bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcome of revascularisation in stable coronary artery disease without ischaemia: a Danish registry-based follow-up study
Authors: Simonsen Jane Angel , Mickley Hans , Johansen Allan , Hess Søren , Thomassen Anders , Gerke Oke , Jensen Lisette O , Hallas Jesper , Vach Werner , Hoilund-Carlsen Poul F
Published: August 2017

Objectives

In stable coronary artery disease (CAD), coronary revascularisation may reduce mortality of patients with a certain amount of left ventricular myocardial ischaemia. However, revascularisation does not always follow the guidance suggested by ischaemia testing. We compared outcomes in patients without ischaemia who had either revascularisation or medical treatment.

Design and population

Based on registries, 1327 consecutive patients with normal myocardial perfusion scintigraphy (MPS) and 278 with fixed perfusion defects were followed for a median of 6.1 years. Most patients received medical therapy alone (Med), but 26 (2%) with a normal MPS and 15 (5%) with fixed perfusion defects underwent revascularisation (Revasc).

Outcome measures

Incidence rates of all-cause death (ACD) and rates of cardiac death/myocardial infarction (CD/MI).

Results

With a normal MPS, the ACD rate was 6.2%/year in the Revasc group versus 1.9%/year in the Med group (p=0.01); the CD/MI rates were 6.9%/year and 0.6%/year, respectively (p<0.00001). Results persisted after adjustment for predictors of revascularisation, in particular angina score, and in comparisons of matched Revasc and Med patients. With fixed defects, the ACD rate was 9.1%/year in the Revasc group and 6.7%/year in the Med group (p=0.44); the CD/MI rate was 5.0%/year versus 4.2%/year, respectively (p=0.69). If adjusted for angiographic variables or analysed in matched subsets, differences remained insignificant.

Conclusions

With normal MPS, revascularisation conferred a higher risk, even after adjustment for predictors of revascularisation. With fixed defects, the Revascversus Med difference was close to equipoise. Hence, in patients with stable CAD without ischaemia, we could not find evidence to justify exceptional revascularisation.
Value of light microscopy to diagnose urogenital gonorrhoea: a diagnostic test study in Indonesian clinic-based and outreach sexually transmitted infections services
Authors: Hananta I Putu Yuda , van Dam Alje P , Bruisten Sylvia Maria , van der Loeff Maarten Franciscus Schim , Soebono Hardyanto , Christiaan de Vries Henry John
Published: August 2017

Introduction

Gonorrhoea is a common sexually transmitted disease caused byNeisseria gonorrhoeae(Ng) infection. Light microscopy of urogenital smears is used as a simple tool to diagnose urogenital gonorrhoea in many resource-limited settings. We aimed to evaluate the accuracy of light microscopy to diagnose urogenital gonorrhoea as compared with a PCR-based test.

Methods

In 2014, we examined 632 male urethral and 360 endocervical smears in clinic-based and outreach settings in Jakarta, Yogyakarta and Denpasar, Indonesia. Using the detection of Ng DNA by a validated PCR as reference test, we evaluated the accuracy of two light microscopic criteria to diagnose urogenital gonorrhoea in genital smears: (1) the presence of intracellular Gram-negative diplococci (IGND) and (2) ≥5 polymorphonuclear leucocytes (PMNL)/oil-immersion field (oif) in urethral or ≥20 PMNL/oif in endocervical smears.

Results

In male urethral smears, IGND testing had a sensitivity (95% CI), specificity (95% CI) and kappa±SE of 59.0% (50.1 to 67.4), 89.4% (86.3 to 91.9) and 0.49±0.04, respectively. For PMNL count, these were 59.0% (50.1 to 67.4), 83.7% (80.2 to 86.9) and 0.40±0.04, respectively. The accuracy of IGND in the clinic-based settings (72.0% (57.5 to 83.3), 95.2% (91.8 to 97.5) and 0.68±0.06, respectively) was better than in the outreach settings (51.2% (40.0 to 62.3), 83.4% (78.2 to 87.8) and 0.35±0.06, respectively). In endocervical smears, light microscopy performed poorly regardless of the setting or symptomatology, with kappas ranging from −0.09 to 0.24.

Conclusion

Light microscopy using IGND and PMNL criteria can be an option with moderate accuracy to diagnose urethral gonorrhoea among males in a clinic-based setting. The poor accuracy in detecting endocervical infections indicates an urgent need to implement advanced methods, such as PCR. Further investigations are needed to identify the poor diagnostic outcome in outreach services.
A cost-effectiveness comparison of the NICE 2015 and WHO 2013 diagnostic criteria for women with gestational diabetes with and without risk factors
Authors: Jacklin Paul Brian , Maresh Michael JA , Patterson Chris C , Stanley Katharine P , Dornhorst Anne , Burman-Roy Shona , Bilous Rudy W
Published: August 2017

Objectives

To compare the cost-effectiveness (CE) of the National Institute for Health and Care Excellence (NICE) 2015 and the WHO 2013 diagnostic thresholds for gestational diabetes mellitus (GDM).

Setting

The analysis was from the perspective of the National Health Service in England and Wales.

Participants

6221 patients from four of the Hyperglycaemia and Adverse Pregnancy Outcomes (HAPO) study centres (two UK, two Australian), 6308 patients from the Atlantic Diabetes in Pregnancy study and 12 755 patients from UK clinical practice.

Primary and secondary outcome measures planned

The incremental cost per quality-adjusted life year (QALY), net monetary benefit (NMB) and the probability of being cost-effective at CE thresholds of £20 000 and £30 000 per QALY.

Results

In a population of pregnant women from the four HAPO study centres and using NICE-defined risk factors for GDM, diagnosing GDM using NICE 2015 criteria had an NMB of £239 902 (relative to no treatment) at a CE threshold of £30 000 per QALY compared with WHO 2013 criteria, which had an NMB of £186 675. NICE 2015 criteria had a 51.5% probability of being cost-effective compared with the WHO 2013 diagnostic criteria, which had a 27.6% probability of being cost-effective (no treatment had a 21.0% probability of being cost-effective). For women without NICE risk factors in this population, the NMBs for NICE 2015 and WHO 2013 criteria were both negative relative to no treatment and no treatment had a 78.1% probability of being cost-effective.

Conclusion

The NICE 2015 diagnostic criteria for GDM can be considered cost-effective relative to the WHO 2013 alternative at a CE threshold of £30 000 per QALY. Universal screening for GDM was not found to be cost-effective relative to screening based on NICE risk factors.
Relationship between estimated cardiovascular disease risk and insulin resistance in a black African population living with HIV: a cross-sectional study from Cameroon
Authors: Noumegni Steve Raoul , Bigna Jean Joel , Ama Moor epse Nkegoum Vicky Jocelyne , Nansseu Jobert Richie , Assah Felix K , Jingi Ahmadou Musa , Guewo-Fokeng Magellan , Leumi Steve , Katte Jean-Claude , Dehayem Mesmin Y , Mfeukeu Kuate Liliane , Kengne Andre Pascal , Sobngwi Eugene
Published: August 2017

Objectives

Cardiovascular disease (CVD) and metabolic diseases are growing concerns among patients with HIV infection as a consequence of the improving survival of this population. We aimed to assess the relationship between CVD risk and insulin resistance in a group of black African individuals with HIV infection.

Methods

This cross-sectional study involved patients with HIV infection aged 30–74 years and followed up at the Yaoundé Central Hospital, Cameroon. Absolute CVD risk was calculated using the Framingham and the DAD CVD risk equations while the HOMA-IR index was used to assess insulin resistance (index ≥2.1).

Results

A total of 452 patients (361 women; 80%) were screened. The mean age was 44.4 years and most of the respondents were on antiretroviral therapy (88.5%). The median 5-year cardiovascular risk was 0.7% (25th−75th percentiles: 0.2–2.0) and 0.6% (0.3–1.3) according to the Framingham and DAD equations respectively. Of all participants, 47.3% were insulin resistant. The Framingham equation derived absolute CVD risk was significantly associated with insulin resistance; while no linear association was found using the DAD equation.

Conclusion

The relationship between cardiovascular risk and insulin resistance in black African patients with HIV infection seems to depend on the cardiovascular risk equation used.
Multicentric randomised study ofHelicobacter pylorieradication and pepsinogen testing for prevention of gastric cancer mortality: the GISTAR study
Authors: Leja Marcis , Park Jin Young , Murillo Raul , Liepniece-Karele Inta , Isajevs Sergejs , Kikuste Ilze , Rudzite Dace , Krike Petra , Parshutin Sergei , Polaka Inese , Kirsners Arnis , Santare Daiga , Folkmanis Valdis , Daugule Ilva , Plummer Martyn , Herrero Rolando
Published: August 2017

Introduction

Population-based eradication ofHelicobacter pylorihas been suggested to be cost-effective and is recommended by international guidelines. However, the potential adverse effects of widespread antibiotic use that this would entail have not been sufficiently studied. An alternative way to decrease gastric cancer mortality is by non-invasive search for precancerous lesions, in particular gastric atrophy; pepsinogen tests are the best currently available alternative. The primary objective of GISTAR is to determine whetherH pylorieradication combined with pepsinogen testing reduces mortality from gastric cancer among 40–64-year-old individuals. The secondary objectives include evaluation ofH pylorieradication effectiveness in gastric cancer prevention in patients with precancerous lesions and evaluation of the potential adverse events, including effects on microbiome.

Methods and analysis

Individuals are recruited from general population (50% men) in areas with high gastric cancer risk in Europe and undergo detailed lifestyle and medical history questionnaire before being randomly allocated to intervention or control groups. The intervention group undergoesH pyloritesting and is offered eradication therapy if positive; in addition, pepsinogen levels are detected in plasma and those with decreased levels are referred for upper endoscopy. All participants are offered faecal occult blood testing as an incentive for study participation. Effectiveness of eradication and the spectrum of adverse events are evaluated in study subpopulations. A 35% difference in gastric cancer mortality between the groups is expected to be detectable at 90% power after 15 years if 30 000 individuals are recruited. Biological materials are biobanked for the main and ancillary studies. The study procedure and assumptions will be tested during the pilot phase.

Ethics and dissemination

The study was approved by the respective ethics committees. An independent Data Safety and Monitoring Board has been established. The findings will be published in peer-reviewed journals and presented at scientific meetings.

Trial registration number

NCT02047994
Comparative effectiveness of six Chinese herb formulas for acute exacerbation of chronic obstructive pulmonary disease: protocol for systematic review and network meta-analysis
Authors: Liu Shaonan , Chen Jing , He Yihan , Wu Lei , Lai Jiaqi , Zuo Jinhong , Yang Lihong , Guo Xinfeng
Published: August 2017

Introduction

Chinese medicine is commonly used to combine with pharmacotherapy for the treatment of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Six Chinese herb formulas involving Weijing decoction, Maxingshigan decoction, Yuebijiabanxia decoction, Qingqihuatan decoction, Dingchuan decoction and Sangbaipi decoction are recommended in Chinese medicine clinical guideline or textbook, to relieve patients with phlegm-heat according to Chinese syndrome differentiation. However, the comparative effectiveness among these six formulas has not been investigated in published randomised controlled trials. We plan to summarise the direct and indirect evidence for these six formulas combined with pharmacotherapy to determine the relative merits options for the management of AECOPD.

Methods and analysis

We will perform the comprehensive search for the randomised controlled trials to evaluate the effectiveness of six Chinese herb formulas recommended in Chinese medicine clinical guideline or textbook. The combination of pharmacotherapy includes bronchodilators, antibiotics and corticosteroids that are routinely prescribed for AECOPD. The primary outcome will be lung function, arterial blood gases and length of hospital stay. The data screening and extraction will be conducted by two different reviewers. The quality of RCT will be assessed according to the Cochrane handbook risk of bias tool. The Bayes of network meta-analysis (NMA) will be conducted with WinBUGS to compare the effectiveness of six formulas. We will also use the surface under the cumulative ranking curve (SUCRA) to obtain the comprehensive rank for these treatments.

Ethics and dissemination

This review does not require ethics approval and the results of NMA will be submitted to a peer-review journal.

Trial registration number

PROSPERO (CRD42016052699).
Effect of endoscopic transpapillary biliary drainage with/without endoscopic sphincterotomy on post-endoscopic retrograde cholangiopancreatography pancreatitis in patients with biliary stricture (E-BEST): a protocol for a multicentre randomised controlled trial
Authors: Kato Shin , Kuwatani Masaki , Sugiura Ryo , Sano Itsuki , Kawakubo Kazumichi , Ono Kota , Sakamoto Naoya
Published: August 2017

Introduction

The effect of endoscopic sphincterotomy prior to endoscopic biliary stenting to prevent post-endoscopic retrograde cholangiopancreatography pancreatitis remains to be fully elucidated. The aim of this study is to prospectively evaluate the non-inferiority of non-endoscopic sphincterotomy prior to stenting for naïve major duodenal papilla compared with endoscopic sphincterotomy prior to stenting in patients with biliary stricture.

Methods and analysis

We designed a multicentre randomised controlled trial, for which we will recruit 370 patients with biliary stricture requiring endoscopic biliary stenting from 26 high-volume institutions in Japan. Patients will be randomly allocated to the endoscopic sphincterotomy group or the non-endoscopic sphincterotomy group. The main outcome measure is the incidence of pancreatitis within 2 days of initial transpapillary biliary drainage. Data will be analysed on completion of the study. We will calculate the 95%confidence intervals(CIs) of the incidence of pancreatitis in each group and analyse weather the difference in both groups with 95% CIs is within the non-inferiority margin (6%) using the Wald method.

Ethics and dissemination

This study has been approved by the institutional review board of Hokkaido University Hospital (IRB: 016–0181). Results will be submitted for presentation at an international medical conference and published in a peer-reviewed journal.

Trial registration number

The University Hospital Medical Information Network ID: UMIN000025727 Pre-results.
Patient experience of NHS health checks: a systematic review and qualitative synthesis
Authors: Usher-Smith Juliet A , Harte Emma , MacLure Calum , Martin Adam , Saunders Catherine L , Meads Catherine , Walter Fiona M , Griffin Simon J , Mant Jonathan
Published: August 2017

Objective

To review the experiences of patients attending NHS Health Checks in England.

Design

A systematic review of quantitative and qualitative studies with a thematic synthesis of qualitative studies.

Data sources

An electronic literature search of Medline, Embase, Health Management Information Consortium, Cumulative Index of Nursing and Allied Health Literature, Global Health, PsycInfo, Web of Science, OpenGrey, the Cochrane Library, National Health Service (NHS) Evidence, Google Scholar, Google, Clinical Trials.gov and the ISRCTN registry to 09/11/16 with no language restriction and manual screening of reference lists of all included papers.

Inclusion criteria

Primary research reporting experiences of patients who have attended NHS Health Checks.

Results

20 studies met the inclusion criteria, 9 reporting quantitative data and 15 qualitative data. There were consistently high levels of reported satisfaction in surveys, with over 80% feeling that they had benefited from an NHS Health Check. Data from qualitative studies showed that the NHS Health Check had been perceived to act as a wake-up call for many who reported having gone on to make substantial lifestyle changes which they attributed to the NHS Health Check. However, some had been left with a feeling of unmet expectations, were confused about or unable to remember their risk scores, found the lifestyle advice too simplistic and non-personalised or were confused about follow-up.

Conclusions

While participants were generally very supportive of the NHS Health Check programme and examples of behaviour change were reported, there are a number of areas where improvements could be made. These include greater clarity around the aims of the programme within the promotional material, more proactive support for lifestyle change and greater appreciation of the challenges of communicating risk and the limitations of relying on the risk score alone as a trigger for facilitating behaviour change.
Bangladesh Environmental Enteric Dysfunction (BEED) study: protocol for a community-based intervention study to validate non-invasive biomarkers of environmental enteric dysfunction
Authors: Mahfuz Mustafa , Das Subhasish , Mazumder Ramendra Nath , Masudur Rahman M , Haque Rashidul , Bhuiyan Md Muzibur Rahman , Akhter Hasina , Sarker Md. Shafiqul Alam , Mondal Dinesh , Muaz Syed Shafi Ahmed , Karim A S M Bazlul , Borowitz Stephen M , Moskaluk Christopher A , Barratt Michael J , Petri William A , Gordon Jeffrey I , Ahmed Tahmeed
Published: August 2017

Introduction

Environmental enteric dysfunction (EED) is a subacute inflammatory condition of the small intestinal mucosa with unclear aetiology that may account for more than 40% of all cases of stunting. Currently, there are no universally accepted protocols for the diagnosis, treatment and ultimately prevention of EED. The Bangladesh Environmental Enteric Dysfunction (BEED) study is designed to validate non-invasive biomarkers of EED with small intestinal biopsy, better understand disease pathogenesis and identify potential therapeutic targets for interventions designed to control EED and stunting.

Methods and analysis

The BEED study is a community-based intervention where participants are recruited from three cohorts: stunted children aged 12–18 months (length for age Z-score (LAZ) <−2), at risk of stunting children aged 12–18 months (LAZ <−1 to −2) and malnourished adults aged 18–45 years (body mass index <18.5 kg/m2). After screening, participants eligible for study provide faecal, urine and plasma specimens to quantify the levels of candidate EED biomarkers before and after receiving a nutritional intervention. Participants who fail to respond to nutritional therapy are considered as the candidates for upper gastrointestinal endoscopy with biopsy. Histopathological scoring for EED will be performed on biopsies obtained from several locations within the proximal small intestine. Candidate EED biomarkers will be correlated with nutritional status, the results of histochemical and immunohistochemical analyses of epithelial and lamina propria cell populations, plus assessments of microbial community structure.

Ethics and dissemination

Ethics approval was obtained in all participating institutes. Results of this study will be submitted for publication in peer-reviewed journals.

Trial registration number

ClinicalTrials.gov ID:NCT02812615. Registered on 21 June 2016.
Characteristics of youth agreeing to electronic sexually transmitted infection risk assessment in the emergency department
Authors: Ahmad Fahd A , Jeffe Donna B , Plax Katie , Schechtman Kenneth B , Doerhoff Dwight E , Garbutt Jane M , Jaffe David M
Published: August 2017

Objectives

Adolescents and young adults are at high risk for sexually transmitted infections (STIs). We previously reported an increase in STI testing of adolescents in our ED by obtaining a sexual history using an Audio-enhanced Computer-Assisted Self-Interview (ACASI). We now examine associations among demographics, sexual behaviour, chief complaint and willingness to be tested.

Methods

This was a prospective study conducted in a paediatric ED between April and December 2011. After triage, eligible patients between 15 and 21 years presenting with non-life-threatening conditions were asked to participate in the study. Consenting participants used an ACASI to provide their demographic data and answer questions about their sexual history and willingness to be tested. Our primary outcome was the association of demographics, chief complaint and ACASI recommendation with the participant’s willingness to be tested.

Results

We approached 1337 patients, of whom 800 (59%) enrolled and completed the ACASI. Eleven who did not answer questions related to their sexual history were excluded from analysis. Of 789 participants, 461 (58.4%) were female and median age was 16.9 years (IQR 16.0–17.8); 509 (64.5%) endorsed a history of anal, oral and/or vaginal intercourse. Disclosing a sexual history and willingness to be tested did not differ significantly by gender. 131 (16.6%) had a chief complaint potentially referable to an STI; among the 658 participants with non-STI-related complaints, 412 (62.6%) were sexually active, many of whom disclosed risky behaviours, including multiple partners (46.4%) and inconsistent condom use (43.7%). The ACASI identified 419 patients as needing immediate STI testing; the majority (81%) did not have a chief complaint potentially related to STIs. 697 (88.3%) participants were willing to receive STI testing. Most (94.6%) of the patients with STI-related complaints were willing to be tested, and 92.1% of patients with a recommendation for immediate testing by the ACASI indicated a willingness to be tested.

Conclusions

Adolescents were willing to disclose sexual activity via electronic questionnaires and were willing to receive STI testing, even when their chief complaint was not STI related. The ACASI facilitated identification of adolescent ED patients needing STI testing regardless of chief complaint.
Predicting outcomes in traumatic out-of-hospital cardiac arrest: the relevance of Utstein factors
Authors: Beck Ben , Bray Janet E , Cameron Peter , Straney Lahn , Andrew Emily , Bernard Stephen , Smith Karen
Published: August 2017

Background

Given low survival rates in cases of traumatic out-of-hospital cardiac arrest (OHCA), there is a need to identify factors associated with outcomes. We aimed to investigate Utstein factors associated with achieving return of spontaneous circulation (ROSC) and survival to hospital in traumatic OHCA.

Methods

The Victorian Ambulance Cardiac Arrest Registry (VACAR) was used to identify cases of traumatic OHCA that received attempted resuscitation and occurred between July 2008 and June 2014. We excluded cases aged <16 years or with a mechanism of hanging or drowning.

Results

Of the 660 traumatic OHCA patients who received attempted resuscitation, ROSC was achieved in 159 patients (24%) and 95 patients (14%) survived to hospital (ROSC on hospital handover). Factors that were positively associated with achieving ROSC in multivariable logistic regression models were age ≥65 years (adjusted OR (AOR)=1.56, 95% CI: 1.01 to 2.43) and arresting rhythm (shockable (AOR=3.65, 95% CI: 1.64 to 8.11) and pulseless electrical activity (AOR=2.15, 95% CI: 1.36 to 3.39) relative to asystole). Similarly, factors positively associated with survival to hospital were arresting rhythm (shockable (AOR=3.92, 95% CI: 1.64 to 9.41) relative to asystole), and the mechanism of injury (falls (AOR=2.16, 95% CI: 1.03 to 4.54) relative to motor vehicle collisions), while trauma type (penetrating (AOR=0.27, 95% CI: 0.08 to 0.91) relative to blunt trauma) and event region (rural (AOR=0.39, 95% CI: 0.19 to 0.80) relative to urban) were negatively associated with survival to hospital.

Conclusions

Few patient and arrest characteristics were associated with outcomes in traumatic OHCA. These findings suggest there is a need to incorporate additional information into cardiac arrest registries to assist prognostication and the development of novel interventions in these trauma patients.
Identifying discordance between senior physicians and trainees on the root cause of ED revisits
Authors: Goldman Michael P , Monuteaux Michael C , Perron Catherine , Bachur Richard G
Published: August 2017

Objective

Analysis of 72-hour ED revisits is a common emergency medicine quality assurance (QA) practice. Our aim was to compare the perceived root cause for 72-hour ED revisits between senior physicians (attendings) and trainees. We proposed that discordance in perception of why the revisit occurred would guide improvements in 72-hour revisits QA and elucidate innovative educational opportunities.

Methods

Questionnaire-based observational study conducted in an urban academic paediatric ED. Treating attendings and trainees independently completed questionnaires on revisit cases. The primary outcome was the revisit’s perceived root cause, dichotomised into ‘potential medical deficiency’ or ‘not potential medical deficiency’. Discordance between provider pairs was measured, stratified by revisit disposition.

Results

During the study period, 31 630 patients were treated in the ED, 559 returned within 72 hours and 218 met inclusion criteria for paired analysis. The proportion of cases assigned ‘potential medical deficiency’ by the attending and trainee was 13% and 9%, respectively. Discordance in the dichotomised root cause between attendings and trainees was 17% (38/218, 95% CI 12% to 22%). Revisit cases requiring admission revealed attending-trainee discordance of 25% (23/92, 95% CI 16% to 34%).

Conclusions

Attendings and trainees frequently disagree on whether a potential medical deficiency was the root cause for an ED revisit, with more disagreement noted for cases requiring admission. These findings support the premise that there may be opportunities to improve 72-hour revisits QA systems through trainee integration. Finally, reuniting attending-trainee pairs around revisit cases may be a novel educational opportunity.
Incidental detection of germline variants of potential clinical significance by massively parallel sequencing in haematological malignancies
Authors: Yannakou Costas K , Jones Kate , Ryland Georgina L , Thompson Ella R , Reid Gareth , McBean Michelle , Trainer Alison , Westerman David , Blombery Piers
Published: August 2017

Massively parallel sequencing (MPS) technology has become routinely available for diagnosis, prognostication and therapeutic decision-making in haematological malignancies. However, increased throughput and wider coverage of genes can have unintended consequences. Germline variants of potential clinical significance (GVPCSs) detected during cancer testing may have implications for patients and families beyond the biological evaluation of a specific tumour. 721 reports generated from MPS panels used in the routine testing of myeloid and lymphoid malignancies were reviewed and variants within genes of potential germline relevance (TP53,RUNX1,GATA2andWT1in all contexts andCBL,KRASandNRASin the setting of juvenile myelomonocytic leukaemia) were analysed. A variant allele fraction threshold of ≥33.09% for considering germline origin of variants within cancer samples was established. The detection rate of incidental, pathogenic germline variants was 0.42%. Patient education and confirmatory germline sample testing of GVPCSs in appropriate circumstances are recommended.
C-myc expression in adrenocortical tumours
Authors: Pennanen Mirkka , Hagström Jaana , Heiskanen Ilkka , Sane Timo , Mustonen Harri , Arola Johanna , Haglund Caj
Published: August 2017

Aims

Widespread use of high-resolution imaging techniques and thus increased prevalence of adrenal lesions has made diagnostics of adrenocortical tumours an increasingly important clinical issue. In non-metastatic tumours, diagnosis is based on histology. New or enhanced information for clinicopathological diagnosis, revealing the malignant potential of the tumour, could emerge by means of biomarkers. The connection of proto-oncogene c-myc to adrenocortical neoplasias is poorly known, although the Wnt/beta-catenin pathway, one of the signalling pathways leading to induction of c-myc expression, has been connected to development of adrenocortical neoplasias. We studied c-myc expression in adrenocortical tumours and investigated molecules associated with the signalling pathway of c-myc, including cell cycle-related proteins p27, cyclin E and cyclin D1.

Methods

We studied 195 consecutive adult patients with 197 primary adrenocortical tumours. Histopathological diagnosis was determined by Weiss score and the novel Helsinki score. C-myc, cyclin D1, cyclin E and p27 expressions were determined by immunohistochemistry.

Results

Benign adenomas showed prominent nuclear c-myc expression comparable to that of normal adrenocortical cells, whereas carcinomas showed increased cytoplasmic expression. Strong cytoplasmic and weak nuclear c-myc expressions associated with malignancy and adverse outcome. C-myc staining did not correlate with cyclin E. Cyclin D1 correlated with cytoplasmic c-myc expression and to a lesser extent with nuclear c-myc. P27 correlated with cytoplasmic c-myc, but not with nuclear c-myc. P27 correlated with cyclin E.

Conclusions

Strong cytoplasmic c-myc expression and weak nuclear expression in adrenocortical tumours associated with malignancy and shorter survival.
Ethical issues when modelling brain disorders innon-human primates
Authors: Neuhaus Carolyn P
Published: August 2017

Non-human animal models of human diseases advance our knowledge of the genetic underpinnings of disease and lead to the development of novel therapies for humans. While mice are the most common model organisms, their usefulness is limited. Larger animals may provide more accurate and valuable disease models, but it has, until recently, been challenging to create large animal disease models. Genome editors, such as Clustered Randomised Interspersed Palindromic Repeat (CRISPR), meet some of these challenges and bring routine genome engineering of larger animals and non-human primates (NHPs) well within reach. There is growing interest in creating NHP models of brain disorders such as autism, depression and Alzheimer’s, which are very difficult to model or study in other organisms, including humans. New treatments are desperately needed for this set of disorders. This paper is novel in asking: Insofar as NHPs are being considered for use as model organisms for brain disorders, can this be done ethically? The paper concludes that it cannot. Notwithstanding ongoing debate about NHPs’ moral status, (1) animal welfare concerns, (2) the availability of alternative methods of studying brain disorders and (3) unmet expectations of benefit justify a stop on the creation of NHP model organisms to study brain disorders. The lure of using new genetic technologies combined with the promise of novel therapeutics presents a formidable challenge to those who call for slow, careful, and only necessary research involving NHPs. But researchers should not create macaques with social deficits or capuchin monkeys with memory deficits just because they can.
Microbiome in lung explants of idiopathic pulmonary fibrosis: a case–control study in patients with end-stage fibrosis
Authors: Kitsios Georgios D , Rojas Mauricio , Kass Daniel J , Fitch Adam , Sembrat John C , Qin Shulin , Veraldi Kristen L , Gibson Kevin F , Lindell Kathleen , Pilewski Joseph M , Methe Barbara , Li Kelvin , McDyer John , McVerry Bryan J , Morris Alison
Published: August 2017

The microbiome has been proposed to play a role in the progression of idiopathic pulmonary fibrosis (IPF) based on bronchoalveolar lavage analyses, but the microbiome of lung tissue in IPF has not been explored. In a case–control study of lung explants analysed by 16S rRNA gene sequencing, we could not reliably detect bacterial DNA in basilar tissue samples from patients with either chronic or acute exacerbations of IPF, in contrast to control candidate-donor lungs or cystic fibrosis explants. Thus, our data do not indicate microbiome alterations in regions of IPF lung with advanced fibrosis.
CT findings of gall bladder rupture in two dogs with gall bladder mucocele
Authors: Gordon Caroline Rose , Fernandez Nuria , Schwarz Tobias
Published: August 2017

A miniature poodle and miniature schnauzer were referred for the investigation of shallow breathing and restless behaviour, and the investigation of bilious vomiting, diarrhoea and the presence of a hepatic mass, respectively. In both cases, CT revealed heterogeneous, hyperattenuating content within the gall bladder, a defect in the gall bladder wall and leakage of biliary content into the perihepatic region compatible with gall bladder mucocele, rupture of the gall bladder and bile peritonitis. Both dogs underwent a cholecystectomy and made uneventful recoveries. Follow‐up was available for both dogs one and two months later which confirmed a return to good health. CT is a helpful aid in the presurgical diagnosis of gall bladder wall rupture and bile peritonitis in dogs.
Tip of an iceberg: complications of an oesophageal foreign body removal in a dog
Authors: Merlin Tristan , Hoy Carol , Rodrigo‐Mocholi Diego
Published: August 2017

A female golden retriever dog was presented for the removal of an oesophageal foreign body. Clinical examination on admission revealed a mild hypovolemia associated with tachypnoea. Radiographic examination of the chest did not reveal any other condition apart from the presence of two oesophageal foreign bodies. The animal was anaesthetised to attempt an endoscopic removal, and after induction of anaesthesia a severe desaturation and difficulties providing manual ventilation were noted. These signs persisted during the entire procedure, and after recovery from anaesthesia a severe aspiration pneumonia was diagnosed. The animal’s condition worsened quickly and required the use of long‐term mechanical ventilation in the intensive care unit. After 3 days of hospitalisation, the animal was euthanased due to the development of an acute respiratory distress syndrome and the lack of clinical improvement.
Mesozoic structural evolution of the New Siberian Islands
Authors: Piepjohn Karsten , Lorenz Henning , Franke Dieter , Brandes Christian , von Gosen Werner , Gaedicke Christoph , Labrousse Loic , Sobolev Nikolay N. , Solobev Piotr , Suan Guillaume , Mrugalla Sabine , Talarico Franco , Tolmacheva Tatiana
Published: August 2017

The New Siberian Islands are affected by a number of Mesozoic tectonic events. The oldest event (D1a) is characterized by NW-directed thrusting within the South Anyui Suture Zone combined with north–south-trending sinistral strike-slip in the foreland during the Early Cretaceous. This compressional deformation was followed by dextral transpression along north–south-trending faults, which resulted in NE–SW shortening in the Kotelny Fold Zone (D1b). The dextral deformation can be related to a north–south-trending boundary fault zone west of the New Siberian Islands, which probably represented the Laptev Sea segment of the Amerasia Basin Transform Fault in pre-Aptian–Albian times. The presence of a transform fault west of the islands may be an explanation for the long and narrow sliver of continental lithosphere of the Lomonosov Ridge and the sudden termination of the South Anyui Suture Zone against the present Laptev Sea Rift System. The intrusion of magmatic rocks 114 myr ago was followed by NW–SE-trending sinistral strike-slip faults of unknown origin (D2). In the Late Cretaceous–Paleocene, east–west extension (D3) west of the New Siberian Islands initiated the development of the Laptev Sea Rift System, which continues until today and is largely related to the development of the Eurasian Basin.
Ice-flow reorganization within the East Antarctic Ice Sheet deep interior
Authors: Beem L. H. , Cavitte M. G. P. , Blankenship D. D. , Carter S. P. , Young D. A. , Muldoon G. R. , Jackson C. S. , Siegert M. J.
Published: August 2017

Near the South Pole, a large subglacial lake exists beneath the East Antarctic Ice Sheet less than 10 km from where the bed temperature is inferred to be −9°C. A thermodynamic model was used to investigate the apparent contradiction of basal water existing in the vicinity of a cold bed. Model results indicate that South Pole Lake is freezing and that neither present-day geothermal flux nor ice flow is capable of producing the necessary heat to sustain basal water at this location. We hypothesize that the lake comprises relict water formed during a different configuration of ice dynamics when significant frictional heating from ice sliding was available. Additional modelling of assumed basal sliding shows frictional heating was capable of producing the necessary heat to fill South Pole Lake. Independent evidence of englacial structures measured by airborne radar revel ice-sheet flow was more dynamic in the past. Ice sliding is estimated to have ceased between 16.8 and 10.7 ka based on an ice chronology from a nearby borehole. These findings reveal major post-Last Glacial Maximum ice-dynamic change within the interior of East Antarctica, demonstrating that the present interior ice flow is different than that under full glacial conditions.
Vascular niche contribution to age-associated neural stem cell dysfunction
Authors: Apple Deana M. , Kokovay Erzsebet
Published: August 2017

Neural stem cells (NSCs) persist throughout life in the dentate gyrus and the ventricular-subventricular zone, where they continuously provide new neurons and some glia. These cells are found in specialized niches that regulate quiescence, activation, differentiation, and cell fate choice. A key aspect of the regulatory niche is the vascular plexus, which modulates NSC behavior during tissue homeostasis and regeneration. During aging, NSCs become depleted and dysfunctional, resulting in reduced neurogenesis and poor brain repair. In this review, we discuss the emerging evidence that changes in the vascular niche both structurally and functionally contribute to reduced neurogenesis during aging and how this might contribute to reduced plasticity and repair in the aged brain.
Small noncoding RNA expression during extreme anoxia tolerance of annual killifish (Austrofundulus limnaeus) embryos
Authors: Riggs Claire L. , Podrabsky Jason E.
Published: August 2017

Small noncoding RNAs (sncRNA) have recently emerged as specific and rapid regulators of gene expression, involved in a myriad of cellular and organismal processes. MicroRNAs, a class of sncRNAs, are differentially expressed in diverse taxa in response to environmental stress, including anoxia. In most vertebrates, a brief period of oxygen deprivation results in severe tissue damage or death. Studies on sncRNA and anoxia have focused on these anoxia-sensitive species. Studying sncRNAs in anoxia-tolerant organisms may provide insight into adaptive mechanisms supporting anoxia tolerance. Embryos of the annual killifish Austrofundulus limnaeus are the most anoxia-tolerant vertebrates known, surviving over 100 days at their peak tolerance at 25°C. Their anoxia tolerance and physiology vary over development, such that both anoxia-tolerant and anoxia-sensitive phenotypes comprise the species. This allows for a robust comparison to identify sncRNAs essential to anoxia-tolerance. For this study, RNA sequencing was used to identify and quantify expression of sncRNAs in four embryonic stages of A. limnaeus in response to an exposure to anoxia and subsequent aerobic recovery. Unique stage-specific patterns of expression were identified that correlate with anoxia tolerance. In addition, embryos of A. limnaeus appear to constitutively express stress-responsive miRNAs. Most differentially expressed sncRNAs were expressed at higher levels during recovery. Many novel groups of sncRNAs with expression profiles suggesting a key role in anoxia tolerance were identified, including sncRNAs derived from mitochondrial tRNAs. This global analysis has revealed groups of candidate sncRNAs that we hypothesize support anoxia tolerance.
The Combination of Metformin and Valproic Acid Induces Synergistic Apoptosis in the Presence of p53 and Androgen Signaling in Prostate Cancer
Authors: Tran Linh N.K. , Kichenadasse Ganessan , Butler Lisa M. , Centenera Margaret M. , Morel Katherine L. , Ormsby Rebecca J. , Michael Michael Z. , Lower Karen M. , Sykes Pamela J.
Published: August 2017

We investigated the potential of combining the hypoglycemic drug metformin (MET) and the antiepileptic drug valproic acid (VPA), which act via different biochemical pathways, to provide enhanced antitumor responses in prostate cancer. Prostate cancer cell lines (LNCaP and PC-3), normal prostate epithelial cells (PrEC), and patient-derived prostate tumor explants were treated with MET and/or VPA. Proliferation and apoptosis were assessed. The role of p53 in response to MET + VPA was assessed in cell lines using RNAi in LNCaP (p53+) and ectopic expression of p53 in PC-3 (p53−). The role of the androgen receptor (AR) was investigated using the AR antagonist enzalutamide. The combination of MET and VPA synergistically inhibited proliferation in LNCaP and PC-3, with no significant effect in PrEC. LNCaP, but not PC-3, demonstrated synergistic intrinsic apoptosis in response to MET + VPA. Knockdown of p53 in LNCaP (p53+, AR+) reduced the synergistic apoptotic response as did inhibition of AR. Ectopic expression of p53 in PC-3 (p53−, AR−) increased apoptosis in response to MET + VPA. In patient-derived prostate tumor explants, MET + VPA also induced a significant decrease in proliferation and an increase in apoptosis in tumor cells. In conclusion, we demonstrate that MET + VPA can synergistically kill more prostate cancer cells than either drug alone. The response is dependent on the presence of p53 and AR signaling, which have critical roles in prostate carcinogenesis. Further in vivo/ex vivo preclinical studies are required to determine the relative efficacy of MET + VPA as a potential treatment for prostate cancer. Mol Cancer Ther; 16(12); 2689–700. ©2017 AACR.
Exploiting Radiation-Induced Signaling to Increase the Susceptibility of Resistant Cancer Cells to Targeted Drugs: AKT and mTOR Inhibitors as an Example
Authors: Eke Iris , Makinde Adeola Y. , Aryankalayil Molykutty J. , Sandfort Veit , Palayoor Sanjeewani T. , Rath Barbara H. , Liotta Lance , Pierobon Mariaelena , Petricoin Emanuel F. , Brown Matthew F. , Stommel Jayne M. , Ahmed Mansoor M. , Coleman C. Norman
Published: August 2017

Implementing targeted drug therapy in radio-oncologic treatment regimens has greatly improved the outcome of cancer patients. However, the efficacy of molecular targeted drugs such as inhibitory antibodies or small molecule inhibitors essentially depends on target expression and activity, which both can change during the course of treatment. Radiotherapy has previously been shown to activate prosurvival pathways, which can help tumor cells to adapt and thereby survive treatment. Therefore, we aimed to identify changes in signaling induced by radiation and evaluate the potential of targeting these changes with small molecules to increase the therapeutic efficacy on cancer cell survival. Analysis of “The Cancer Genome Atlas” database disclosed a significant overexpression of AKT1, AKT2, and MTOR genes in human prostate cancer samples compared with normal prostate gland tissue. Multifractionated radiation of three-dimensional–cultured prostate cancer cell lines with a dose of 2 Gy/day as a clinically relevant schedule resulted in an increased protein phosphorylation and enhanced protein–protein interaction between AKT and mTOR, whereas gene expression of AKT, MTOR, and related kinases was not altered by radiation. Similar results were found in a xenograft model of prostate cancer. Pharmacologic inhibition of mTOR/AKT signaling after activation by multifractionated radiation was more effective than treatment prior to radiotherapy. Taken together, our findings provide a proof-of-concept that targeting signaling molecules after activation by radiotherapy may be a novel and promising treatment strategy for cancers treated with multifractionated radiation regimens such as prostate cancer to increase the sensitivity of tumor cells to molecular targeted drugs. Mol Cancer Ther; 17(2); 355–67. ©2017 AACR.

See all articles in this MCT Focus section, “Developmental Therapeutics in Radiation Oncology.”
MicroRNA-720 Regulates E-cadherin–αE-catenin Complex and Promotes Renal Cell Carcinoma
Authors: Bhat Nadeem S. , Colden Melissa , Dar Altaf A. , Saini Sharanjot , Arora Prerna , Shahryari Varahram , Yamamura Soichiro , Tanaka Yuichiro , Kato Taku , Majid Shahana , Dahiya Rajvir
Published: August 2017

miRNAs are implicated in regulating cancer progression and metastasis. Here, we show that miR-720 is positively associated with renal cell carcinoma (RCC). Elevated levels of miR-720 were observed in a panel of RCC cell lines and clinical tissues compared with nonmalignant cell line and normal samples. Loss of miR-720 function inhibited proliferation, migration, and invasion and induced apoptosis in RCC cell lines in vitro and repressed tumor growth in xenograft mouse models. Conversely, gain of miR-720 function in nonmalignant HK-2 cells induced procancerous characteristics. Silencing of miR-720 caused a marked induction in the levels of endogenous αE-catenin and E-cadherin protein levels in anti720 transfected cells compared with control, whereas miR-720 overexpression in RCC cell lines reduced activity of a luciferase reporter gene fused to the wild-type αE-catenin or E-cadherin 3′UTR compared with nonspecific 3′UTR control, indicating that αE-catenin–E-cadherin complex is a direct and functional target of miR-720 in RCC. We also observed attenuation of β-catenin, CD44, and Akt expression in RCC cells transfected with miR-720 inhibitor compared with control. Furthermore, miR-720 exhibited clinical significance in RCC. Expression of miR-720 significantly distinguished malignant from normal samples. Elevated miR-720 levels positively correlated with higher Fuhrman grade, pathologic stage, and poor overall survival of RCC patients. These findings uncover a new regulatory network in RCC involving metastasis-promoting miR-720 that directly targets expression of key metastasis-suppressing proteins E-cadherin and αE-catenin complex. These results suggest that therapeutic regulation of miR-720 may provide an opportunity to regulate EMT and metastasis in RCC. Mol Cancer Ther; 16(12); 2840–8. ©2017 AACR.