancer who had synchronous distant metastases and underwent simultaneous resection of primary and distant disease or sequential staged resection at short intervals between 1997 and 2007 were included.

MAIN OUTCOME MEASURES:

The primary outcomes measured were patterns of recurrence site, treatments, and survival.

RESULTS:

A total of 1133 patients were identified, of whom 1073 were eligible. In total, 809 of the 1073 patients developed recurrence after curative resection, and 323 of these underwent repeat resection for recurrence. Of these, 211 developed re-recurrence; 80 of these patients underwent a second repeat resection. When stratified by site of recurrence, the 5-year overall survival rate in patients who underwent repeat resection was 56% in those with recurrence in the liver only, 43% in those with recurrence in the lung only, 30% in those with peritoneal seeding only, and 28% in those with multiple organ involvement. In patients who underwent a second repeat resection, the 5-year overall survival rates were 56%, 46%, 100%, and 50%.

LIMITATIONS:

This study was limited by its retrospective study design.

CONCLUSIONS:

Repeat surgery could have long-term survival benefit in patients with metastatic colorectal cancer who develop recurrence or re-recurrence in the liver or lung following curative resection. However, repeat surgery should be considered carefully in patients with peritoneal seeding only or recurrence at multiple sites. See Video Abstract at http://links.lww.com/DCR/A838.
Thermal Photodynamic Therapy for Actinic Keratoses on Facial Skin: A Proof-of-Concept Study
Authors: Willey Andrea
Published: January 2019

BACKGROUND

Warming the skin during the incubation of 5-aminolevulinic acid (ALA) has the potential to improve the efficacy and efficiency of cutaneous photodynamic therapy (PDT) through multiple mechanisms. The aim of this proof-of-concept study is to investigate the efficacy and tolerability of thermal PDT on facial skin and evaluate porphyrin production objectively during the warming period.

METHODS

Facial skin of 10 subjects was heated during a 20-minute incubation with ALA followed by 10 J/cm2 blue light illumination. Lesion counts were performed at baseline and 2 months. Porphyrin images were captured and the intensity of fluorescence was measured. The mean intensity of fluorescence after incubation with ALA was compared with baseline.

RESULTS

Ten subjects with 363 actinic keratoses completed the study. The average temperature during incubation with the warming mask was 38 to 42°C. Porphyrin intensity increased significantly after the incubation period (p = .001). The average lesion clearance rate was 91.48%. Five subjects had complete lesion clearance (50%).

CONCLUSION

This small proof-of-concept study shows that warming facial skin within the range of physiologic tolerability during the incubation of ALA is well tolerated by patients and that porphyrins are efficiently and effectively produced during this defined time and temperature range.
Management of Keratoacanthoma: 157 Tumors Treated With Surgery or Intralesional Methotrexate
Authors: Moss Max , Weber Emma , Hoverson Kara , Montemarano Andrew D.
Published: January 2019

BACKGROUND

Keratoacanthomas (KAs) are common tumors of squamous cell origin that grow rapidly and may regress; however, differentiation from an aggressive squamous cell carcinoma is problematic.

OBJECTIVE

To report the authors' experience in managing KA with intralesional methotrexate (MTX) or surgical excision.

MATERIALS AND METHODS

The authors collected data on 157 tumors (136 patients) over 6 months from a single institution.

RESULTS

There were 73 tumors (54 patients) treated with intralesional MTX. There were 9 tumors that did not resolve with intralesional MTX (88% cure). Nonresolving tumors were excised with no recurrences or complications. In all 9 cases, the nonresolving tumors were of the same size or smaller after MTX. Of the 73 tumors treated with MTX, 29 tumors (11 patients) were multiple KAs. All 29 tumors resolved (100% tumor clearance). There were no complications in any of the MTX-treated patients. Tumor clearance was defined by clinical resolution for a minimum of 6 weeks without a recurrence. There were 84 tumors (83 patients) treated with surgical excision. There were no complications and no recurrences (100% cure) with surgery.

CONCLUSION

Intralesional MTX may be considered as the initial treatment for solitary KA, multiple KA, or in poor surgical candidates.
An Unknown Renaissance Portrait of Tagliacozzi (1545–1599), the Founder of Plastic Surgery
Authors: Ménard Sophie
Published: January 2019

This article examines a recently discovered painting of a young scholar holding a reconstructed nose. Experts in ancient paintings have confirmed that the portrait is an authentic painting of the School of Bologna in Italy, from the last quarter of the Renaissance. In the 1580s, Gaspare Tagliacozzi (1545–1599), a young professor in surgery and anatomy at the University of Bologna, Italy, was the only one to carry out reconstructions of the nose and other missing parts of the face. We have looked whether different relevant components of this painting, which is presented for the first time to the medical community, could match with Tagliacozzi’s life and achievements. We have also compared the portrait to another portrait of Tagliacozzi painted circa 1597, which belongs to the institute Rizzoli in Bologna, Italy. The latter depicts Tagliacozzi as an older established surgeon. He is seen presenting his illustrated book, De Curtorum Chirurgia per Insitionem (On the surgical restoration of defects), which is the first book devoted to plastic surgery. We have concluded that the young Renaissance scholar is Tagliacozzi. This portrait and the Rizzoli’s portrait represent Tagliacozzi at the beginning and at the peak of his professional involvement in the field of plastic surgery. Tagliacozzi is the first medical doctor to practice plastic surgery as well as write about it. He also taught plastic surgery for the first time in a prestigious Renaissance school of medicine. Tagliacozzi’s illustrated book of plastic surgery published in 1597, disrupted the contemporary medical community. For all these reasons, Tagliacozzi can be considered as the founder of plastic surgery. Unfortunately, he died at the age of 54, which put a term to the development of this field. Tagliacozzi’s work was rediscovered, 2 centuries later, by the English surgeon J.C. Carpue (1764–1846) during the revival of plastic surgery.
The Diagnostic and Clinical Utility of the Myeloperoxidase–DNA Complex as a Biomarker in Otitis Media With Antineutrophil Cytoplasmic Antibody-associated Vasculitis
Authors: Morita Shinya , Nakamaru Yuji , Nakazawa Daigo , Suzuki Masanobu , Hoshino Kimiko , Fukuda Atsushi , Hattanda Fumihiko , Kusunoki Kanako , Tomaru Utano , Ishizu Akihiro , Homma Akihiro
Published: January 2019

Objective:

This prospective study aimed to evaluate the diagnostic and clinical utility of the myeloperoxidase (MPO)–DNA complex as a NETosis-derived product in the middle ear fluid of patients with otitis media with antineutrophil cytoplasmic antibody-associated vasculitis (OMAAV).

Study Design:

Prospective study.

Setting:

Tertiary referral center.

Patients:

Twenty-two patients diagnosed with OMAAV.

Intervention:

Collection of the fluid samples from middle ear.

Main Outcome Measure:

The levels of the MPO–DNA complex in the fluid samples were quantified using an enzyme-linked immunosorbent assay.

Results:

Patients with both systemic and localized forms of OMAAV showed significantly higher levels of the MPO–DNA complex compared to the controls (p < 0.001 and p = 0.002, respectively). In particular, they showed significantly higher levels of MPO–DNA complex compared to the controls, regardless of serum antineutrophil cytoplasmic antibody status (p < 0.001 and p < 0.001, respectively) or immunosuppressive therapy (p < 0.001 and p < 0.001, respectively) at the time of sampling. An optical density cutoff value of 0.16 at 405 nm according to the receiver operating characteristic curve showed a sensitivity of 86.4%, specificity of 95.5%, positive predictive value of 95.0% and negative predictive value of 87.5% for the diagnosis of OMAAV. Significant positive correlations were observed between the levels of MPO–DNA complex and the values for air conduction – (r = 0.49, p = 0.022) and bone conduction – pure tone average thresholds (r = 0.45, p = 0.035).

Conclusions:

The detection and quantification of the MPO–DNA complex in the otitis media fluid may aid in providing a definite diagnosis as well as predicting the activity and severity of OMAAV.
Sustained Improvement in Type 2 Diabetes Mellitus is Common After Treatment of Hepatitis C Virus With Direct-acting Antiviral Therapy
Authors: Gilad Amir , Fricker Zachary P. , Hsieh Adam , Thomas Dylan D. , Zahorian Toni , Nunes David P.
Published: January 2019

Goals:

To determine whether diabetic patients with hepatitis C virus (HCV) treated with direct-acting antiviral agents have improved diabetes, accounting for change in both hemoglobin A1c (HbA1c) and diabetes medications, and whether any improvement was sustained.

Background:

HCV infection is associated with an increased risk of diabetes, with improvement in glycemic control after eradication. There remains uncertainty about the durability and magnitude of this effect.

Study:

HbA1c and diabetes medications were recorded at 6-month intervals for 1.5 years pretreatment and posttreatment for 122 patients. Subjects were classified as having improved diabetes if there was a decrease in HbA1c≥0.5% with no increase in diabetes medications or a decrease in diabetes medications with a stable HbA1c.

Results:

HbA1c at the nearest time point before treatment was 8.4%±1.9%, compared with 7.8%±1.7% after treatment, a mean difference of 0.6% [95% CI (0.2, 0.9), P<0.01]. A linear mixed effects model incorporating each subject’s repeated measurements over time also demonstrated a reduction after treatment of 0.5% [95% CI, (0.3, 0.8), P<0.001]. Accounting for both HbA1c and diabetes medications, 42 of 122 (34%) had an improvement in diabetes after HCV treatment, and 20 of 28 (71%) of these subjects sustained improvement at 1.5 years follow-up. Prescription of insulin was associated with improved diabetes.

Conclusions:

Treatment of HCV with direct-acting antiviral agents was associated with improved diabetes in a significant portion of patients with an average reduction in HbA1c of clinically significant magnitude. Among responders, this effect was sustained over 1.5 years of follow-up.
Improved Understanding of Female Pelvic Medicine and Reconstructive Surgery Concepts Through Targeted Case-Based Educational Intervention: A Pilot Study
Authors: Valant Roseanna , Grigorescu Bogdan , Benerofe Sara , Lazarou George
Published: January 2019

Objectives

Given the complex anatomy and pathophysiology of urogynecologic disorders, obstetrics and gynecology residents can have difficulty learning the subject's principles. There are no standardized resources for educators in this subspecialty. We hypothesized that our case-based educational intervention was associated with enhanced knowledge and greater resident satisfaction versus traditional urogynecology lectures.

Methods

This is a prospective study involving 19 obstetrics and gynecology residents at a single institution. Residents participated in three 1-hour case-based lectures, which included prelecture and postlecture topic knowledge assessments. Nonparametric Wilcoxon signed-rank tests were used to compare the before and after responses. Resident satisfaction was assessed using a 5-point Likert scale questionnaire.

Results

The median scores for the pretraining and posttraining assessments of resident urogynecology subject knowledge were 8 (5–10) and 10 (8–10), respectively. A stratified analysis was performed based on postgraduate year (PGY) and median prelectures and postlectures scores showed statistically significance (P < 0.001). Analysis of the PGY subgroups demonstrated statistical significance in PGY1 (P = 0.004), PGY2 (P = 0.008), and PGY3 (P = 0.03). However, the PGY4 subgroup (P = 0.06) did not reach statistical significance.

All residents regardless of PGY level either agreed or strongly agreed that the case-based educational intervention enhanced resident knowledge, engagement, and clarity of the relevant teaching points and decreased resident stress about urogynecology topics.

Conclusions

The case-based educational intervention significantly improved resident knowledge in urogynecology and enhanced resident satisfaction with this teaching method versus traditional lectures.
Systematic Development of Sandwich Immunoassays for the Plasma Secretome
Authors: Häussler Ragna S. , Bendes Annika , Iglesias MariaJesus , Sanchez-Rivera Laura , Dodig-Crnković Tea , Byström Sanna , Fredolini Claudia , Birgersson Elin , Dale Matilda , Edfors Fredrik , Fagerberg Linn , Rockberg Johan , Tegel Hanna , Uhlén Mathias , Qundos Ulrika , Schwenk Jochen M.
Published: January 2019

The plasma proteome offers a clinically useful window into human health and disease. With recent progress made on the development of highly multiplexed immunoassays with high sample throughput, a remaining need is to establish a pipeline for validating the individual proteins that build such bio-signatures by using targeted assays. In order to streamline such efforts, we developed a workflow to build dual binder sandwich immunoassays (SIA) and chose to evaluate this on proteins predicted to be secreted form cells and tissues. Utilizing the multiplexing capacities of the bead array technology, we first screened ~ 1,800 unique antibody pairs against 209 protein targets and collected data from dilution series of recombinant proteins as well as EDTA plasma. Employing 624 unique antibodies from the Human Protein Atlas, we obtained dilution-dependent curves in plasma and concentration-dependent curves of full-length proteins for 102 (49%) of the targets. For 22 protein assays, the longitudinal, inter-individual and technical performance was determined in a set of plasma samples collected from 18 healthy subjects every third month over one year. Lastly, we compared 14 of these assays with SIAs composed of other binders, proximity extension assays and affinity-free targeted mass spectrometry. Our workflow provides a multiplexed approach to screen for SIA pairs that suggests using at least three antibodies per target. This design is applicable for a wider range of targets of the plasma proteome, while the assays can be applied for discovery but also to validate emerging candidates derived from other platforms.
Compressive Stress Enhances Invasive Phenotype of Cancer Cells via Piezo1 Activation
Authors: Luo Mingzhi , K. Y. Ho Kenneth , Tong Zhaowen , Deng Linhong , P. Liu Allen
Published: January 2019

Uncontrolled growth in solid tumor generates compressive stress that drives cancer cells into invasive phenotypes, but little is known about how such stress affects the invasion and matrix degradation of cancer cells and the underlying mechanisms. Here we show that compressive stress enhanced invasion, matrix degradation, and invadopodia formation of breast cancer cells. We further identified Piezo1 channels as the putative mechanosensitive cellular components that transmit the compression to induce calcium influx, which in turn triggers activation of RhoA, Src, FAK, and ERK signaling, as well as MMP-9 expression. Interestingly, for the first time we observed invadopodia with matrix degradation ability on the apical side of the cells, similar to those commonly observed at the cell’s ventral side. Furthermore, we demonstrate that Piezo1 and caveolae were both involved in mediating the compressive stress-induced cancer cell invasive phenotype as Piezo1 and caveolae were often colocalized, and reduction of Cav-1 expression or disruption of caveolae with methyl-β-cyclodextrin led to not only reduced Piezo1 expression but also attenuation of the invasive phenotypes promoted by compressive stress. Taken together, our data indicate that mechanical compressive stress activates Piezo1 channels to mediate enhanced cancer cell invasion and matrix degradation that may be a critical mechanotransduction pathway during, and potentially a novel therapeutic target for, breast cancer metastasis
Continual evolution through coupled fast and slow feedbacks
Authors: Wortel Meike T. , Peters Han , Bonachela Juan A. , Stenseth Nils Chr.
Published: January 2019

The Red Queen Hypothesis, which suggests that continual evolution can result from solely biotic interactions, has been studied in macroevolutionary and microevolutionary contexts. While microevolutionary studies have described examples in which evolution does not cease, understanding which general conditions lead to continual evolution or to stasis remains a major challenge. In many cases, it is unclear which experimental features or model assumptions are necessary for the observed continual evolution to emerge, and whether the described behavior is robust to variations in the given setup. Here, we aim to find the minimal set of conditions under which continual evolution occurs. To this end, we present a theoretical framework that does not assume any specific functional form and, therefore, can be applied to a wide variety of systems. Our framework is also general enough to cast predictions about both monomorphic and polymorphic populations. We show that the combination of a fast positive and a slow negative feedback causes continual evolution to emerge even from the evolution of one single evolving trait, provided that the ecological timescale is sufficiently separated from the timescales of mutation and the negative feedback. Our approach and results thus contribute to a deeper understanding of the evolutionary dynamics resulting from biotic interactions.
Discovering footprints of evolutionary chromatin response to transposons activity: merging biophysics with bioinformatics
Authors: Vitali S. , Giampieri E. , Criscione S. , Sala C. , Faria do Valle I. , Neretti N. , Castellani G.
Published: January 2019

Transposons are genome components that account for the majority of genome size in many organisms, behaving as parasitic entities and interfering with the translation mechanism. Chromatin structure influences the activity of transposons, by coordinating genome accessibility for the expression and insertion of these sequences. As a case study, we show evidences of an evolutionary response of the chromatin structure to a variation in the activity of Long Interspersed Elements (LINEs) during mammals evolution, with focus on the murine radiation and primate evolution. LINEs activity was measured using a biophysical approach for modeling LINEs as an ecosystem, where different strains of transposons might reproduce, die and compete for access to the translational machinery of the host. The model, based on the discrete stochastic processes of amplification and deactivation of LINEs copies, has been adapted to the data using Bayesian statistics to estimate its main parameters: rate of growth of transposons copy number and rate of past competition between transposons variants. This approach allows to estimate the activity of ancient LINE strains still present in the genome as deactivated components, and the possible competition among different strains. We leverage these results to highlight how the change in the chromatin structure of the murine species seems to be following an increase of LINEs activity during the appearance of the murine specific strain Lx. On the contrary, a similar response is absent in primates evolution, which follows a decrease of LINEs activity during the amplication of primate specific LIMA/LPB strains.
Cyclin A2/Cdk1 is Essential for the in vivo S Phase Entry by Phosphorylating Top2a
Authors: Jin Miaomiao , Hu Ruikun , Xu Baijie , Huang Weilai , Wang Hong , Chen Bo , He Jie , Cao Ying
Published: January 2019

Cyclin-dependent kinase 1 (CDK1) plays essential roles in cell cycle regulation. However, due to the early embryonic lethality of mouse Cdk1 mutants, the in vivo role of CDK1 in regulating cell cycle and embryonic development remains unclear. Here, by generating zebrafish cdk1 mutants using CRISPR/Cas9 system, we show that cdk1−/− embryos exhibit severe microphthalmia accompanied with multiple defects in polarized cell division, S phase entry and M phase progression, cell apoptosis and cell differentiation, but not in interkinetic nuclear migration (IKNM). By informatics analysis, we identified Top2a as a potential downstream target, and Cyclin A2 and Cyclin B1 as partners of Cdk1 in cell cycle. Depletion of either Cyclin A2 or Top2a leads to decreased S phase entry and increased DNA damage response in zebrafish retinal cells, and depletion of Cyclin B1 leads to M phase arrest. Immunoprecipitation shows that Cdk1 and Cyclin A2 physically interact in vivo. Moreover, phosphorylation of Top2a on Serine 1213 (S1213) site is almost absent in either cdk1 or ccna2 mutants, but in not ccnb1 mutants. Furthermore, overexpression of TOP2AS1213, the phosphomimetic form of human TOP2A, rescues S phase entry and microphthalmia defects in cdk1−/− and ccna2−/− embryos. Taken together, our data suggests that Cdk1 interacts with Cyclin A2 to regulate S phase entry through phosphorylating Top2a, and with Cyclin B1 to regulate M phase progression in vivo.
Are drug targets with genetic support twice as likely to be approved? Revised estimates of the impact of genetic support for drug mechanisms on the probability of drug approval
Authors: King Emily A. , Davis J. Wade , Degner Jacob F.
Published: January 2019

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Despite strong vetting for disease activity, only 10% of candidate new molecular entities in early stage clinical trials are eventually approved. Analyzing historical pipeline data, Nelson et al. 2015 (Nat. Genet.) concluded pipeline drug targets with human genetic evidence of disease association are twice as likely to lead to approved drugs. Taking advantage of recent clinical development advances and rapid growth in GWAS datasets, we extend the original work using updated data, test whether genetic evidence predicts future successes and introduce statistical models adjusting for target and indication-level properties. Our work confirms drugs with genetically supported targets were more likely to be successful in Phases II and III. When causal genes are clear (Mendelian traits and GWAS associations linked to coding variants), we find the use of human genetic evidence increases approval from Phase I by greater than two-fold, and, for Mendelian associations, the positive association holds prospectively. Our findings suggest investments into genomics and genetics are likely to be beneficial to companies deploying this strategy.
TheNopp140gene inDrosophila melanogasterdisplays length polymorphisms in its large repetitive second exon
Authors: Baral Sonu Shrestha , DiMario Patrick J.
Published: January 2019

Nopp140, often called the nucleolar and Cajal body phosphoprotein (NOLC1), is a predicted chaperone for the transcription and processing of rRNA as it assembles into small and large ribosomal subunits. Nopp140 is conserved among the metazoans with an amino terminal LisH dimerization domain followed by a large central domain consisting of alternating acidic and basic motifs of low sequence complexity, and then a carboxyl terminus that can be variable due to alternative splicing. Treacle is another nucleolar chaperon in vertebrates that is structurally and functionally related to Nopp140. While the large central domains of vertebrate Nopp140 and treacle are encoded by several exons, the similar domain inDrosophilaNopp140 is encoded by a single exon. We define three overlapping repeat sequence patterns (P, P’, and P’’) within the central domain ofD. melanogasterNopp140. These repeat patterns are poorly conserved in otherDrosophilaspecies. A length polymorphism for the P’ pattern inD. melanogasterdisplays either two or three 96 base pair repeats, respectively referred to asNopp140-ShortandNopp140-Long. PCR characterization of the long and short alleles shows a poorly-defined, artefactual bias toward amplifying the long allele over the short allele. Fly lines homozygous for one or the other allele, or heterozygous for both alleles, show no discernible phenotypes. The significance of this polymorphism lies in discerning the properties of the Nopp140’s large central domain in assemblage and phase separations in nucleoli and Cajal bodies.
MS-EmpiRe utilizes peptide-level noise distributions for ultra sensitive detection of differentially abundant proteins
Authors: Ammar Constantin , Gruber Markus , Csaba Gergely , Zimmer Ralf
Published: January 2019

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Mass spectrometry based proteomics is the method of choice for quantifying genome-wide differential changes of proteins in a wide range of biological and biomedical applications. Protein changes need to be reliably derived from a large number of measured peptide intensities and their corresponding fold changes. These fold changes vary considerably for a given protein.

Numerous instrumental setups aim to reduce this variability, while current computational methods only implicitly account for this problem. We introduce a new method, MS-EmpiRe (github.com/zimmerlab/MS-EmpiRe), which explicitly accounts for the noise underlying peptide fold changes. We derive dataset-specific, intensity-dependent empirical error distributions, which are used for individual weighing of peptide fold changes to detect differentially abundant proteins. The method requires only peptide intensities mapped to proteins and, thus, can be applied to any common quantitative proteomics setup. In a recently published proteome-wide benchmarking dataset, MS-EmpiRe doubles the number of correctly identified changing proteins at a correctly estimated FDR cutoff in comparison to state-of-the-art tools. We confirm the superior performance of MS-EmpiRe on simulated data. MS-EmpiRe provides rapid processing (< 2min) and is an easy to use, general-purpose tool.
Perceptions and prospects in life sciences in a heterogeneous Latin American population
Authors: Ferreira Leonardo M.R. , Carosso Giovanni A. , Lopez-Videla Bruno , Diez Gustavo Vaca , Rivera-Betancourt Laura Ines , Rodriguez Yara , Ordonez Dalila G. , Duran Natalia Montellano , Alatriste-Gonzalez Diana K. , Vacaflores Aldo , Bohorquez Soad , Auza Lilian Gonzalez , Schuetz Christian , Alexander-Savino Carolina V. , Cuellar Omar Gandarilla , Mostajo-Radji Mohammed A.
Published: January 2019

Particular challenges exist for science education in the developing world, where limited resources beget curricula designed to balance state-of-the-art knowledge with practical and political considerations in region-specific contexts. Project-based biology teaching is particularly difficult to execute due to high infrastructural costs and limited teacher training. Here, we report our results implementing short, challenging, and low-cost biology courses to high school and college students in Bolivia, designed and taught in collaboration between scientists from developed nations and local science instructors. We find our approach to be effective at transmitting advanced topics in disease modeling, microscopy, genome engineering, neuroscience, microbiology, and regenerative biology. Importantly, this approach was unaffected by the students’ backgrounds, education level, socioeconomic status, or initial interest in the course, and increased participants’ interest in pursuing scientific careers. These results demonstrate efficacy of participatory learning in a developing nation, and suggest that such techniques could drive scientific engagement in other developing economies.
Implementation and Integration of Microbial Source Tracking in a River Watershed Monitoring Plan
Authors: Ballesté Elisenda , Demeter Katalin , Masterson Bartholomew , Timoneda Natàlia , Meijer Wim G.
Published: January 2019

Fecal pollution of water bodies poses a serious threat for public health and ecosystems. Microbial source tracking (MST) using host specific bacteria are used to track the source of this potential pollution and be able to perform a better management of the pollution at the source. In this study we tested 12 molecular MST markers to track human, ruminant, sheep, horse, pig and gull pollution to determine their usefulness in their application for an effective management of water quality. First, the potential of the selected markers to track the source was evaluated using fresh fecal samples. Subsequently, we evaluated their performance in a catchment with different impacts, considering land use and environmental conditions. All MST markers showed high sensitivity and specificity, although none achieved 100% for both. Although some of the MST markers were detected in hosts other than the intended ones, their abundance in the target group was always several orders of magnitude higher than in the non-target hosts, demonstrating their suitability to distinguish between sources of pollution. The MST analysis matched the land use in the watershed allowing a very accurate assessment of the main hazards and sources of pollution, in this case mainly human and ruminant pollution. Correlating environmental parameters like temperature and rainfall with the levels of the MST markers provided insight into the dynamics of the pollution along the catchment. The levels of the human associated marker showed a significant negative correlation with rainfall in human polluted areas suggesting a dilution of the pollution, whereas at agricultural areas the ruminant marker increased with rainfall. There were no seasonal differences in the levels of human marker, indicating human pollution as a constant pressure throughout the year, whereas the levels of the ruminant marker was influenced by the seasons, being more abundant in summer and autumn. Performing MST analysis integrated with land uses and environmental data can improve the management of fecal polluted areas and set up good practices.