bluuebunny/crossref_metadata_2025 huggingface dataset:
Conspiracy theories as part of history: The role of societal crisis situations
Authors: van Prooijen Jan-Willem , Douglas Karen M
Published: July 2017

In the present contribution, we examine the link between societal crisis situations and belief in conspiracy theories. Contrary to common assumptions, belief in conspiracy theories has been prevalent throughout human history. We first illustrate historical incidents suggesting that societal crisis situations—defined as impactful and rapid societal change that calls established power structures, norms of conduct, or even the existence of specific people or groups into question—have stimulated belief in conspiracy theories. We then review the psychological literature to explain why this is the case. Evidence suggests that the aversive feelings that people experience when in crisis—fear, uncertainty, and the feeling of being out of control—stimulate a motivation to make sense of the situation, increasing the likelihood of perceiving conspiracies in social situations. We then explain that after being formed, conspiracy theories can become historical narratives that may spread through cultural transmission. We conclude that conspiracy theories originate particularly in crisis situations and may form the basis for how people subsequently remember and mentally represent a historical event.
Assessment and management of testicular pain
Authors: Smith Peter , Hemmant Joshua
Published: July 2017

Testicular pain can be a particularly challenging problem to manage in primary care, with potential pitfalls for the unwary. The most important acute diagnosis to consider is testicular torsion, as ischaemia, infarction and subsequent loss of function can occur within a few hours of onset. This article considers a range of different conditions that may present with testicular pain, sometimes with other accompanying symptoms. An accurate history is important in assessing testicular pain, and GPs should be aware of the perceived embarrassing nature of testicular symptoms. Examination skills are essential when considering the different causes of testicular pain. This article describes how to assess patients presenting with testicular pain in primary care, the different conditions causing testicular pain and when to refer to secondary care.
Testosterone deficiency
Authors: Rahim Syukri
Published: July 2017

As its symptoms are non-specific and develop progressively, testosterone deficiency is often misdiagnosed and overlooked. Symptoms may be mild and accepted as normal manifestations of ageing. Some of these symptoms can indeed occur in ageing men who do not have testosterone deficiency. Diagnosis of testosterone deficiency in ageing men can be challenging, as symptoms of testosterone deficiency overlap with those of ’normal’ physiological ageing. GPs’ prescriptions of testosterone have increased significantly over the past decade. An increased awareness among GPs, when coupled with extra demand from patients, is likely to lead to increased prescribing of testosterone. Patient demand has increased with sophisticated drug marketing and guidelines promoting testing and treatment of testosterone deficiency. This article reviews the common clinical features and diagnosis of testosterone deficiency, identifies the risk and benefits of testosterone replacement therapy, and briefly discusses the associated controversies regarding prostate cancer and cardiovascular risk.
Injectable scaffold materials differ in their cell instructive effects on primary human myoblasts
Authors: Hejbøl Eva Kildall , Sellathurai Jeeva , Nair Prabha Damodaran , Schrøder Henrik Daa
Published: July 2017

Scaffolds are materials used for delivery of cells for regeneration of tissues. They support three-dimensional organization and improve cell survival. For the repair of small skeletal muscles, injections of small volumes of cells are attractive, and injectable scaffolds for delivery of cells offer a minimally invasive technique. In this study, we examined in vitro the cell instructive effects of three types of injectable scaffolds, fibrin, alginate, and poly(lactic-co-glycolic acid)-based microparticles on primary human myoblasts. The myoblast morphology and progression in the myogenic program differed, depending on the type of scaffold material. In alginate gel, the cells obtained a round morphology, they ceased to proliferate, and entered quiescence. In the fibrin gels, differentiation was promoted, and myotubes were observed within a few days in culture, while poly(lactic-co-glycolic acid)-based microparticles supported prolonged proliferation. Myoblasts released from the alginate and fibrin gels were studied, and cells released from these scaffolds had retained the ability to proliferate and differentiate. Thus, the study shows that human myogenic cells combined with injectable scaffold materials are guided into different states depending on the choice of scaffold. This opens for in vivo experiments, including testing of the significance of the cell state on regeneration potential of primary human myoblasts.
The Role of Language in Religious Identity Making
Authors: Skerrett Allison
Published: July 2017

This article explores the processes of religious identity development in a Caribbean-Chinese adolescent who is from a multifaith, multilingual home. Findings include (1) the youth developed a Christian religious identity through his multiple situatedness within home and school worlds that privileged that faith and the dominant language of English with which it was associated and (2) the youth’s limited knowledge of his mother’s Chinese languages was associated with his limited exploration of an additional religious faith within his home. While previous links have been established between youths’ religious and cultural identities, this analysis submits the significance of language in religious identity development.
Parenteral Histamine2-Receptor Antagonists in the Pediatric Population
Authors: O'Mara Neeta Bahal , Nahata Milap C.
Published: July 2017

Objective:

To provide a review of the use of parenteral histamine2 (H2)-receptor antagonists cimetidine, ranitidine, and famotidine in the pediatric population.

Data Sources:

Information was identified by MEDLINE and a review of journals. References cited in published articles and manufacturers' product information also were used.

Study Selection:

Information was selected for review if it addressed the parenteral administration of H2-receptor antagonists in the pediatric population.

Data Extraction:

Data were extracted from references pertaining to the topic.

Data Synthesis:

Despite the lack of Food and Drug Administration pediatric labeling, the H2-receptor antagonists often are used for a variety of indications in infants and children. Although these agents differ somewhat in chemical structure, potency, and pharmacokinetics, the most important differences exist in their drug interactions and adverse effect profiles. Further, administration methods, compatibility, and stability data differ slightly among the agents.

Conclusions:

Parenteral H2-receptor antagonists are used for a variety of indications in infants and children. Despite their widespread use, additional studies are needed to define the optimal dosage regimens in this population.
Diagnosis and Treatment of Bacterial Vaginosis: Survey of Family Physicians in West Virginia
Authors: Ponte Charles D. , Martinec Cindy L.
Published: July 2017

Background:

Vulvovaginitis is a common gynecologic complaint with millions of women seeking medical attention for this disorder. Bacterial vaginosis (BV) is the most common form of vaginal infection. Its nonspecific symptomatology and its diagnostic and therapeutic controversies pose many challenges.

Methods:

A 10-question self-administered survey was mailed to family physicians in West Virginia. The survey assessed the occurrence of BV, diagnostic criteria, and treatment options. The results were reported as descriptive statistics.

Results:

Overall, 107 physicians responded to the survey. Seventy-nine surveys were used in the tabulation of results. All respondents diagnosed vaginitis on a weekly basis. On average, BV is diagnosed in 25 percent of women with vaginal problems. Discharge, odor, and irritation were the most common signs/symptoms. History, physical examination, and microscopic examination of vaginal secretions were employed routinely for diagnosis. A detectable odor, a homogeneous discharge, and vaginal pH >4.5 were inconsistent objective clinical findings. However, the presence of clue cells was noted in the majority of patients. The preferred drug for the treatment of BV was metronidazole, usually administered in a dosage of 500 mg/d po bid for seven days. Fifty percent of the respondents treat men partners, and again, the drug of choice was metronidazole. The majority do not treat asymptomatic BV during pregnancy nor asymptomatic nonpregnant women during routine gynecologic examination. Recurrence was noted in fewer than 30 percent of treated women.

Conclusions:

On the basis of the results, BV is a common gynecologic diagnosis. Classic signs/symptoms were universally present and the diagnostic approach was consistent with established medical norms. The usual objective clinical findings were not always evident, although the presence of clue cells was a frequent finding. The therapeutic approach to the patient with BV was also consistent with contemporary medical practice in 1991. Whether the small sample size or inconsistent reporting affected the study results remains indeterminate. Future research will be directed toward larger patient populations and assessment of newer therapeutic modalities and their costs.
Atypical Presentation of Angioedema Associated with an Angiotensin-Converting Enzyme Inhibitor
Authors: Hamilton John D. , Raymond Claire H.
Published: July 2017

Objective:

To report a case of atypical angioedema associated with the use of lisinopril, an angiotensin-converting enzyme (ACE) inhibitor.

Data Synthesis:

Literature evaluating ACE inhibitor-induced angioedema was selected from a topical search in MEDLINE. Information regarding the case report was obtained from a review of the medical chart.

A 23-year-old man presents with lisinopril-induced angioedema confined to the left pectoral area. Angioedema associated with ACE inhibitors has been described in the literature, manifesting primarily as edema of the face, throat, and mucous membranes. A review of the possible mechanism, cross-reactivity within the drug class, and treatment of ACE inhibitor-induced angioedema is also discussed.

Conclusions:

The use of ACE inhibitors in the treatment of hypertension and congestive heart failure is expected to increase, given their proven efficacy and favorable adverse effect profile. Clinicians need to be aware that, although the frequency of ACE inhibitor-induced angioedema is low, it may present in an atypical fashion. J Pharm Technol 1994;10:255–7.
Rifabutin Hepatotoxicity in a Pediatric Liver Transplant Patient
Authors: Ascher David P. , Jaffers Gregory J. , Davis Steven G.
Published: July 2017

Objective:

To report a case of hepatotoxicity associated with administration of rifabutin in a pediatric liver transplant patient.

Case Summary:

A child developed disseminated Mycobacterium avium-intracellulare eight years after liver transplantation, requiring a reduction in immunosuppression and concomitant therapy with amikacin, azithromycin, ciprofloxin, ethambutol, and clofazimine. Despite clinical improvement, rifabutin was added because of residual sterile hepatic and pulmonary granuloma identified during preparation for retransplantation. She developed acute hepatic decompensation upon initiation of rifabutin, which resolved after discontinuation of this antibiotic.

Conclusions:

This case demonstrates the potential for serious hepatotoxicity with the use of rifabutin in complicated medical patients with hepatic insufficiency.
Comparison of Methods Used for Estimating Pharmacist Counseling Behaviors
Authors: Schommer Jon C. , Sullivan Donald L. , Wiederholt Joseph B.
Published: July 2017

Objective:

To compare the rates reported for provision of types of information conveyed by pharmacists among studies for which different methods of estimation were used and different dispensing situations were studied.

Data Sources:

Empiric studies conducted in the US, reported from 1982 through 1992, were selected from International Pharmaceutical Abstracts, MEDLINE, and noncomputerized sources.

Study Selection:

Empiric studies were selected for review if they reported the provision of at least three types of counseling information.

Data Extraction:

Four components of methods used for estimating pharmacist counseling behaviors were extracted and summarized in a table: (1) sample type and area, (2) sampling unit, (3) sample size, and (4) data collection method. In addition, situations that were investigated in each study were compiled.

Data Synthesis:

Twelve studies met our inclusion criteria. Patients were interviewed via telephone in four studies and were surveyed via mail in two studies. Pharmacists were interviewed via telephone in one study and surveyed via mail in two studies. For three studies, researchers visited pharmacy sites for data collection using the shopper method or observation method. Studies with similar methods and situations provided similar results.

Conclusions:

Data collected by using patient surveys, pharmacist surveys, and observation methods can provide useful estimations of pharmacist counseling behaviors if researchers measure counseling for specific, well-defined dispensing situations.
Cost Implications of Using Inhaled Nitric Oxide Compared with Epoprostenol for Pulmonary Hypertension
Authors: Petros Andy J , Turner Sean C , Nunn Anthony J
Published: July 2017

Objective:

To compare the cost of using intravenous epoprostenol with that of inhaled nitric oxide (NO) for treating episodes of pulmonary hypertension in children with congenital heart disease.

Design:

An analysis of the cost of epoprostenol and NO use over the previous 18 months was performed. Three 6-month periods were identified, two in which epoprostenol was used and the third in which inhaled NO was introduced for the treatment of pulmonary hypertension.

Setting:

A 10-bed pediatric cardiac intensive care unit, Royal Liverpool Children's Hospital, Alder Hey, Liverpool, England.

Subjects:

Children with congenital heart disease and persistently elevated pulmonary artery pressure following cardiac surgery.

Main Outcome Measures:

The total duration of use of epoprostenol and inhaled NO was documented. The costs per hour for epoprostenol and inhaled NO were calculated and the annual cost of each agent was estimated.

Results:

In the two 6-month periods prior to the introduction of inhaled NO, epoprostenol was used on 14 occasions (5 in the first period, 3 in the second). In the last 6-month period, nine children required pulmonary vasodilator therapy on 14 occasions. All nine children were treated successfully with inhaled NO; none were given or needed epoprostenol, as NO always was effective in providing pulmonary vasodilatation. For resistant pulmonary hypertension, increasing the concentration of NO would have been the next therapeutic option. The cost for the two 6-month periods using epoprostenol was $19,483.48 for the drug and $283.25 for equipment costs (total cost $19,766.73). There was no expenditure on epoprostenol in the final 6-month period. The cost of NO was $465. However, the total expenditure, including the delivery and monitoring system, was $4,722.85.

Conclusions:

Using inhaled NO in our pediatric cardiac intensive care unit abolished the use of epoprostenol during the reported monitoring period. The cost savings were significant, amounting to 12% of the annual drug budget for the unit. The cost of setting up the inhaled NO delivery system is recouped rapidly. The ease of delivery and measurement of inhaled NO also may have contributed to its increased clinical use.
Digestive Enzyme Adjunct to Oral Headache Medication to Improve Absorption and Reduce Vomiting
Authors: Detweiler Mark B
Published: July 2017

Objective:

To report a case in which a digestive enzyme complex (Nature's Plus Digestive Enzymes: pancreatin, pepsin, ox bile extract, malt diatase, and papain) apparently improved the absorption and efficacy of an oral headache medication and alleviated vomiting associated with the headache.

Case Summary:

A 47-year-old white woman with a history of adverse drug reactions and allergies had been experiencing one to four disabling headaches per week for 2 years. One or two headaches each week would be accompanied by vomiting. This patient experienced adverse effects with most standard headache medications. For 40 months since taking a complex of digestive enzymes as an adjunct to her headache medication, the patient's vomiting has been eliminated, and her postheadache symptoms have been reduced.

Discussion:

Altered digestive processes are a common finding in severe headache episodes. Exogenous digestive enzymes may facilitate the absorption of oral medication during gastric disruption and consequently increase drug efficacy and the relief of symptoms.

Conclusions:

Digestive enzymes merit further study to ascertain their effectiveness in increasing the absorption and efficacy of oral medications prescribed for headaches accompanied by emesis.
Bioequivalence Study Between Two Extended-Release Formulations of Theophylline Using Saliva
Authors: Payssé Helena M , Vázquez Marta , Fagiolino Pietro L
Published: July 2017

Objective:

To assess the bioequivalence between two extended-release formulations of theophylline using saliva as the biologic fluid.

Design:

Randomized two-way crossover design.

Participants:

Eight healthy, nonsmoking volunteers (7 women, 1 man) between 23 and 41 years of age took a single dose (250 mg) of two extended-release formulations of theophylline (form A, tablet; form B, capsule).

Results:

Significant differences were found at 2, 4, 6, and 8 hours (p < 0.001), with the in vitro dissolution test between both formulations. ANOVA for AUC, maximum concentration (Cmax), average concentration, and %Cmax – 100 showed significant differences between both formulations in the in vivo trial.

Conclusions:

The tablet and capsule formulations of extended-release theophylline are bioinequivalent when saliva is used as the biologic fluid for performing these studies.
Effectiveness of Two-Step Tuberculin Skin Testing in Hospital Employees
Authors: Tran Jennifer H , Seeger John D
Published: July 2017

Objective:

To review the literature discussing the use of two-step tuberculin skin testing for hospital employees.

Data Sources:

English-language journal articles involving human subjects.

Study Selection:

Selected articles describing the use of two-step tuberculin skin testing.

Data Extraction:

Information relevant to the topic was extracted from the articles and synthesized into this report.

Data Synthesis:

People infected with tuberculosis exhibit a skin-test reaction to tuberculin, but this reaction can diminish over time. A two-step tuberculin skin test involves the administration of a second injection of tuberculin 1–3 weeks after the initial injection. The rationale for the use of the two-step tuberculin skin test is to help differentiate between individuals with new tuberculosis infections and those with previous infections whose immune response to tuberculin had decreased to levels not detectable with a single skin test.

Conclusions:

Two-step tuberculin skin testing is effective at detecting a booster effect. Despite the recent mandate by the Occupational Safety and Health Administration to use two-step tuberculin testing in all healthcare facilities, such testing may not be cost-effective in institutions with young employees, high employee turnover, and a low risk of tuberculosis. The requirements for universal two-step tuberculin testing may need to be reevaluated to account for these factors.
Lamotrigine Use in Pregnancy
Authors: Lilly Carol L , Kaplan-Machlis Barbara
Published: July 2017

Objective:

To review the literature on the proposed mechanisms of teratogenicity of older antiepileptic drugs (AEDs) compared with lamotrigine.

Data Sources:

Published articles on the use of AEDs during pregnancy were identified from a comprehensive MEDLINE search of the English-language literature (January 1966-January 1998). Additional articles were selected from the references. Search terms included antiepileptic drugs, lamotrigine, and pregnancy.

Study Selection:

Only human clinical and pharmacokinetic trials and case studies performed in Europe and the US were included.

Data Synthesis:

Pharmacologic characteristics of the older AEDs that appear to contribute to teratogenicity include antifolate effects, metabolism to oxide metabolites, induction of the hepatic cytochrome P450 system, and a high degree of protein binding. The pharmacokinetics and pharmacodynamics of lamotrigine may offer advantages over other AEDs in terms of teratogenicity because lamotrigine is metabolized by the glucuronidation pathway and is not known to induce the hepatic cytochrome P450 system or to form oxide metabolites. The protein-binding capacity of lamotrigine is considerably lower than that of older AEDs, and antifolate effects have not been observed in humans.

Conclusions:

Although few data are available, lamotrigine appears to have pharmacokinetic and pharmacodynamic properties that suggest a safer outcome with its use in pregnancy compared with older AEDs.
Depressive and anxious symptoms and the risk of secondary school non-completion
Authors: Brière Frédéric N. , Pascal Sophie , Dupéré Véronique , Castellanos-Ryan Natalie , Allard Francis , Yale-Soulière Gabrielle , Janosz Michel
Published: July 2017

Background

Evidence regarding the association between adolescent internalising symptoms and school non-completion has been limited and inconclusive.

Aims

To examine whether depressive and anxious symptoms at secondary school entry predict school non-completion beyond confounders and whether associations differ by baseline academic functioning.

Method

We used logistic regression to examine associations between depressive and anxious symptoms in grade 7 (age 12–14) and school non-completion (age 18–20) in 4962 adolescents.

Results

Depressive symptoms did not predict school non-completion after adjustment, but moderation analyses revealed an association in students with elevated academic functioning. A curvilinear association was found for anxiety: both low and high anxious symptoms predicted school non-completion, although only low anxiety remained predictive after adjustment.

Conclusions

Associations between internalising symptoms and school non-completion are modest. Common school-based interventions targeting internalising symptoms are unlikely to have a major impact on school non-completion, but may prevent non-completion in selected students.
Sleep loss as a trigger of mood episodes in bipolar disorder: Individual differences based on diagnostic subtype and gender
Authors: Lewis Katie Swaden , Gordon-Smith Katherine , Forty Liz , Di Florio Arianna , Craddock Nick , Jones Lisa , Jones Ian
Published: July 2017

Background

Sleep loss may trigger mood episodes in people with bipolar disorder but individual differences could influence vulnerability to this trigger.

Aims

To determine whether bipolar subtype (bipolar disorder type I (BP-I) or II (BD-II)) and gender were associated with vulnerability to the sleep loss trigger.

Method

During a semi-structured interview, 3140 individuals (68% women) with bipolar disorder (66% BD-I) reported whether sleep loss had triggered episodes of high or low mood. DSM-IV diagnosis of bipolar subtype was derived from case notes and interview data.

Results

Sleep loss triggering episodes of high mood was associated with female gender (odds ratio (OR) = 143, 95% CI 1.17–1.75,P<0.001) and BD-I subtype (OR=2.81, 95% CI 2.26–3.50,P<0.001). Analyses on sleep loss triggering low mood were not significant following adjustment for confounders.

Conclusions

Gender and bipolar subtype may increase vulnerability to high mood following sleep deprivation. This should be considered in situations where patients encounter sleep disruption, such as shift work and international travel.
Integration of Electronic Patient-Reported Outcomes Into Routine Cancer Care: An Analysis of Factors Affecting Data Completeness
Authors: Wysham Nicholas G. , Wolf Steven P. , Samsa Gregory , Abernethy Amy P. , LeBlanc Thomas W.
Published: July 2017

Purpose

Routinely collected patient-reported outcomes (PROs) could provide invaluable data to a patient-centered learning health system but are often highly missing in clinical trials. We analyzed our experience with PROs to understand patterns of missing data using electronic collection as part of routine clinical care.

Methods

This is an analysis of a prospectively collected observational database of electronic PROs captured as part of routine clinical care in four different outpatient oncology clinics at an academic referral center.

Results

More than 24,000 clinical encounters from 7,655 unique patients are included. Data were collected via an electronic tablet–based survey instrument (Patient Care Monitor, version 2.0), at the time of clinical care, as part of routine care processes. Missing instruments (ie, no items completed) were submitted for 6.8% of clinical encounters, and 15.8% of encounters had missing items. Nearly 90% of all encounters involved < 10% missing items. In multivariable analyses, younger age, private health insurance, being seen in the breast oncology clinic, less time spent on the instrument, and longitudinal care were significantly associated with less missingness.

Conclusion

Embedding collection of electronic PRO data into routine clinical care yielded low rates of missing data in this real-world, prospectively collected database. In contrast to clinical trial experience, missingness improve with longitudinal care. This approach may be a solution to minimizing missingness of PROs in research or clinical care settings in support of learning health care systems.
Algorithm to Identify Systemic Cancer Therapy Treatment Using Structured Electronic Data
Authors: Carroll Nikki M. , Burniece Kate M. , Holzman Jeff , McQuillan Deanna B. , Plata Angela , Ritzwoller Debra P.
Published: July 2017

Purpose

With the shift in the majority of oncology clinical care in the United States from paper records to electronic health records, researchers need efficient and validated processes to obtain accurate data about the entire treatment history of patients diagnosed with cancer. The objective of this study was to develop and validate an algorithm that is agnostic to the source of data but that can identify specific regimens in the entire course of systemic therapy treatment for patients diagnosed with breast, colorectal, or lung cancer.

Methods

A cohort of patients with incident breast, colorectal, and lung cancer were randomly distributed into six groups. The algorithm was iteratively modified, and the performance was assessed until no additional modifications could be identified in the first three groups. The performance of the algorithm was confirmed in the three groups that remained.

Results

The final model produced ranges of sensitivity between 97.2% and 100% for first-course systemic therapy across all cancers, with a false-positive rate of 0%. The algorithm matched the exact number of courses and the exact regimens of systemic therapy agents as captured by infusion, pharmacy, and procedure electronic medical record data for all courses of therapy 88% to 100% of the time.

Conclusion

Use of our validated algorithm that characterizes entire courses of systemic therapy treatment in patients diagnosed with breast, colorectal, and lung cancer will allow researchers in a variety of settings to conduct comparative effectiveness studies related to the uptake, safety, outcomes, and costs associated with the use of both novel and standard regimens.
Acral Lentiginous Melanoma Harboring a ROS1 Gene Fusion With Clinical Response to Entrectinib
Authors: Couts Kasey L. , McCoach Caroline E. , Murphy Danielle , Christiansen Jason , Turner Jacqueline , Lewis Karl D. , Robinson William A. , Doebele Robert C.
Published: July 2017

Purpose

ROS1 gene fusions demonstrate oncogenic activity, and patients with non–small-cell lung cancer (NSCLC) harboring a ROS1 fusion benefit from the use of a ROS1 inhibitor; however, clinical response to ROS1 inhibitors remains largely uncharacterized outside of NSCLC. ROS1 fusions have been identified in multiple tumor types but have not been reported in cutaneous melanoma.

Patients and Methods

Tumors from 22 patients with acral lentiginous melanoma (ALM) were analyzed with targeted RNA sequencing to detect fusions in ROS1, NTRK1, NTRK2, NTRK3, and ALK genes. A patient harboring a ROS1 fusion was enrolled in a phase I basket trial of a ROS1/TRK/ALK inhibitor (entrectinib). An additional 78 tumors with different subtypes of melanoma were screened by ROS1 immunohistochemistry.

Results

Targeted sequencing identified a GOPC- ROS1 fusion in a patient with ALM. The patient underwent a dramatic and durable response to entrectinib, with a RECIST (version 1.1) partial response of −38% at 3 months and −55% at 11 months. The response is ongoing, and the patient has not developed any new lesions. No additional ROS1 fusions were identified by immunohistochemistry, resulting in a frequency of 3.0% in ALM and 1.3% in all melanomas.

Conclusion

ROS1 fusions occur and can respond to targeted therapy in cutaneous melanoma; however, they may be specific to ALM subtype. This report expands knowledge of ROS1 inhibitor response outside of NSCLC and identifies new therapeutic options for a subset of patients with ALM.
Unexpected CDH1 Mutations Identified on Multigene Panels Pose Clinical Management Challenges
Authors: Lowstuter Katrina , Espenschied Carin R. , Sturgeon Duveen , Ricker Charité , Karam Rachid , LaDuca Holly , Culver Julie O. , Dolinsky Jill S. , Chao Elizabeth , Sturgeon Julia , Speare Virginia , Ma Yanling , Kingham Kerry , Melas Marilena , Idos Gregory E. , McDonnell Kevin J. , Gruber Stephen B.
Published: July 2017

Purpose

Mutations in the CDH1 gene confer up to an 80% lifetime risk of diffuse gastric cancer and up to a 60% lifetime risk of lobular breast cancer. Testing for CDH1 mutations is recommended for individuals who meet the International Gastric Cancer Linkage Consortium (IGCLC) guidelines. However, the interpretation of unexpected CDH1 mutations identified in patients who do not meet IGCLC criteria or do not have phenotypes suggestive of hereditary diffuse gastric cancer is clinically challenging. This study aims to describe phenotypes of CDH1 mutation carriers identified through multigene panel testing (MGPT) and to offer informed recommendations for medical management.

Patients and Methods

This cross-sectional prevalence study included all patients who underwent MGPT between March 2012 and September 2014 from a commercial laboratory (n = 26,936) and an academic medical center cancer genetics clinic (n = 318) to estimate CDH1 mutation prevalence and associated clinical phenotypes. CDH1 mutation carriers were classified as IGCLC positive (met criteria), IGCLC partial phenotype, and IGCLC negative.

Results

In the laboratory cohort, 16 (0.06%) of 26,936 patients were identified as having a pathogenic CDH1 mutation. In the clinic cohort, four (1.26%) of 318 had a pathogenic CDH1 mutation. Overall, 65% of mutation carriers did not meet the revised testing criteria published in 2015. All three CDH1 mutation carriers who had risk-reducing gastrectomy had pathologic evidence of diffuse gastric cancer despite not having met IGCLC criteria.

Conclusion

The majority of CDH1 mutations identified on MGPT are unexpected and found in individuals who do not fit the accepted diagnostic testing criteria. These test results alter the medical management of CDH1-positive patients and families and provide opportunities for early detection and risk reduction.
Next-Generation Rapid Autopsies Enable Tumor Evolution Tracking and Generation of Preclinical Models
Authors: Pisapia David J. , Salvatore Steven , Pauli Chantal , Hissong Erika , Eng Ken , Prandi Davide , Sailer Verena-Wilbeth , Robinson Brian D. , Park Kyung , Cyrta Joanna , Tagawa Scott T. , Kossai Myriam , Fontugne Jacqueline , Kim Robert , Sigaras Alexandros , Rao Rema , Pancirer Danielle , Faltas Bishoy , Bareja Rohan , Molina Ana M. , Nanus David M. , Rajappa Prajwal , Souweidane Mark M. , Greenfield Jeffrey , Emde Anne-Katrin , Robine Nicolas , Elemento Olivier , Sboner Andrea , Demichelis Francesca , Beltran Himisha , Rubin Mark A. , Mosquera Juan Miguel
Published: July 2017

Purpose

Patients with cancer who graciously consent for autopsy represent an invaluable resource for the study of cancer biology. To advance the study of tumor evolution, metastases, and resistance to treatment, we developed a next-generation rapid autopsy program integrated within a broader precision medicine clinical trial that interrogates pre- and postmortem tissue samples for patients of all ages and cancer types.

Materials and Methods

One hundred twenty-three (22%) of 554 patients who consented to the clinical trial also consented for rapid autopsy. This report comprises the first 15 autopsies, including patients with metastatic carcinoma (n = 10), melanoma (n = 1), and glioma (n = 4). Whole-exome sequencing (WES) was performed on frozen autopsy tumor samples from multiple anatomic sites and on non-neoplastic tissue. RNA sequencing (RNA-Seq) was performed on a subset of frozen samples. Tissue was also used for the development of preclinical models, including tumor organoids and patient-derived xenografts.

Results

Three hundred forty-six frozen samples were procured in total. WES was performed on 113 samples and RNA-Seq on 72 samples. Successful cell strain, tumor organoid, and/or patient-derived xenograft development was achieved in four samples, including an inoperable pediatric glioma. WES data were used to assess clonal evolution and molecular heterogeneity of tumors in individual patients. Mutational profiles of primary tumors and metastases yielded candidate mediators of metastatic spread and organotropism including CUL9 and PIGM in metastatic ependymoma and ANKRD52 in metastatic melanoma to the lung. RNA-Seq data identified novel gene fusion candidates.

Conclusion

A next-generation sequencing–based autopsy program in conjunction with a premortem precision medicine pipeline for diverse tumors affords a valuable window into clonal evolution, metastasis, and alterations underlying treatment. Moreover, such an autopsy program yields robust preclinical models of disease.
PTEN Loss-of-Function Alterations Are Associated With Intrinsic Resistance to BRAF Inhibitors in Metastatic Melanoma
Authors: Catalanotti Federica , Cheng Donavan T. , Shoushtari Alexander N. , Johnson Douglas B. , Panageas Katherine S. , Momtaz Parisa , Higham Catherine , Won Helen H. , Harding James J. , Merghoub Taha , Rosen Neal , Sosman Jeffrey A. , Berger Michael F. , Chapman Paul B. , Solit David B.
Published: July 2017

Purpose

The clinical use of BRAF inhibitors in patients with melanoma is limited by intrinsic and acquired resistance. We asked whether next-generation sequencing of pretreatment tumors could identify coaltered genes that predict for intrinsic resistance to BRAF inhibitor therapy in patients with melanoma as a prelude to rational combination strategies.

Patients and Methods

We analyzed 66 tumors from patients with metastatic BRAF-mutant melanoma collected before treatment with BRAF inhibitors. Tumors were analyzed for > 250 cancer-associated genes using a capture-based next-generation sequencing platform. Antitumor responses were correlated with clinical features and genomic profiles with the goal of identifying a molecular signature predictive of intrinsic resistance to RAF pathway inhibition.

Results

Among the 66 patients analyzed, 11 received a combination of BRAF and MEK inhibitors for the treatment of melanoma. Among the 55 patients treated with BRAF inhibitor monotherapy, objective responses, as assessed by Response Evaluation Criteria in Solid Tumors (RECIST), were observed in 30 patients (55%), with five (9%) achieving a complete response. We identified a significant association between alterations in PTEN that would be predicted to result in loss of function and reduced progression-free survival, overall survival, and response grade, a metric that combines tumor regression and duration of treatment response. Patients with melanoma who achieved an excellent response grade were more likely to have an elevated BRAF-mutant allele fraction.

Conclusion

These results provide a rationale for cotargeting BRAF and the PI3K/AKT pathway in patients with BRAF-mutant melanoma when tumors have concurrent loss-of-function mutations in PTEN. Future studies should explore whether gain of the mutant BRAF allele and/or loss of the wild-type allele is a predictive marker of BRAFi sensitivity.
Breast and Ovarian Cancer Penetrance Estimates Derived From Germline Multiple-Gene Sequencing Results in Women
Authors: Kurian Allison W. , Hughes Elisha , Handorf Elizabeth A. , Gutin Alexander , Allen Brian , Hartman Anne-Renee , Hall Michael J.
Published: July 2017

Purpose

Multiple-gene, next-generation sequencing panels are increasingly used to assess hereditary cancer risks of patients with diverse personal and family cancer histories. The magnitude of breast and ovarian cancer risk associated with many clinically tested genes, and independent of family cancer history, remains to be quantified.

Methods

We queried a commercial laboratory database of 95,561 women tested clinically for hereditary cancer risk with a 25-gene ( APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CHEK2, MLH2, MSH2, MSH6, MUTYH, NBN, P14ARF, P16, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, and TP53) next-generation sequencing panel. Multivariable logistic regression models accounting for family history were used to examine the association between pathogenic mutations and breast or ovarian cancer. As a confirmatory approach, a matched case-control analysis was conducted, defining cases as patients with breast or ovarian cancer and controls as women without cancer.

Results

One or more pathogenic mutations were detected in 6,775 (7%) of 95,561 women. Eight genes ( ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, PTEN, and TP53) were associated with breast cancer, with odds ratios (ORs) ranging from two-fold ( ATM: OR, 1.74; 95% CI, 1.46 to 2.07) to six-fold ( BRCA1: OR, 5.91; 95% CI, 5.25 to 6.67). Eleven genes ( ATM, BRCA1, BRCA2, BRIP1, MLH1, MSH2, MSH6, NBN, STK11, RAD51C, and RAD51D) were associated with ovarian cancer, with OR ranging from two-fold ( ATM: OR, 1.69; 95% CI, 1.19 to 2.40) to 40-fold ( STK11: OR, 41.9; 95% CI, 5.55 to 315). Multivariable models and matched case-control analyses yielded similar results.

Conclusion

Among nearly 100,000 clinically tested women, 7% carried a pathogenic mutation in one or more cancer-associated genes. Associated breast and ovarian cancer risks ranged from two- to 40-fold after controlling for family history. These results may inform cancer risk counseling.
Molecular and Clinical Characterization of a Claudin-Low Subtype of Gastric Cancer
Authors: Nishijima Tomohiro F. , Kardos Jordan , Chai Shengjie , Smith Christof C. , Bortone Dante S. , Selitsky Sara R. , Parker Joel S. , Sanoff Hanna K. , Lee Michael S. , Vincent Benjamin G.
Published: July 2017

Purpose

Claudin-low molecular subtypes have been identified in breast and bladder cancers and are characterized by low expression of claudins, enrichment for epithelial-to-mesenchymal transition (EMT), and tumor-initiating cell (TIC) features. We evaluated whether the claudin-low subtype also exists in gastric cancer.

Materials and Methods

Four hundred fifteen tumors from The Cancer Genome Atlas (TCGA) gastric cancer mRNA data set were clustered on the claudin, EMT, and TIC gene sets to identify claudin-low tumors. We derived a 24-gene predictor that classifies gastric cancer into claudin-low and non–claudin-low subtypes. This predictor was validated with the Asian Cancer Research Group (ACRG) data set. We characterized molecular and clinical features of claudin-low tumors.

Results

We identified 46 tumors that had consensus enrichment for claudin-low features in TCGA data set. Claudin-low tumors were most commonly diffuse histologic type (82%) and originally classified as TCGA genomically stable (GS) subtype (78%). Compared with GS subtype, claudin-low subtype had significant activation in Rho family of GTPases signaling, which appears to play a key role in its EMT and TIC properties. In the ACRG data set, 28 of 300 samples were classified as claudin-low tumors by the 24-gene predictor and were phenotypically similar to the initially derived claudin-low tumors. Clinically, claudin-low subtype had the worst overall survival. Of note, the hazard ratios that compared claudin-low versus GS subtype were 2.10 (95% CI, 1.07 to 4.11) in TCGA and 2.32 (95% CI, 1.18 to 4.55) in the ACRG cohorts, with adjustment for age and pathologic stage.

Conclusion

We identified a gastric claudin-low subtype that carries a poor prognosis likely related to therapeutic resistance as a result of its EMT and TIC phenotypes.
Έμφυλες αναπαραστάσεις στα σχολικά εγχειρίδια θετικής κατεύθυνσης των δύο τελευταίων τάξεων του Δημοτικού σχολείου
Authors: Πλιόγκου Βασιλική , Κανταρτζή Ευαγγελία , Τριανταφύλλου Μαίρη
Published: July 2017

Σκοπός της παρούσας μελέτης είναι η ανίχνευση των στοιχείων που συνθέτουν την παρουσία του φύλου στα σχολικά εγχειρίδια θετικής κατεύθυνσης του Δημοτικού σχολείου. Συγκεκριμένα, εξετάζονται τα σχολικά εγχειρίδια -Βιβλία και Τετράδια Εργασιών- των Μαθηματικών, της Φυσικής και της Γεωγραφίας των δύο τελευταίων τάξεων του Δημοτικού. Τα σχολικά εγχειρίδια επιτελούν έναν διττό ρόλο. Από τη μια, αποτελούν ένα εργαλείο που βοηθάει στην πρόσβαση στη γνώση και από την άλλη, συμβάλλουν στην υιοθέτηση αντιλήψεων και ιδεολογιών από τους/τις μαθητές/τριες. Για αυτόν τον λόγο θεωρείται σκόπιμο να μελετηθεί ο τρόπος που απεικονίζονται τα φύλα στα σχολικά εγχειρίδια του Δημοτικού. Αρχικά, γίνεται μια σύντομη επισκόπηση των ερευνών που έλαβαν χώρα σε Ελλάδα και εξωτερικό και διερεύνησαν τον τρόπο με τον οποίο προσεγγίζεται το φύλο στο σχολείο, στην ευρύτερη εκπαιδευτική κοινότητα και απεικονίζεται στα σχολικά εγχειρίδια. Τα αποτελέσματα των ερευνών αναδεικνύουν την ανισότητα που υπάρχει στην παρουσίαση αγοριών και κοριτσιών, κυρίως, στα σχολικά εγχειρίδια θετικής κατεύθυνσης, αλλά και στην απόκλιση που παρατηρείται μεταξύ των φύλων στην επίδοση στα παραπάνω μαθήματα. Ως μέθοδος επεξεργασίας και διερεύνησης των εγχειριδίων χρησιμοποιήθηκε η μέθοδος ανάλυσης περιεχομένου. Μετά την εμβριθή μελέτη των εγχειριδίων, εντοπίστηκαν και ορίστηκαν οι τέσσερις προς διερεύνηση κατηγορίες. Τα ευρήματα της μελέτης έδειξαν ότι τα σχολικά εγχειρίδια θετικής κατεύθυνσης του Δημοτικού σχολείου παρουσιάζουν, ακόμη και σήμερα, στερεότυπες αντιλήψεις γύρω από το φύλο. Από τα αποτελέσματα διαφαίνεται ότι οι άντρες εμφανίζονται περισσότερο, αναλαμβάνουν πρωταγωνιστικούς ρόλους και ηγετικές θέσεις και απασχολούνται σε όλων των ειδών τα επαγγέλματα. Εν αντιθέσει, οι γυναίκες  εμφανίζονται πιο περιορισμένα, ασχολούνται με πιο παραδοσιακές εργασίες και παρουσιάζονται πιο ευάλωτες και αδύναμες. Παρ’ όλο που τα σημερινά σχολικά εγχειρίδια, συγκριτικά με τα παλαιότερα, επιχειρούν μια πιο δίκαιη παρουσίαση του γυναικείου φύλου και μεγαλύτερη συμμετοχή της γυναίκας στον επαγγελματικό και κοινωνικό στίβο, η προσπάθεια αυτή παραμένει περιορισμένη και αποσπασματική. Τα στερεότυπα μεταξύ των φύλων παραμένουν και η ολιστική αποδόμηση των έμφυλων ταυτοτήτων δεν έχει επιτευχθεί. Ζητούμενο, ωστόσο, αποτελεί και ο τρόπος διαχείρισης των εγχειριδίων από τον/την εκπαιδευτικό, του/της οποίου/ας η στάση οφείλει να προωθεί την ισότητα αγοριών και κοριτσιών εντός και εκτός τάξης. Τέλος, παρουσιάζονται δράσεις που στοχεύουν στην ευαισθητοποίηση των εκπαιδευτικών απέναντι σε ζητήματα φύλου.
A sequencer coming of age: De novo genome assembly using MinION reads
Authors: de Lannoy Carlos , de Ridder Dick , Risse Judith
Published: July 2017

Nanopore technology provides a novel approach to DNA sequencing that yields long, label-free reads of constant quality. The first commercial implementation of this approach, the MinION, has shown promise in various sequencing applications. This review gives an up-to-date overview of the MinION's utility as a de novo sequencing device. It is argued that the MinION may allow for portable and affordable de novo sequencing of even complex genomes in the near future, despite the currently error-prone nature of its reads. Through continuous updates to the MinION hardware and the development of new assembly pipelines, both sequencing accuracy and assembly quality have already risen rapidly. However, this fast pace of development has also lead to a lack of oversight in the expanding landscape of analysis tools, as performance evaluations are outdated quickly. Now that the MinION is approaching a state of maturity, a thorough comparative benchmarking effort of de novo assembly pipelines may be at place. An earlier version of this article can be found on BioRxiv.
Reporting deaths to the coroner
Authors: Griffith Richard
Published: July 2017

The Chief Coroner has issued new guidance in relation to death where the person is subject to a deprivation of liberty safeguards standard authorisation ( Chief Coroner, 2017 ).

In this article, Richard Griffith discusses the impact of the Police and Crime Act 2017, section 178 on the need to report deaths of patients' subject to a deprivation of liberty safeguards standard authorisation to the coroner.
The challenges of dysphagia in treating motor neurone disease
Authors: Vesey Siobhan
Published: July 2017

Motor neurone disease (MND) is a relatively rare degenerative disorder. Its impacts are manifested in progressive loss of motor function and often accompanied by wider non-motor changes. Swallowing and speech abilities are frequently severely impaired. Effective management of dysphagia (swallowing difficulty) symptoms and nutritional care requires a holistic multidisciplinary approach. Care must be patient focused, facilitate patient decision making, and support planning towards end of life care. This article discusses the challenges of providing effective nutritional care to people living with motor neurone disease who have dysphagia.
Integrating social media into routine midwifery services: Maternity Direct+
Authors: Tranter Rebecca , McGraw Caroline
Published: July 2017

The use of social media to disseminate and receive health messages has increased over the past ten years, and many women use social media to access pregnancy information. However, the NHS has been slow to integrate consumer facing Internet technologies into routine care services. This article describes an innovative social media project, Maternity Direct+, an Internet midwife employed by Basildon and Thurrock University Hospitals NHS Foundation Trust. The Internet midwife uses Facebook to disseminate health messages and answer non-urgent questions from pregnant women, mothers up to 28 days after birth, and women planning a pregnancy. Findings from the project evaluation demonstrated a high level of demand for a responsive, evidence-based, non-urgent information and advice service for pregnant women and new mothers, and high levels of user satisfaction. The authors conclude that social media can be integrated into routine midwifery services and used to complement existing communication channels.
Turkey's childcare services facing unique challenges
Authors: Mart Mehmet , Campbell-Barr Verity
Published: July 2017

This series on international perspectives of ECEC is designed to offer a window into what is happening in other countries in the hope of fostering a process of reflection. This month, early years in Turkey.
Blended learning opens up Montessori qualifications
Authors: Johns Penny
Published: July 2017

Using an innovative approach, one that is bringing together tradition and technology, Montessori Centre International is opening up access to professional development and study to a much wider audience.