bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of Nephrotoxicity Associated with Once-Daily Administration of Aminoglycoside
Authors: Nodoushani Mojgan , Nicolau David P , Hitt Catherine M , Quintiliani Richard , Nightingale Charles H
Published: July 2017

Objective:

To determine the potential risk factors associated with nephrotoxicity in patients receiving once-daily aminoglycoside (ODA) therapy.

Design:

Case series.

Setting:

Large community teaching hospital.

Patients:

Twenty-five patients considered nephrotoxic during ODA therapy.

Main Outcome Measures:

This study is a retrospective chart review of patients in whom nephrotoxicity developed during ODA therapy. Nephrotoxicity was defined as a rise in serum creatinine (SCr) concentration of 0.5 mg/dL or more above the preaminoglycoside baseline value. Patients were identified from our institutional ODA database. Based on the previously identified risk factors for aminoglycoside-associated nephrotoxicity with conventional aminoglycoside therapy published by Bertino et al., a data collection tool was developed. Collected data included demographic information, concurrently administered drugs, diagnostic agents used, and potential comorbidity risk factors.

Results:

Similar to what has been found in patients receiving conventional aminoglycoside regimens, numerous risk factors, such as the concomitant use of cephalosporins, loop diuretics, intravenous contrast dye, angiotensin-converting enzyme inhibitors, and nonsteroidal antiinflammatory drugs, may have been responsible for the rise in SCr observed in our study population. In addition, common comorbidity risk factors in this population were pleural effusion, pneumonia, decrease in systolic blood pressure to less than 80 mm Hg, and preexisting renal disease.

Conclusions:

Nephrotoxicity is the result of multifactorial processes and is not solely due to the ODA administration technique.
Tissue-type plasminogen activator regulates macrophage activation and innate immunity
Authors: Mantuano Elisabetta , Azmoon Pardis , Brifault Coralie , Banki Michael A. , Gilder Andrew S. , Campana Wendy M. , Gonias Steven L.
Published: July 2017

Key Points

Tissue-type plasminogen activator inhibits the activity of the innate immune system in macrophages in vitro and in vivo in mice. Suppression of macrophage proinflammatory responses by tPA requires the NMDA receptor.
Joint analysis of left ventricular expression and circulating plasma levels of Omentin after myocardial ischemia
Authors: Saddic Louis A. , Nicoloro Sarah M. , Gupta Olga T. , Czech Michael P. , Gorham Joshua , Shernan Stanton K. , Seidman Christine E. , Seidman Jon G. , Aranki Sary F. , Body Simon C. , Fitzgibbons Timothy P. , Muehlschlegel Jochen D.
Published: July 2017

Background

Omentin-1, also known as Intelectin-1 (ITLN1), is an adipokine with plasma levels associated with diabetes, obesity, and coronary artery disease. Recent studies suggest that ITLN1 can mitigate myocardial ischemic injury but the expression of ITLN1 in the heart itself has not been well characterized. The purpose of this study is to discern the relationship between the expression pattern of ITLN1 RNA in the human heart and the level of circulating ITLN1 protein in plasma from the same patients following myocardial ischemia.

Methods

A large cohort of patients (n = 140) undergoing elective cardiac surgery for aortic valve replacement were enrolled in this study. Plasma and left ventricular biopsy samples were taken at the beginning of cardiopulmonary bypass and after an average of 82 min of ischemic cross clamp time. The localization of ITLN1 in epicardial adipose tissue (EAT) was also further characterized with immunoassays and cell fate transition studies.

Results

mRNA expression of ITLN1 decreases in left ventricular tissue after acute ischemia in human patients (mean difference 280.48, p = 0.001) whereas plasma protein levels of ITLN1 increase (mean difference 5.24, p < 0.001). Immunohistochemistry localized ITLN1 to the mesothelium or visceral pericardium of EAT. Epithelial to mesenchymal transition in mesothelial cells leads to a downregulation of ITLN1 expression.

Conclusions

Myocardial injury leads to a decrease in ITLN1 expression in the heart and a corresponding increase in plasma levels. These changes may in part be due to an epithelial to mesenchymal transition of the cells that express ITLN1 following ischemia.

Trial Registration Clinicaltrials.gov ID: NCT00985049
Automating the Determination of Prostate Cancer Risk Strata From Electronic Medical Records
Authors: Gregg Justin R. , Lang Maximilian , Wang Lucy L. , Resnick Matthew J. , Jain Sandeep K. , Warner Jeremy L. , Barocas Daniel A.
Published: July 2017

Purpose

Risk stratification underlies system-wide efforts to promote the delivery of appropriate prostate cancer care. Although the elements of risk stratum are available in the electronic medical record, manual data collection is resource intensive. Therefore, we investigated the feasibility and accuracy of an automated data extraction method using natural language processing (NLP) to determine prostate cancer risk stratum.

Methods

Manually collected clinical stage, biopsy Gleason score, and preoperative prostate-specific antigen (PSA) values from our prospective prostatectomy database were used to categorize patients as low, intermediate, or high risk by D’Amico risk classification. NLP algorithms were developed to automate the extraction of the same data points from the electronic medical record, and risk strata were recalculated. The ability of NLP to identify elements sufficient to calculate risk (recall) was calculated, and the accuracy of NLP was compared with that of manually collected data using the weighted Cohen’s κ statistic.

Results

Of the 2,352 patients with available data who underwent prostatectomy from 2010 to 2014, NLP identified sufficient elements to calculate risk for 1,833 (recall, 78%). NLP had a 91% raw agreement with manual risk stratification (κ = 0.92; 95% CI, 0.90 to 0.93). The κ statistics for PSA, Gleason score, and clinical stage extraction by NLP were 0.86, 0.91, and 0.89, respectively; 91.9% of extracted PSA values were within ± 1.0 ng/mL of the manually collected PSA levels.

Conclusion

NLP can achieve more than 90% accuracy on D’Amico risk stratification of localized prostate cancer, with adequate recall. This figure is comparable to other NLP tasks and illustrates the known tradeoff between recall and accuracy. Automating the collection of risk characteristics could be used to power real-time decision support tools and scale up quality measurement in cancer care.
Survival Disparities by Hospital Volume Among American Women With Gynecologic Cancers
Authors: Seagle Brandon-Luke L. , Strohl Anna E. , Dandapani Monica , Nieves-Neira Wilberto , Shahabi Shohreh
Published: July 2017

Purpose

We describe survival disparities among women with uterine, ovarian, or cervical cancer by cancer-specific mean annual hospital volume.

Methods

National Cancer Database 1998-2011 uterine (n = 441,863), ovarian (n = 223,017), and cervical (n = 146,698) cancer data sets were used. Cancer-specific mean annual hospital volumes were calculated. Overall survival (OS) was plotted by hospital volume using restricted mean OS times from Cox regression.

Results

Uterine, ovarian, and cervical cancers were reported from 1,651, 1,633, and 1,600 hospitals, respectively. Median values of mean annual hospital volumes among hospitals were 8.6 (interquartile range [IQR], 2.6 to 20.8), 4.4 (IQR, 1.4 to 10.3), and 2.4 (IQR, 0.6 to 6.6) for uterine, ovarian, and cervical cancers, respectively. Increased hospital volume was associated with increased OS among women with stage III to IV high-grade serous ovarian cancer, stage II to IV squamous or adenocarcinoma cervical cancer, and stage I to IV endometrioid, clear cell, serous, or carcinosarcoma uterine cancers (all P < .03). Differential OS between women treated at higher- versus lower-volume cancer centers exceeded 5, 5, and 13 months among women with advanced endometrial, ovarian, or cervical cancer, respectively (all P < .001). Hospital volume was not associated with OS among patients with stage II to IV cervical cancer treated with brachytherapy ( P = .17). Use of adjuvant therapies decreased OS disparities by hospital volume among women with advanced ovarian or endometrial cancer.

Conclusion

Increased delivery of brachytherapy for treatment of cervical cancer may decrease survival disparities by hospital volume. Standardization of adjuvant therapies may diminish survival disparities by hospital volume among women with advanced ovarian or endometrial cancer. In addition, survival of American women with gynecologic cancer may be increased by centralization of care.
Chart Review Versus an Automated Bioinformatic Approach to Assess Real-World Crizotinib Effectiveness in Anaplastic Lymphoma Kinase–Positive Non–Small-Cell Lung Cancer
Authors: Bui Nam , Henry Solomon , Wood Douglas , Wakelee Heather A. , Neal Joel W.
Published: July 2017

Purpose

The efficacy of targeted therapies such as crizotinib in anaplastic lymphoma kinase–positive non–small-cell lung cancer has been well established by multiple clinical trials. However, clinical trials involve highly selected participants, and manual data curation is resource intensive. With the increasing use of electronic medical records, there is potential for the development of electronic algorithms that could quickly generate outcomes data, but the validation of such algorithms requires comparison with historical methods, such as retrospective chart review.

Materials and Methods

Using a cohort of patients with anaplastic lymphoma kinase–positive non–small-cell lung cancer, we performed manual chart review to retrospectively evaluate time on treatment (TOT) for crizotinib and cytotoxic chemotherapies. Thirty-three patients were identified, with a total of 70 regimens administered. We developed a computational algorithm to mine electronic charts for crizotinib therapy data and correlated that with manually curated data.

Results

Among the 24 patients who received crizotinib, the median TOT was 8.5 months. The computational algorithm was able to extract TOT data for 15 out of 24 patients treated with crizotinib (62.5%). Most of the patients for whom data could not be automatically extracted were treated within a clinical trial. Pearson’s correlation coefficient between the two methods was 0.39 ( P = .15); however, there were five outliers as a result of incorrect provider notation and nonstandard treatment patterns that severely skewed the correlation.

Conclusion

An automated method of extracting patient TOT is feasible but requires additional optimizations to handle outliers. We are currently working on improving the algorithm to better correct for outliers. Automated generation of treatment data potentially represents a viable approach to perform retrospective outcomes analysis.
Visualization of Cancer and Cardiovascular Disease Co-Occurrence With Network Methods
Authors: Duarte Christine W. , Lindner Volkhard , Francis Sanjeev A. , Schoormans Dounya
Published: July 2017

Purpose

Cancer and cardiovascular disease (CVD) are common causes of morbidity and mortality, and measurement and interpretation of their co-occurrence rate have important implications for public health and patient care. Here, we present the raw and adjusted co-occurrence rates of cancer and CVD in the overall population by using a visually intuitive network approach.

Methods

By using baseline survey and linked health outcome data from 490,842 individuals age 40 to 69 years from the UK Biobank, we recorded diagnoses between 1997 and 2014 of specific cancers and specific CVDs ascertained through hospital claims. We measured raw and adjusted rates of CVD for the following groups: individuals with Hodgkin or non-Hodgkin lymphoma, lung and trachea cancer, uterus cancer, colorectal cancer, prostate cancer, breast cancer, or no recorded diagnosed cancer during this time period. Analysis accounted for age, sex, and behavioral risk factors, without regard to the order of occurrence of cancer and CVD.

Results

A significantly increased rate of CVD was found in patients with multiple types of cancers, including Hodgkin and non-Hodgkin lymphoma and lung and trachea, uterus, colorectal, and breast cancer, compared with patients without cancer by using age and sex-adjusted models. Increased co-occurrence for many CVD categories remained after correction for behavioral risk factors. Construction of co-occurrence networks highlighted heart failure as a shared CVD diagnosis across multiple cancer types, including breast cancer, lung cancer, non-Hodgkin lymphoma, and colorectal cancer. Smoking, physical activity, and other lifestyle factors accounted for some but not all of the increased co-occurrence for many of the CVD diagnoses.

Conclusion

Increased co-occurrence of several common CVD conditions is seen widely across multiple malignancies, and shared diagnoses, such as heart failure, were highlighted by using network methods.
Epidemiologic Analysis Along the Mevalonate Pathway Reveals Improved Cancer Survival in Patients Who Receive Statins Alone and in Combination With Bisphosphonates
Authors: El-Refai Sherif M. , Brown Joshua D. , Arnold Susanne M. , Black Esther P. , Leggas Markos , Talbert Jeffery C.
Published: July 2017

Purpose

Cohort studies report associations between statin use and improved survival in patients with cancer. We used pharmacoepidemiologic methods to evaluate the survival of patients with cancer who received statins alone or in ostensibly synergistic drug combinations.

Materials and Methods

Patients with cancer who were diagnosed from 2010 to 2013 were identified in a large health care claims database. The rate of all-cause death up to 1 year after diagnosis was compared by Cox proportional hazard regression. Sensitivity analyses included age stratification, statin type and intensity, and comparison with or without bisphosphonates and dipyridamole.

Results

Among 312,907 identified patients with cancer, treatment groups included statin users (n = 65,440), nonstatin users who received medications that block cholesterol absorption (n = 9,289), and nonusers (n = 226,007). Statin use before diagnosis was associated with improved overall survival compared with no treatment (hazard ratio [HR], 0.85; 95% CI, 0.80 to 0.91) and specifically in patients with leukemia, lung, or renal cancers. Nonstatin users had increased overall survival compared with no treatment (HR, 0.73; 95% CI, 0.62 to 0.85); when stratified, this difference held true only for pancreatic cancer and leukemia. No differences were observed between statin and nonstatin groups. Bisphosphonate use alone had no effect (n = 4,528), but patients who used both statins and bisphosphonates (n = 4,090) had increased survival compared with no treatment (HR, 0.60; 95% CI, 0.45 to 0.81). The effect of the combination of dipyridamole and statin use (n = 651) was not significant compared with no treatment.

Conclusion

This study suggests that the combination of statins with drugs that affect isoprenylation, such as bisphosphonates, improves survival in patients with cancer. Consideration of pathway-specific pharmacology allows for hypotheses testing with the pharmacoepidemiologic approach. Prospective evaluation of these findings warrants clinical investigation and preclinical mechanistic studies.
Feasibility and Acceptability of a Web Site to Promote Survivorship Care in Survivors of Hodgkin Disease
Authors: Underhill Meghan L. , Hong Fangxin , Jones Tarsha , Sprunck-Harrild Kim , Walsh Sarah K. , Boyajian Richard , Berry Donna L. , Partridge Ann
Published: July 2017

Purpose

Evaluate rates of enrollment, completion, and patient-reported acceptability of an educational survivorship-care Web site for survivors of Hodgkin disease (HD).

Patients and Methods

The study was a mixed-method evaluation design. Eligible participants were adults who had completed treatment of a primary diagnosis of HD ≥ 2 years before enrollment. Patients were recruited through postal mail and telephone and were asked to review a Web site, complete an adapted version of the Acceptability E-scale (total score of 24 or greater indicates acceptability), and respond to a structured telephone or e-mail interview to discuss experiences with the Web site.

Results

Of 259 potentially eligible participants identified by medical record review, 124 survivors had confirmed contact with study staff and were invited to participate; 63 people (50.8%; 90% CI, 43% to 59%) enrolled; 37 participants (58.7%) were men. The median age at time of enrollment was 51.0 years (range, 29.3 to 80.0 years), and the median time since completion of treatment of HD was 14.9 years (range, 3 to 38.75 years). Overall, 82.5% of those enrolled viewed all Web site content. Forty-eight participants completed the acceptability survey, which resulted in a mean acceptability score of 26.5 (standard deviation, 3.5). The majority of enrollees (67%) completed a follow-up interview.

Conclusion

Overall, HD survivor participants viewed the content and reviewed it favorably. A Web-based intervention is a promising way to provide survivors of HD with information about how to manage the long-term and late effects from cancer and treatment, and provide trusted survivorship resources.
Next-Generation Sequencing Reveals Potentially Actionable Alterations in the Majority of Patients With Lymphoid Malignancies
Authors: Goodman Aaron M. , Choi Michael , Wieduwilt Matthew , Mulroney Carolyn , Costello Caitlin , Frampton Garrett , Miller Vincent , Kurzrock Razelle
Published: July 2017

Purpose

Next-generation sequencing (NGS) identifies potentially targetable alterations by US Food and Drug Administration (FDA)–approved drugs and/or by available experimental agents that may not have otherwise been contemplated. Many targeted drugs have been developed for diverse solid cancers; a smaller number of genomically targeted drugs have been approved for lymphoid malignancies.

Materials and Methods

We analyzed NGS results from 60 patients with various lymphoid malignancies and found 224 alterations (median per patient, three alterations).

Results

Forty-nine patients (82%) had potentially actionable alterations with the use of FDA-approved drugs and/or experimental therapies; only 11 patients (18%) had no theoretically actionable alterations. Only three patients (5%) had an alteration for which an approved drug in the disease is available (on label); 45 patients (75%) had an alteration for which an approved drug is available for another disease (off label). The median number of alterations per patient potentially actionable by an FDA-approved drug was one. Of note, 19 (32%) of 60 patients had intermediate to high tumor mutational burden, which may predict response to certain immunotherapy agents.

Conclusion

NGS identifies alterations that may be pharmacologically tractable in most patients with lymphoid malignancies, albeit with drugs that have usually been developed in the context of solid tumors. These observations merit expanded exploration in the clinical trials setting.
Circulating Tumor DNA Analysis and Functional Imaging Provide Complementary Approaches for Comprehensive Disease Monitoring in Metastatic Melanoma
Authors: Wong Stephen Q. , Raleigh Jeanette M. , Callahan Jason , Vergara Ismael A. , Ftouni Sarah , Hatzimihalis Athena , Colebatch Andrew J. , Li Jason , Semple Timothy , Doig Kenneth , Mintoff Christopher , Sinha Devbarna , Yeh Paul , Silva Maria Joao , Alsop Kathryn , Thorne Heather , Bowtell David D. , Gyorki David E. , Arnau Gisela Mir , Cullinane Carleen , Kee Damien , Brady Benjamin , Kelleher Fergal , Dawson Mark A. , Papenfuss Anthony T. , Shackleton Mark , Hicks Rodney J. , McArthur Grant A. , Sandhu Shahneen , Dawson Sarah-Jane
Published: July 2017

Purpose

Circulating tumor DNA (ctDNA) allows noninvasive disease monitoring across a range of malignancies. In metastatic melanoma, the extent to which ctDNA reflects changes in metabolic disease burden assessed by 18F-labeled fluorodeoxyglucose positron emission tomography (FDG-PET) is unknown. We assessed the role of ctDNA analysis in combination with FDG-PET to monitor tumor burden and genomic heterogeneity throughout treatment.

Patients and Methods

We performed a comprehensive analysis of serial ctDNA and FDG-PET in 52 patients who received systemic therapy for metastatic melanoma. Next-generation sequencing and digital polymerase chain reaction were used to analyze plasma samples from the cohort.

Results

ctDNA levels were monitored across patients with mutant BRAF, NRAS, and BRAF/NRAS wild type disease. Mutant BRAF and NRAS ctDNA levels correlated closely with changes in metabolic disease burden throughout treatment. TERT promoter mutant ctDNA levels also paralleled changes in tumor burden, which provide an alternative marker for disease monitoring. Of note, subcutaneous and cerebral disease sites were not well represented in plasma. Early changes in ctDNA and metabolic disease burden were important indicators of treatment response. Patients with an early decrease in ctDNA post-treatment had improved progression-free survival compared with patients in whom ctDNA levels remained unchanged or increased over time (hazard ratio, 2.6; P = .05). ctDNA analysis contributed key molecular information through the identification of putative resistance mechanisms to targeted therapy. A detailed comparison of the genomic architecture of plasma and multiregional tumor biopsy specimens at autopsy revealed the ability of ctDNA to comprehensively capture genomic heterogeneity across multiple disease sites.

Conclusion

The findings highlight the powerful role of ctDNA in metastatic melanoma as a complementary modality to functional imaging that allows real-time monitoring of both tumor burden and genomic changes throughout therapy.
ROS1 Gene Fusion in Advanced Lung Cancer in Women: A Systematic Analysis, Review of the Literature, and Diagnostic Algorithm
Authors: Marchetti Antonio , Barberis Massimo , Di Lorito Alessia , Pace Maria Vittoria , Di Lisio Chiara , Felicioni Lara , Guerini-Rocco Elena , Vingiani Andrea , D’Antuono Tommaso , Liberatore Marcella , Filice Giampaolo , De Luca Graziano , De Marinis Filippo , Passaro Antonio , Guetti Luigi , Irtelli Luciana , Crinò Lucio , Mucilli Felice , Buttitta Fiamma
Published: July 2017

Purpose

Crizotinib, a mesenchymal-epithelial transition/anaplastic lymphoma kinase/c-ros oncogene 1 (ROS1) inhibitor, has recently been approved by the US Food and Drug Administration for the treatment of patients with advanced ROS1-positive non–small-cell lung cancer (NSCLC). Therefore, interest in ROS1 testing is growing. ROS1 gene fusions affect approximately 0.5% to 2% of unselected NSCLCs. Limited data are available on the prevalence and distribution of ROS1 fusions in patients with advanced-stage NSCLC.

Material and Methods

A series of 727 lung adenocarcinomas from patients with stage IV disease, negative for epidermal growth factor receptor and anaplastic lymphoma kinase alterations, were tested for ROS1 fusions by fluorescent in situ hybridization analysis, with confirmation by immunohistochemistry. Results were correlated with clinicopathologic parameters and compared with data from the literature.

Results

ROS1 fusions were detected in 29 patients (4%), including 27 of 266 females (10.2%) and two of 461 males (0.4%; P = 1.2E-10). The mean age of patients with ROS1-positive disease was lower than that of patients with ROS1-negative disease (49.21 v 62.96 years, respectively; P = 1.1E-10). Eleven of 583 smokers (1.9%) and 18 of 144 nonsmokers (12.5%) showed ROS1 rearrangement ( P = 4.05E-7). By logistic regression analysis, ROS1 fusions were independently associated with female sex, younger age at diagnosis, and absence of smoking history, (odds ratios, 12.4, 7.9, and 3.6, respectively). These data, integrated with those reported in the literature, indicate that the prevalence of ROS1 fusions in females and in nonsmokers was higher in patients with advanced disease than in patients with operable disease (11.2% v 3.1%, P < .001; 11.6% v 2.8%, P < .001, respectively). The mean age at diagnosis was significantly lower in patients with advanced disease (49.8 years) than in patients with operable disease (55.6 years; P < .001).

Conclusion

Our data indicate that ROS1 fusions in patients with advanced-stage lung adenocarcinoma are more frequent in females, particularly if young and nonsmokers. A diagnostic algorithm for an accurate screening of ROS1 alterations was elaborated.
Combined Targeted Therapy for BRAF-Mutant, Treatment-Related Acute Myeloid Leukemia
Authors: Wander Seth A. , Hasserjian Robert P. , Oduro Kwadwo , Glomski Krzysztof , Nardi Valentina , Cote Gregory M. , Graubert Timothy A. , Brunner Andrew M. , Chen Yi-Bin A. , Fathi Amir T.
Published: July 2017

A 44-year-old woman with a prior history of myxoid liposarcoma who was previously treated with radiation, chemotherapy, and resection, was admitted with syncope and pancytopenia. She was diagnosed with a high-grade therapy-related myelodysplastic syndrome and treated with decitabine. Her disease soon progressed to overt acute myeloid leukemia (AML). She was treated with cytotoxic chemotherapy including cytarabine and topotecan, but she was not a candidate for further anthracycline exposure given her prior treatment for sarcoma and concern for cardiotoxicity. Her AML was refractory to two sequential induction regimens. Given that targeted genomic sequencing had revealed a BRAF V600E mutation with a high allelic fraction, she was then placed on combined targeted BRAF/MEK therapy with dabrafenib and trametinib for her refractory disease. This resulted in a dramatic response with clearance of circulating myeloblasts, restoration of normal hematopoiesis, a significant decrease in marrow leukemic burden, and a concordant decrease in the BRAF V600E allelic burden. The response was transient, however, with a rapid increase in circulating blasts a few weeks later. At the time of subsequent progression, four separate KRAS mutations were identified. She died approximately 4 months after her diagnosis from rapidly progressive AML.
Molecular Testing in Patients With Castration-Resistant Prostate Cancer and Its Impact on Clinical Decision Making
Authors: Tao Derrick L. , Bailey Shawna , Beer Tomasz M. , Foss Erik , Beckett Brooke , Fung Alice , Foster Bryan R. , Guimaraes Alexander , Cetnar Jeremy P. , Graff Julie N. , Eilers Kristine M. , Small Eric J. , Corless Christopher L. , Thomas George V. , Alumkal Joshi J.
Published: July 2017

Purpose

Metastatic castration-resistant prostate cancer (CRPC) is the lethal form of the disease. Many groups have performed mutational or immunohistochemistry (IHC) testing in metastatic CRPC to identify treatment targets. However, the frequency with which mutational or IHC data have an impact on clinical decision making and the outcomes of molecularly guided therapy in CRPC are largely unknown. We report our institution’s experience with mutational and IHC testing in patients with metastatic CRPC and its impact on clinical decision making and patient outcomes.

Methods

Between 2012 and 2015, 59 patients with CRPC underwent metastatic tissue biopsies and were genotyped with a 37–cancer gene panel in a Clinical Laboratory Improvement Amendments–certified laboratory. PTEN expression by IHC testing was also measured in 35 of these samples. A retrospective chart review was performed to determine whether the genomic information was acted upon and the outcome of patients whose treatment was guided by molecular testing.

Results

Forty-six of 59 patients with CRPC (78.0%) had biopsies with adequate tumor for mutational testing. Thirty-one of 46 subjects (67.4%) had mutations identified by sequencing. Of the 35 patients with CRPC whose biopsies were evaluated for PTEN expression by IHC testing, 13 had PTEN loss. Two patients had treatment on the basis of molecular testing, and one of these subjects had greater tumor control with molecularly guided therapy than his immediate prior therapy.

Conclusion

Targeted sequencing and IHC can identify clinically informative molecular abnormalities in CRPC. Despite this, a small minority of patients in our series underwent therapies guided by mutational or IHC testing. Actionability of abnormalities identified in metastatic CRPC may be improved with access to clinical trials, insurance approval for unapproved uses of existing anticancer drugs, and larger gene sequencing panels that include more frequently mutated genes.
Presidential Address: Memory and Mobility: Grandma’s Mahnomen, White Earth
Authors: O’Brien Jean M.
Published: July 2017

In Jean M. O’Brien’s 2013 American Society for Ethnohistory Presidential Address, “Memory and Mobility: Grandma’s Mahnomen, White Earth,” she uses reminiscences of her grandmother, Edna Wright Tonneson, to explore the coming of her family to the White Earth Ojibwe Reservation in northwestern Minnesota in the late nineteenth century. Like many others from White Earth, her family’s story of reservation life involved ongoing patterns of mobility that predated and postdated their life on White Earth. While allotment policy drew them to the reservation, subsequent dispossession spurred further mobility but did not displace their identity as White Earth Ojibwes.
Defects in dosage compensation impact global gene regulation in the mouse trophoblast
Authors: Sakata Yuka , Nagao Koji , Hoki Yuko , Sasaki Hiroyuki , Obuse Chikashi , Sado Takashi
Published: July 2017

Xist RNA, which is responsible for X inactivation, is a key epigenetic player in the embryogenesis of female mammals. Of the several repeats conserved in Xist RNA, the A-repeat has been shown to be essential for its silencing function in differentiating embryonic stem cells. Here, we introduced a new Xist allele into mouse that produces mutated Xist RNA lacking the A-repeat (XistCAGΔ5′). XistCAGΔ5′ RNA expressed in the embryo coated the X chromosome but failed to silence it. Although imprinted X inactivation was substantially compromised upon paternal transmission, allele-specific RNA-seq in the trophoblast revealed that XistCAGΔ5′ RNA still retained some silencing ability. Furthermore, the failure of imprinted X inactivation had more significant impacts than expected on genome-wide gene expression. It is likely that dosage compensation is required not only for equalizing X-linked gene expression between the sexes but also for proper global gene regulation in differentiated female somatic cells.
Acetylcholinesterase plays a non-neuronal, non-esterase role in organogenesis
Authors: Pickett Melissa A. , Dush Michael K. , Nascone-Yoder Nanette M.
Published: July 2017

Acetylcholinesterase (AChE) is crucial for degrading acetylcholine at cholinergic synapses. In vitro studies suggest that, in addition to its role in nervous system signaling, AChE can also modulate non-neuronal cell properties, although it remains controversial whether AChE functions in this capacity in vivo. Here, we show that AChE plays an essential non-classical role in vertebrate gut morphogenesis. Exposure of Xenopus embryos to AChE-inhibiting chemicals results in severe defects in intestinal development. Tissue-targeted loss-of-function assays (via microinjection of antisense morpholino or CRISPR-Cas9) confirm that AChE is specifically required in the gut endoderm tissue, a non-neuronal cell population, where it mediates adhesion to fibronectin and regulates cell rearrangement events that drive gut lengthening and digestive epithelial morphogenesis. Notably, the classical esterase activity of AChE is dispensable for this activity. As AChE is deeply conserved, widely expressed outside of the nervous system, and the target of many environmental chemicals, these results have wide-reaching implications for development and toxicology.
Wnt signalling controls the response to mechanical loading during zebrafish joint development
Authors: Brunt Lucy H. , Begg Katie , Kague Erika , Cross Stephen , Hammond Chrissy L.
Published: July 2017

Joint morphogenesis requires mechanical activity during development. Loss of mechanical strain causes abnormal joint development, which can impact long-term joint health. Although cell orientation and proliferation are known to shape the joint, dynamic imaging of developing joints in vivo has not been possible in other species. Using genetic labelling techniques in zebrafish we were able, for the first time, to dynamically track cell behaviours in intact moving joints. We identify that proliferation and migration, which contribute to joint morphogenesis, are mechanically controlled and are significantly reduced in immobilised larvae. By comparison with strain maps of the developing skeleton, we identify canonical Wnt signalling as a candidate for transducing mechanical forces into joint cell behaviours. We show that, in the jaw, Wnt signalling is reduced specifically in regions of high strain in response to loss of muscle activity. By pharmacological manipulation of canonical Wnt signalling, we demonstrate that Wnt acts downstream of mechanical activity and is required for joint patterning and chondrocyte maturation. Wnt16, which is also downstream of muscle activity, controls proliferation and migration, but plays no role in chondrocyte intercalation.
Chelsea, Pimlico and Belgravia District Nursing Association 1930–1939: A case study
Authors: Bliss Julie
Published: July 2017

The case study explores how the expansion of the health services during the interwar period impacted upon the status of district nursing and examines how being a voluntary service shaped district nursing associations. A range of primary sources were used; the Association Annual Reports, the Medical Officer for Health Annual Reports for the Borough of Chelsea, the Ministry of Health records, the archives of the Queen's Nursing Institute (QNI) and the Borough of Chelsea Council Minutes.

The Medical Officer for Health Reports and the Council minutes identify efforts to improve environmental factors that impacted upon health. These primary sources briefly note the contribution of the Association suggesting that it was integral to the health care provision but considered a constant. The impact of changes to the 1932 Sunday Entertainments Act provide an interesting juxtaposition between the acknowledged value of district nursing and the constant struggle to fundraise in order to provide home nursing. Throughout the 1930s the Association experienced staff shortages and challenges regarding recruitment. The complexities of payment for municipal health services following the 1929 Local Government Act contributed to the staffing challenges. The move to a block grant in 1938 provided increased stability with regards to income.

The case study identifies a contradiction regarding the esteem and value placed upon district nursing associations providing home nursing and the constant challenge of resources. District nursing services face similar challenges and this is the 130th anniversary of the Queen's Nursing Institute.
Pet dogs as promoters of wellbeing
Authors: While Alison
Published: July 2017

The rise in life expectancy requires strategies to enable healthy ageing and the promotion of a high quality of life in old age. Poor mental health including depression and social isolation can blight older people's lives. Despite the positive benefits of physical activity for both mental and physical health, only a minority of those over 65 years are attaining the recommended levels of physical activity. The evidence relating to the benefits of pet dogs as promoters of wellbeing is set out in this article, although meeting their care needs may place an additional strain on an older person and/or their carer who has limited resources and physical capabilities.
Fathers and breastfeeding: Attitudes, involvement and support
Authors: Al Namir Hibah Maki A , Brady Anne-Marie , Gallagher Louise
Published: July 2017

Background

Fathers are recognised as a major source of social support for breastfeeding mothers. Mothers repeatedly identify their infant's father as an important part of the decision to breastfeed, yet limited research has focused on fathers and breastfeeding.

Aims

To review existing literature on the attitudes of fathers towards breastfeeding and their involvement in supporting mothers.

Methods

Studies were initially grouped according to research design, then each appraised against quality standards for respective designs. The selected studies were then re-grouped under themes and a narrative synthesising approach to findings was undertaken to develop the discussion. Data sources included a library and electronic search, conducted between January 2014 and June 2015, of the literature published between 1992 and 2015.

Findings

Fathers' positive attitude, involvement and support greatly influenced breastfeeding decision and commitment among mothers and was associated with increased breastfeeding rates and duration. The exclusion of fathers from breastfeeding support and preparation may result in decreased quality of life and self-efficacy among fathers. There is, however, a lack of clear evidence regarding what exactly constitutes the nature of fathers' support.

Conclusions

Taken collectively, the review findings demonstrate that focusing on fathers as a major part of the breastfeeding family and engaging them in the preparation and support process would certainly impact positively on breastfeeding rates.
Compensation for psychiatric harm after a mismanaged birth
Authors: Griffith Richard
Published: July 2017

Midwives have a legal duty of care to the women and babies in their charge. But, as Richard Griffith explains, in cases of negligence, other parties may also have a claim
Surviving second year studies
Authors: Axcell Claire
Published: July 2017

Many students find their midwifery course as challenging as it is rewarding. Claire Axcell, winner of the BJM Student Midwife of the Year award 2017, reflects on her second year of study
Crate confinement of dogs following orthopaedic surgery. Part 1: benefits and possible drawbacks
Authors: Dorn Marianne
Published: July 2017

Following orthopaedic surgery, crate restriction helps to control patient activity, hence reducing risk of damage to healing tissues and to surgical implants. Running, jumping, use of stairs and slick flooring must generally be avoided until late in recovery. It is postulated that rates of surgical complications may be reduced if post-operative activity restriction is optimised. Musculoskeletal structures tend to become stronger with increased loading, and weaker with reduced loading; crate confinement should therefore only be prescribed in conjunction with a graduated exercise programme. Prescription of crate confinement is not a trivial decision for patient or owner. Unaccustomed confinement has potential welfare implications. The behavioural response of a dog to ‘crate rest’ depends on genetic factors, previous training and experience, and management factors. Clinicians must be aware that confinement may be distressing for some dogs, and be prepared to offer advice on improving patient comfort during recovery.
Approach to the mandibular and maxillofacial trauma patient. Part 1
Authors: Gazzola Krista M
Published: July 2017

Oral and maxillofacial trauma in the dog and cat is a common occurrence secondary to vehicular trauma, fighting with other animals, falls or blunt force trauma, or even gunshot wounds. These cases are often challenging to treat, as they may have concurrent and severe traumatic injuries. The diagnosis of oral and maxillofacial trauma can also be challenging, as often there are multiple injuries to both the mandible and the maxilla. Postoperative nursing care is just as important as the surgical repair and should be thoroughly explained to the owner as well as individually designed for each patient, to ensure adequate nutritional support and appropriate healing. This first article serves as a general overview of this topic and will discuss the approach to the oral and maxillofacial trauma patient, and the considerations and principles for surgical repair. The second article will discuss in more detail anaesthetic considerations, including the technique for pharyngostomy intubation; options for analgesia; nutritional management; and specific methods of stabilisation.
A general practitioner's guide to FAST cageside ultrasound techniques
Authors: Milley Ellen , Boysen Søren , Stillion Jenefer
Published: July 2017

An overview of FAST (focused assessment with sonography for trauma, triage and tracking) is provided, including imaging techniques for both abdominal and thoracic FAST (AFAST and TFAST). This article serves as a practical guide for general and emergency room veterinary surgeons wanting to incorporate the ultrasound FAST scan into everyday practice. Indications for FAST scan, methodology and common pitfalls are reviewed, with the aim of making this diagnostic technique accessible to every practice with ultrasound capabilities. Rapid early detection of pneumothorax, and of peritoneal, pericardial and pleural effusions, allows for further appropriate patient-directed diagnostic evaluation and therapy.
A less-usual case of canine urolithiasis
Authors: Haydon Shona
Published: July 2017

A 6-year-old male entire Irish Terrier presented following 24 hours of stranguria, pollakiuria, haematuria and dysuria. Investigations performed to determine the underlying cause of the lower urinary tract signs included urinalysis, abdominal radiography and ultrasonography. Cystine crystals were identified on urine microscopy. Uroliths were identified on abdominal imaging and were considered to be the cause of the urethral obstruction and resultant dysuria. Analysis of retrieved stones confirmed the uroliths to be composed entirely of cystine. This article uses a case example to discuss cystinuria in the dog and briefly review the approach to diagnosis, treatment and management of dogs presenting with lower urinary tract signs.
What are the regulations and pitfalls for treating backyard chickens?
Authors: Roberts Victoria
Published: July 2017

The rise in keeping chickens as ‘pets’ has become exponential, with an estimated 600 000 households taking part. Families expect their chickens to be treated by veterinary surgeons as competently as their other companion animals, but food-producing species have restrictions on medications and are subject to certain regulations, knowledge of which is generally sparse in companion animal veterinary surgeons. Relevant regulations are annotated and licensed medications listed.
Nature's playground is a very serious business
Authors: Curnock Sue
Published: July 2017

Children's contact with nature is diminishing at an alarming rate, and there is increasing demand for practitioners to help redress the balance. A Forest School training programme is a good place to start.
We need more representation
Authors: Leitch Neil
Published: July 2017

A Freedom of Information Act request to every single Local Authority in England, asking for details of schools forum members, revealed barely statutory levels of members from the PVI early years sector.
Looking for the hidden surprises in illustrations
Authors: Leeper Marion
Published: July 2017

This series of articles explores modern picture books to see how they get children thinking and talking about text, and to see how they convey their ‘deep reading secrets’ to the reader – this month, looking.
Making movement matter
Authors: McTavish Anni
Published: July 2017

Anni McTavish explores Mini Movers, a whole-school approach to supporting physical development, based in Tower Hamlets, London, which re-imagines play sessions and outdoor space in an urban environment.
Students' experience of the use of an online learning channel in teaching and learning: A sports therapy perspective
Authors: Wilson Lynsey , Greig Matt
Published: July 2017

Background/Aims:

The inclusion of blended e-learning approaches to teaching has become more prevalent in higher education. The purpose of this paper was to examine sports therapy students' experiences of using an online learning channel designed to assist practical skills. Moreover, creating an understanding of students' adoption of the learning channel to determine its efficacy.

Methods:

The design was a qualitative exploratory study in which a questionnaire was designed to investigate students' experience of using the learning channel across all undergraduate BSc Sports Therapy modules. One-hundred and sixty-four (level four: n=67; level five: n=51; level six: n=46) students completed the questionnaire relating to their experience of an online video-based learning channel.

Findings:

BSc Sports Therapy students across all levels found the learning channel useful, with the most common responses related to revision and consolidation of practical skills. Exam preparation was associated to this suggesting students' beliefs were driven by resources which could facilitate grade improvement in practical exams.

Conclusions:

The sports therapy learning channel was received very positively, with both the visual and practical nature of online instructional videos deemed important.
Synthesis of Magnetite Nanoparticles by Biological Technique
Authors: Reza Ghorbani Hamid , Pazoki Hossein , Shokuhi Rad Ali
Published: July 2017

ABSTRACT: The development of synthesis routes for oxide nanoparticles is a matter of considerable topical attention. Green synthesis of nanoparticles with the help of microorganisms as reducing agents is an efficient, cost effective, fast and eco-friendly in nature. This paper presents a simple technique to synthesize magnetite (Fe3O4) nanoparticles. In this routine, an aqueous solution of ferrous and ferric salts was mixed with Magnetospirillum and heated for 10 minutes at 70℃. UV–vis absorption spectra, dynamic light scattering (DLS) and transmission electron microscopy (TEM) have been used to illustrate the form process and explain the structure of the magnetite nanoparticles. UV–Vis absorption spectrum showed surface plasmon resonance absorption bands about 240 nm that confirmed magnetite nanoparticles existence. We obtain magnetite nanoparticles of size 42±20 nm after separation and washing procedures by dynamic light scattering (DLS).
Production of Bacalin, Bacalein and Wogonin in Hairy Root Culture of American Skullcap (Scutellaria lateriflora)by Auxin Treatment
Authors: Yeon Kwon Do , Hoon Kim Haeng , Seok Park Jong , Un Park Sang , Il Park Nam
Published: July 2017

ABSTRACT: The hairy root culture of American Skullcap (Scutellaria lateriflora) was studied to investigate the biomass and flavonoids content (baicalin, baicalein and wogonin) in response of various auxin concentrations.The growth rates of the hairy roots varied significantly only at IBA 0.1 mg/L and for all other auxin treatments did not vary significantly. The biomass of hairy roots was 8% higher when treated with IBA 0.1 mg/L and biomass was almost similar and slightly lower levels when treated with various IAA concentration and NAA, respectively. However, the auxins treatments responsed positively to increase flavone production in American Skullcaphairy root culture. The auxin indole-3-butyric acid (IBA) at 1 mg/L performed the best for the accumulation of baicalin and wogonin. The auxin IBA at 1 mg/L accumulated 1.64 and 2.92 times higher baicalin and wogonin, respectively compared to control treatment. Meanwhile, the highest levels of baicalein were observed for hair root cultures in the presence of 1-naphthaleneacetic acid (NAA) at 0.1 mg/L achieving 2.38 times higher than that of accumulated in the control. These findings indicate that hairy root cultures of S. lateriflorausing liquid 1/2MS medium supplemented with auxin could be a valuable alternative approach for flavonoid production.