bluuebunny/crossref_metadata_2025 huggingface dataset:
Antimicrobial Resistance: a One Health Perspective
Authors: McEwen Scott A. , Collignon Peter J.
Published: March 2018

One Health is the collaborative effort of multiple health science professions to attain optimal health for people, domestic animals, wildlife, plants, and our environment. The drivers of antimicrobial resistance include antimicrobial use and abuse in human, animal, and environmental sectors and the spread of resistant bacteria and resistance determinants within and between these sectors and around the globe. Most of the classes of antimicrobials used to treat bacterial infections in humans are also used in animals. Given the important and interdependent human, animal, and environmental dimensions of antimicrobial resistance, it is logical to take a One Health approach when addressing this problem. This includes taking steps to preserve the continued effectiveness of existing antimicrobials by eliminating their inappropriate use and by limiting the spread of infection. Major concerns in the animal health and agriculture sectors are mass medication of animals with antimicrobials that are critically important for humans, such as third-generation cephalosporins and fluoroquinolones, and the long-term, in-feed use of medically important antimicrobials, such as colistin, tetracyclines, and macrolides, for growth promotion. In the human sector it is essential to prevent infections, reduce over-prescribing of antimicrobials, improve sanitation, and improve hygiene and infection control. Pollution from inadequate treatment of industrial, residential, and farm waste is expanding the resistome in the environment. Numerous countries and several international agencies have included a One Health approach within their action plans to address antimicrobial resistance. Necessary actions include improvements in antimicrobial use regulation and policy, surveillance, stewardship, infection control, sanitation, animal husbandry, and alternatives to antimicrobials. WHO recently has launched new guidelines on the use of medically important antimicrobials in food-producing animals, recommending that farmers and the food industry stop using antimicrobials routinely to promote growth and prevent disease in healthy animals. These guidelines aim to help preserve the effectiveness of antimicrobials that are important for human medicine by reducing their use in animals.
Measuring quality of life of people with predementia and dementia and their caregivers: a systematic review protocol
Authors: Landeiro Filipa , Walsh Katie , Ghinai Isaac , Mughal Seher , Nye Elsbeth , Wace Helena , Roberts Nia , Lecomte Pascal , Wittenberg Raphael , Wolstenholme Jane , Handels Ron , Roncancio-Diaz Emilse , Potashman Michele H , Tockhorn-Heidenreich Antje , Gray Alastair M
Published: March 2018

Introduction

Dementia is the fastest growing major cause of disability globally and may have a profound impact on the health-related quality of life (HRQoL) of both the patient with dementia and those who care for them. This review aims to systematically identify and synthesise the measurements of HRQoL for people with, and their caregivers across the full spectrum of, dementia from its preceding stage of predementia to end of life.

Methods and analysis

A systematic literature review was conducted in Medical Literature Analysis and Retrieval System Online , ExcerptaMedicadataBASE, Cochrane Database of Systematic Reviews , Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effect, National Health Service Economic Evaluation Database and PsycINFO between January 1990 and the end of April 2017. Two reviewers will independently assess each study for inclusion and disagreements will be resolved by a third reviewer. Data will be extracted using a predefined data extraction form following best practice. Study quality will be assessed with the Effective Public Health Practice Project quality assessment tool. HRQoL measurements will be presented separately for people with dementia and caregivers by instrument used and, when possible, HRQoL will be reported by disease type and stage of the disease. Descriptive statistics of the results will be provided. A narrative synthesis of studies will also be provided discussing differences in HRQoL measurements by instrument used to estimate it, type of dementia and disease severity.

Ethics and dissemination

This systematic literature review is exempt from ethics approval because the work is carried out on published documents. The findings of the review will be disseminated in a related peer-reviewed journal and presented at conferences. They will also contribute to the work developed in the Real World Outcomes across the Alzheimer’s disease spectrum for better care: multimodal data access platform (ROADMAP).

Trial registration number

CRD42017071416.
Effect of levosimendan on mortality in severe sepsis and septic shock: a meta-analysis of randomised trials
Authors: Chang Wei , Xie Jian-Feng , Xu Jing-Yuan , Yang Yi
Published: March 2018

Objective

We aim to synthesise up-to-date randomised trials to investigate the effects of levosimendan on mortality and clinical outcomes in severe sepsis and septic shock.

Methods

A collection of databases including PubMed, EMBASE, Cochrane Central Register and Web of Science were searched updated to August 2017. Randomised trials were included when they pertain to the use of levosimendan in severe sepsis or septic shock compared with any category of inotropes, or as an adjunct to standard therapy with mortality reported. The primary outcome was mortality, and the secondary outcomes were clinical performances including serum lactate, cardiac function, vasopressor requirement and fluid infusion.

Results

A total of 10 studies with 1036 patients were included in this meta-analysis. The results revealed that levosimendan could not reduce mortality significantly in severe sepsis and septic shock (OR 0.89, 95% CI 0.69 to 1.16, P=0.39). Levosimendan use could reduce serum lactate more effectively, and enhance cardiac contractibility with increased cardiac index and left ventricular ejection fraction. However, its use could also increase fluid infusion but not reduce norepinephrine dose. No significant benefit in mortality could be observed of levosimendan versus dobutamine use, or in patients with proven cardiac dysfunction.

Conclusions

Current evidence is not sufficient to support levosimendan as superior to dobutamine or as an optimal adjunct in severe sepsis and septic shock. More large-scale randomised trials are necessary to validate levosimendan use in sepsis.
Dentists’ intention to report suspected violence: a cross-sectional study in eight Arab countries
Authors: El Tantawi Maha , Gaffar Balgis , Arheiam Arheiam , AbdelAziz Wafaa , Al-Batayneh Ola B , Alhoti Mansur F , Al-Maweri Sadeq , Dama Mai A , Zaghez Mounir , Hassan Khalid Saddiq , Al-Sane Mona , AbdelSalam Maha , Sabbah Wael , Owais Arwa I , Abdelgawad Fatma , Aldhelai Thiyezen Abdullah , El Meligy Omar Abd El Sadek , AlHumaid Jehan , Al-Harbi Fahad
Published: March 2018

Objectives

This study assessed dentists’ intention in eight Arab countries to report suspected exposure to violence among patients and factors associated with this intention based on the theory of planned behaviour.

Methods

A cross-sectional study was conducted in 2016 including a convenience sample of dentists practising in public, private and academic sectors in Algeria, Egypt, Jordan, Kuwait, Libya, Palestine, Saudi Arabia and Yemen. Respondents answered a self-administered questionnaire collecting information about personal and professional background and perceived ability to identify victims of violence. The questionnaire assessed (on a scale from 1 to 10 using six negative statements) dentists’ perception of healthcare system mandated reporting of suspected violence. Six statements were used to assess professional attitude towards reporting suspected violence. Logistic regression was used to assess the association between intention to report suspected violence and perceived ability, perception and attitude adjusting for confounders.

Results

The response rate was 65.2% (n=2936/4506) from general practitioners (70.9%) of mean age=31 years with 56.7% women. Of those, 68.8% intended to report and 52.2% considered themselves able to identify violence victims. The mean (SD) negative perception score=5.3/10 (2.1) and the mean (SD) professional attitude score=7.5/10 (1.9). In multivariate regression, intention to report was associated with professional attitude (OR 1.08, 95% CI 1.03 to 1.14), ability to identify violence victims (OR 1.76, 95% CI 1.45 to 2.12) and negative perception that reporting is not mandated (OR 0.89, 95% CI 0.85 to 0.94). Significant differences existed among countries in intention to report.

Conclusion

Most dentists intended to report suspected violence and their intention could be explained by the theory of planned behaviour which offers a framework for professional development to support violence victims. Sharing of training resources, policies and guidelines is needed to ensure that practices similar to international guidelines are consistently adopted by dentists across Arab countries.
Protocol for the mixed-methods process and context evaluation of theTB & Tobaccorandomised controlled trial in Bangladesh and Pakistan: a hybrid effectiveness–implementation study
Authors: Boeckmann Melanie , Nohavova Iveta , Dogar Omara , Kralikova Eva , Pankova Alexandra , Zvolska Kamila , Huque Rumana , Fatima Razia , Noor Maryam , Elsey Helen , Sheikh Aziz , Siddiqi Kamran , Kotz Daniel
Published: March 2018

Introduction

Tuberculosis (TB) remains a significant public health problem in South Asia. Tobacco use increases the risks of TB infection and TB progression. TheTB& Tobaccoplacebo-controlled randomised trial aims to (1) assess the effectiveness of the tobacco cessation medication cytisine versus placebo when combined with behavioural support and (2) implement tobacco cessation medication and behavioural support as part of general TB care in Bangladesh and Pakistan. This paper summarises the process and context evaluation protocol embedded in the effectiveness–implementation hybrid design.

Methods and analysis

We are conducting a mixed-methods process and context evaluation informed by an intervention logic model that draws on the UK Medical Research Council’s Process Evaluation Guidance. Our approach includes quantitative and qualitative data collection on context, recruitment, reach, dose delivered, dose received and fidelity. Quantitative data include patient characteristics, reach of recruitment among eligible patients, routine trial data on dose delivered and dose received, and a COM-B (‘capability’, ‘opportunity’, ‘motivation’ and ‘behaviour’) questionnaire filled in by participating health workers. Qualitative data include semistructured interviews with TB health workers and patients, and with policy-makers at district and central levels in each country. Interviews will be analysed using the framework approach. The behavioural intervention delivery is audio recorded and assessed using a predefined fidelity coding index based on behavioural change technique taxonomy.

Ethics and dissemination

The study complies with the guidelines of the Declaration of Helsinki. Ethics approval for the study and process evaluation was granted by the University of Leeds (qualitative components), University of York (trial data and fidelity assessment), Bangladesh Medical Research Council and Bangladesh Drug Administration (trial data and qualitative components) and Pakistan Medical Research Council (trial data and qualitative components). Results of this research will be disseminated through reports to stakeholders and peer-reviewed publications and conference presentations.

Trial registration number

ISRCTN43811467; Pre-results.
A cross-sectional survey of physical strains among offshore wind farm workers in the German exclusive economic zone
Authors: Velasco Garrido Marcial , Mette Janika , Mache Stefanie , Harth Volker , Preisser Alexandra M
Published: March 2018

Objectives

To assess the physical strains of employees in the German offshore wind industry, according to job type and phase of the wind farm (under construction or operation).

Design

Web-based cross-sectional survey.

Setting

Offshore wind farm companies operating within the German exclusive economic zone.

Participants

Male workers with regular offshore commitments and at least 28 days spent offshore in the past year (n=268).

Outcome measures

Physical strains (eg, climbing, noise, working overhead, with twisted upper body or in confined spaces, vibration, heavy lifting, humidity, odours).

Results

The most frequently mentioned physical strain was ’climbing’ with 63.8% of the respondents reporting to be always or frequently confronted with climbing and ascending stairs during offshore work. Work as a technician was associated with a greater exposition to noise, vibrations, humidity, cold, heat, chemical substances, lifting/carrying heavy loads, transport of equipment, working in non-ergonomic positions and in cramped spaces, as well as climbing.

Indeed, statistical analyses showed that, after adjusting for phase of the wind farm, age, nationality, offshore experience, work schedule and type of shift, compared with non-technicians, working as a technician was associated with more frequently lifting/carrying of heavy loads (OR 2.58, 95% CI 1.58 to 4.23), transport of equipment (OR 2.06 95% CI 1.27 to 3.33), working with a twisted upper body (OR 2.85 95% CI 1.74 to 4.69), working overhead (OR 2.77 95% CI 1.67 to 4.58) and climbing (OR 2.30 95% CI 1.40 to 3.77). Working in wind farms under construction was strongly associated with increased and decreased exposure to humidity (OR 2.32 95% CI 1.38 to 3.92) and poor air quality (OR 0.58 95% CI 0.35 to 0.95), respectively.

Conclusions

Workers on offshore wind farms constitute a heterogeneous group, including a wide variety of occupations. The degree of exposure to detrimental physical strains varies depending on the type of job. Technicians are more exposed to ergonomic challenges than other offshore workers.
Association between refill adherence to lipid-lowering medications and the risk of cardiovascular disease and mortality in Swedish patients with type 2 diabetes mellitus: a nationwide cohort study
Authors: Karlsson Sofia Axia , Hero Christel , Svensson Ann-Marie , Franzén Stefan , Miftaraj Mervete , Gudbjörnsdottir Soffia , Eeg-Olofsson Katarina , Eliasson Björn , Andersson Sundell Karolina
Published: March 2018

Objectives

To analyse the association between refill adherence to lipid-lowering medications, and the risk of cardiovascular disease (CVD) and mortality in patients with type 2 diabetes mellitus.

Design

Cohort study.

Setting

National population-based cohort of Swedish patients with type 2 diabetes mellitus.

Participants

86 568 patients aged ≥18 years, registered with type 2 diabetes mellitus in the Swedish National Diabetes Register, who filled at least one prescription for lipid-lowering medication use during 2007–2010, 87% for primary prevention.

Exposure and outcome measures

Refill adherence of implementation was assessed using the medication possession ratio (MPR), representing the proportion of days with medications on hand during an 18-month exposure period. MPR was categorised by five levels (≤20%, 21%–40%, 41%–60%, 61%–80% and >80%). Patients without medications on hand for ≥180 days were defined as non-persistent. Risk of CVD (myocardial infarction, ischaemic heart disease, stroke and unstable angina) and mortality by level of MPR and persistence was analysed after the exposure period using Cox proportional hazards regression and Kaplan-Meier, adjusted for demographics, socioeconomic status, concurrent medications and clinical characteristics.

Results

The hazard ratios for CVD ranged 1.33–2.36 in primary prevention patients and 1.19–1.58 in secondary prevention patients, for those with MPR ≤80% (p<0.0001). The mortality risk was similar regardless of MPR level. The CVD risk was 74% higher in primary prevention patients and 33% higher in secondary prevention patients, for those who were non-persistent (p<0.0001). The mortality risk was 6% higher in primary prevention patients and 18% higher in secondary prevention patients, for non-persistent patients (p<0.0001).

Conclusions

Higher refill adherence to lipid-lowering medications was associated with lower risk of CVD in primary and secondary prevention patients with type 2 diabetes mellitus.
How will South Africa’s mandatory salt reduction policy affect its salt iodisation programme? A cross-sectional analysis from the WHO-SAGE Wave 2 Salt & Tobacco study
Authors: Charlton Karen , Ware Lisa Jayne , Baumgartner Jeannine , Cockeran Marike , Schutte Aletta E , Naidoo Nirmala , Kowal Paul
Published: March 2018

Objective

The WHO’s global targets for non-communicable disease reduction recommend consumption of<5 g salt/day. In 2016, South Africa was the first country to legislate maximum salt levels in processed foods. South Africa’s salt iodisation fortification programme has successfully addressed iodine deficiency but information is dated. Simultaneous monitoring of sodium reduction and iodine status is required to ensure compatibility of the two public health interventions.

Design/setting/participants

A nested cohort design within WHO’s 2015 Study on global AGEing and adult health (n=2887) including individuals from households across South Africa. Randomly selected adults (n=875) provided 24-hour and spot urine samples for sodium and iodine concentration analysis (the primary and secondary outcome measures, respectively). Median 24-hour urinary iodine excretion (UIE) and spot urinary iodine concentrations (UIC) were compared by salt intakes of <5g/day, 5–9g/dayand >9 g/day.

Results

Median daily sodium excretion was equivalent to 6.3 g salt/day (range 1–43 g/day); 35% had urinary sodium excretion values within the desirable range (<5 g salt/day), 37% had high values (5–9 g salt/day) and 28% had very high values (>9 g salt/day). Median UIC was 130 µg/L (IQR=58–202), indicating population iodine sufficiency (≥100 µg/L). Both UIC and UIE differed across salt intake categories (p<0.001) and were positively correlated with estimated salt intake (r=0.166 and 0.552, respectively; both p<0.001). Participants with salt intakes of <5 g/day were not meeting the Estimated Average Requirement for iodine intake (95 µg/day).

Conclusions

In a nationally representative sample of South African adults, the association between indicators of population iodine status (UIC and UIE) and salt intake, estimated using 24-hour urinary sodium excretion, indicate that low salt intakes may compromise adequacy of iodine intakes in a country with mandatory iodisation of table salt. The iodine status of populations undergoing salt reduction strategies needs to be closely monitored to prevent re-emergence of iodine deficiency.
LncRNAs in genetic basis of glaucoma
Authors: Cissé Yacouba , Bai Lang , Meng Ting
Published: March 2018

Glaucoma is an umbrella term used to designate a heterogeneous group of ocular disorders characterised by progressive excavation of the optic disc, optic atrophy and gradual loss of the visual field caused by the slow death of retinal ganglion cells and their axons. Glaucoma can potentially lead to blindness if left untreated. It usually starts from the periphery and progresses gradually toward the centre of the visual field. Vision loss caused by glaucoma is irreversible and causes a heavy burden on affected families and society, therefore the importance of early diagnosis and prevention should be emphasised. Genetic factors appear to play a role in glaucoma pathogenesis; it has been shown that individuals with a positive family history are at a greater risk because they are more likely predisposed be affected. Notable advances have been recorded in the past decade concerning the genetic and environmental factors likely to contribute or cause glaucoma with the discovery of multiple glaucoma-associated genes and genetic loci. Thorough investigations by a handful of studies on the function of long non-coding RNAs discovered that, although lacking protein-coding potential, lncRNAs can still participate in the regulation of gene expression at various levels, thus their possible implication in different disease aetiologies. In this review, we focus on the lncRNAs characteristics and its regulation, and summarise these results from separate, independent, glaucoma-related studies in addition to discussing possible pathways by which lncRNAs might contribute to glaucoma.
Epithelial ingrowth following laser in situ keratomileusis (LASIK): prevalence, risk factors, management and visual outcomes
Authors: Ting Darren Shu Jeng , Srinivasan Sathish , Danjoux Jean-Pierre
Published: March 2018

The number of laser in situ keratomileusis (LASIK) procedures is continuing to rise. Since its first application for correcting simple refractive errors over 25 years ago, the role of LASIK has extended to treat other conditions, including postkeratoplasty astigmatism/ametropia, postcataract surgery refractive error and presbyopia, among others. The long-term effectiveness, predictability and safety have been well established by many large studies. However, due to the creation of a potential interface between the flap and the underlying stroma, interface complications such as infectious keratitis, diffuse lamellar keratitis and epithelial ingrowth may occur. Post-LASIK epithelial ingrowth (PLEI) is an uncommon complication that usually arises during the early postoperative period. The reported incidence of PLEI ranged from 0%–3.9% in primary treatment to 10%–20% in retreatment cases. It can cause a wide spectrum of clinical presentations, ranging from asymptomatic interface changes to severe visual impairment and flap melt requiring keratoplasty. PLEI can usually be treated with mechanical debridement of the affected interface; however, additional interventions, such as alcohol, mitomycin C, fibrin glue, ocular hydrogel sealant, neodymium:yttriumaluminum garnet laser and amniotic membrane graft, may be required for recurrent or refractory cases. The aims of this review are to determine the prevalence and risk factors of PLEI; to describe its pathogenesis and clinical features and to summarise the therapeutic armamentarium and the visual outcome of PLEI.
Development of a new patient-derived xenograft humanised mouse model to study human-specific tumour microenvironment and immunotherapy
Authors: Zhao Yue , Shuen Timothy Wai Ho , Toh Tan Boon , Chan Xue Ying , Liu Min , Tan Sue Yee , Fan Yong , Yang Hechuan , Lyer Shridhar Ganpathi , Bonney Glenn Kunnath , Loh Eva , Chang Kenneth Tou En , Tan Thiam Chye , Zhai Weiwei , Chan Jerry Kok Yen , Chow Edward Kai-Hua , Chee Cheng Ean , Lee Guan Huei , Dan Yock Young , Chow Pierce Kah-Hoe , Toh Han Chong , Lim Seng Gee , Chen Qingfeng
Published: March 2018

Objective

As the current therapeutic strategies for human hepatocellular carcinoma (HCC) have been proven to have limited effectiveness, immunotherapy becomes a compelling way to tackle the disease. We aim to provide humanised mouse (humice) models for the understanding of the interaction between human cancer and immune system, particularly for human-specific drug testing.

Design

Patient-derived xenograft tumours are established with type I human leucocyte antigen matched human immune system in NOD-scid Il2rg−/−(NSG) mice. The longitudinal changes of the tumour and immune responses as well as the efficacy of immune checkpoint inhibitors are investigated.

Results

Similar to the clinical outcomes, the human immune system in our model is educated by the tumour and exhibits exhaustion phenotypes such as a significant declination of leucocyte numbers, upregulation of exhaustion markers and decreased the production of human proinflammatory cytokines. Notably, cytotoxic immune cells decreased more rapidly compared with other cell types. Tumour infiltrated T cells have much higher expression of exhaustion markers and lower cytokine production compared with peripheral T cells. In addition, tumour-associated macrophages and myeloid-derived suppressor cells are found to be highly enriched in the tumour microenvironment. Interestingly, the tumour also changes gene expression profiles in response to immune responses by upregulating immune checkpoint ligands. Most importantly, in contrast to the NSG model, our model demonstrates both therapeutic and side effects of immune checkpoint inhibitors pembrolizumab and ipilimumab.

Conclusions

Our work provides a model for immune-oncology study and a useful parallel-to-human platform for anti-HCC drug testing, especially immunotherapy.
Supple bodies, healthy minds: yoga, psychedelics and American mental health
Authors: Richert Lucas , DeCloedt Matthew
Published: March 2018

Much discussion about mental health has revolved around treatment models. As interdisciplinary scholarship has shown, mental health knowledge, far from being a neutral product detached from the society that generated it, was shaped by politics, economics and culture. By drawing on case studies of yoga, religion and fitness, this article will examine the ways in which mental health practices—sometimes scientific, sometimes spiritual—have been conceived, debated and applied by researchers and the public. More specifically, it will interrogate the relationship between yoga, psychedelics, South Asian and Eastern religion (as understood and practiced in the USA) and mental health.
Relationship between stroke recurrence, infarct pattern, and vascular distribution in patients with symptomatic intracranial stenosis
Authors: Raghuram Karthikram , Durgam Aditya , Kohlnhofer Jennifer , Singh Ayush
Published: March 2018

Objective

In view of recent literature suggesting that stroke recurrence and risks related to intervention may be related to plaque physiology/instability, our study sought to discern the pattern of stroke and rates of stoke recurrence as they relate to the anatomy and presentation of the underlying stenosis.

Methods

Retrospective chart as well as CT and MR angiographic imaging review of patients in the institutional stroke database was performed, including identification of patient risk factors, medical therapeutic optimization, compliance, serum cholesterol (low density lipoprotein) levels, blood pressure, physical therapy referrals, follow-up clinical status (using the modified Rankin Scales), and rate of recurrent stroke. 39 patients met the inclusion criteria. We evaluated infarct pattern (embolic, adjacent perforator, or watershed) and vascular distribution.

Results

Basilar artery stenosis was most likely to present as a perforator stroke and least likely to recur. Patients discharged with suboptimal medical therapy were twice as likely to have a recurrent stroke. Among patients with optimized medical therapy, no recurrent strokes were seen in patients with an embolic infarct pattern, while a 57% recurrence rate was seen in patients with a watershed infarct pattern.

Conclusions

Our results suggest that hemodynamic intracranial vascular stenoses may be less responsive to medical therapy, while stenotic lesions caused by plaque destabilization or in perforator territories may benefit from aggressive medical management with delayed or staged endovascular therapy. Recurrence of stroke may be affected both by vascular territory and by aggressive risk factor control, although the latter remains difficult to evaluate.
Clinical presentation of CIED infection following initial implant versus reoperation for generator change or lead addition
Authors: Harper Mariko W , Uslan Daniel Z , Greenspon Arnold J , Baddour Larry M , Carrillo Roger G , Danik Stephan B , Tolosana Jose M , Le Katherine , Miro Jose M , Naber Christoph K , Peacock James , Sohail Muhammad Rizwan , Vikram Holenarasipur R , Prutkin Jordan M
Published: March 2018

Objective

To explore differences in clinical manifestations and outcomes in those patients who develop infection after undergoing initial implantation versus reoperation.

Methods

We compared cases of cardiac implantable electronic device (CIED) infection based on initial implantation versus reoperation from 11 centres.

Results

There were 432 patients with CIED infection, 178 occurring after initial device placement and 254 after repeat reoperation. No differences were seen in age, sex or device type. Those with infection after initial implant had a higher Charlson Comorbidity Score (median 3 (IQR 2–6) vs 2 (IQR 1–4), p<0.001), shorter time since last procedure (median 8.9 months (IQR 0.9–33.3) vs 19.5 months (IQR 1.1–62.9), p<0.0001) and fewer leads (2.0±0.6vs 2.5±0.9, p<0.001). Pocket infections were more likely to occur after a reoperation (70.1%vs48.9%, p<0.001) and coagulase negative staphylococci (CoNS) was the most frequently isolated organism in this group (p=0.029). In contrast, initial implant infections were more likely to present with higher white cell count (10.5±5.1 g/dL vs 9.5±5.4 g/dL, p=0.025), metastatic foci of infection (16.9%vs8.7%, p=0.016) and sepsis (30.9%vs19.3%, p=0.006). There were no differences in in-hospital (7.9%vs5.2%, p=0.31) or 6-month mortality (21.9%vs14.0%, p=0.056).

Conclusions

CIED infections after initial device implant occur earlier, more aggressively, and often due toStaphylococcus aureus. In contrast, CIED infections after reoperation occur later, are due to CoNS, and have more indolent manifestations with primary localisation to the pocket.
Ocular hypertension in a diabetic acromegalic dog
Authors: Pugh Benjamin Marc , Losowski Claudine
Published: March 2018

A seven‐year eight‐month‐old, female entire, Staffordshire Bull Terrier presented with bilateral third eyelid protrusion, polyuria, polydipsia and respiratory stridor. Diabetes mellitus and acromegaly were diagnosed, suspected to be secondary to elevated circulating endogenous progestogen levels. These elevated levels occur during the luteal phase of the oestrus cycle. The finding of bilateral ocular hypertension is proposed to be secondary to the acromegaly. The ocular hypertension resolved post‐ovariohysterectomy and mammary mass removal, along with the resolution of the acromegaly.

This case highlights an unusual presentation for acromegaly and demonstrates the value of tonometry even in cases where glaucoma seems unlikely. To the authors’ knowledge, this is the first report of ocular hypertension secondary to acromegaly in the dog.
Drawing the line in clinical treatment of companion animals: recommendations from an ethics working party
Authors: Grimm Herwig , Bergadano Alessandra , Musk Gabrielle C , Otto Klaus , Taylor Polly M , Duncan Juliet Clare
Published: March 2018

Modern veterinary medicine offers numerous options for treatment and clinicians must decide on the best one to use. Interventions causing short‐term harm but ultimately benefitting the animal are often justified as being in the animal's best interest. Highly invasive clinical veterinary procedures with high morbidity and low success rates may not be in the animal's best interest. A working party was set up by the European College of Veterinary Anaesthesia and Analgesia to discuss the ethics of clinical veterinary practice and improve the approach to ethically challenging clinical cases. Relevant literature was reviewed. The ‘best interest principle’ was translated into norms immanent to the clinic by means of the ‘open question argument’. Clinical interventions with potential to cause harm need ethical justification, and suggest a comparable structure of ethical reflection to that used in the context of in vivo research should be applied to the clinical setting. To structure the ethical debate, pertinent questions for ethical decision‐making were identified. These were incorporated into a prototype ethical tool developed to facilitate clinical ethical decision‐making. The ethical question ‘Where should the line on treatment be drawn’ should be replaced by ‘How should the line be drawn?’
Prioritizing lingering bugs
Authors: Akbarinasaji Shirin
Published: March 2018

As the software projects become more complex, the release deci-sion is made without resolving all the bugs in the issue tracking system. Accumulation of the bugs in the bug repository is similar to nancial obligation as we borrow time and resources to engage in another activity rather than resolving the bugs. Deferring the bug in the next release may have some consequences. Therefore, the decision whether to resolve the bug in the current release or postponing it to the next release is a crucial decision. In this proposal, we study the deferred bugs (lingering bugs) against the non-deferred bugs (regular bugs). Our aim is to develop the pre-dictive model which can predict whether the bug would linger or not. Additionally, we are interested in measuring of the linger-ing bug in terms of principal (standard time it takes to x them) and risk of liability (impact). We propose to use reinforcement learning for prioritization of lingering bugs with respect to their impact.
One-Time Contributors to FLOSS
Authors: Lee Amanda
Published: March 2018

Free/Libre Open Source Software (FLOSS) projects rely on a steady influx of newcomer volunteer developers to survive. As these projects, unlike traditional software projects, often do not pay their contributors to work on them, volunteers must be obtained instead. Once obtained, a volunteer goes through a lengthy process in order to join the project, including obtaining sufficient knowledge of the codebase and learning the rules of the community. However, some developers drop out after they make a single commit to the code database. These developers are knowledgeable enough to commit code and make it through the onboarding process, but leave the project rather than join, therefore depriving the project of potential talent. We propose to understand these One-Time code Contributors (OTCs) through surveys and through data-mining the projects? software repositories: if they are a unique demographic, why they only commit once, if anything can be done to assist them. Once they are determined as a separate demographic, the study pivots to examine other factors that might affect OTCs, including such factors as project governance and project architecture.
Human muscle-specific A-kinase anchoring protein polymorphisms modulate the susceptibility to cardiovascular diseases by altering cAMP/PKA signaling
Authors: Suryavanshi Santosh V. , Jadhav Shweta M. , Anderson Kody L. , Katsonis Panagiotis , Lichtarge Olivier , McConnell Bradley K.
Published: March 2018

One of the crucial cardiac signaling pathways is cAMP-mediated PKA signal transduction, which is regulated by a family of scaffolding proteins, i.e., A-kinase anchoring proteins (AKAPs). Muscle-specific AKAP (mAKAP) partly regulates cardiac cAMP/PKA signaling by binding to PKA and phosphodiesterase 4D3 (PDE4D3), among other proteins, and plays a central role in modulating cardiac remodeling. Moreover, genetics plays an incomparable role in modifying the risk of cardiovascular diseases (CVDs). Single-nucleotide polymorphisms (SNPs) in various proteins have especially been shown to predispose individuals to CVDs. Hence, we hypothesized that human mAKAP polymorphisms found in humans with CVDs alter the cAMP/PKA pathway, influencing the susceptibility of individuals to CVDs. Our computational analyses revealed two mAKAP SNPs found in cardiac disease-related patients with the highest predicted deleterious effects, Ser 1653 Arg (S1653R) and Glu 2124 Gly (E2124G). Coimmunoprecipitation data in human embryonic kidney-293T cells showed that the S1653R SNP, present in the PDE4D3-binding domain of mAKAP, changed the binding of PDE4D3 to mAKAP and that the E2124G SNP, flanking the 3′-PKA binding domain, changed the binding of PKA before and after stimulation with isoproterenol. These SNPs significantly altered intracellular cAMP levels, global PKA activity, and cytosolic PDE activity compared with the wild type before and after isoproterenol stimulation. PKA-mediated phosphorylation of pathological markers was found to be upregulated after cell stimulation in both mutants. In conclusion, human mAKAP polymorphisms may influence the propensity of developing CVDs by affecting cAMP/PKA signaling, supporting the clinical significance of PKA-mAKAP-PDE4D3 interactions.

NEW & NOTEWORTHY We found that single-nucleotide polymorphisms in muscle-specific A-kinase anchoring protein found in human patients with cardiovascular diseases significantly affect the cAMP/PKA signaling pathway. Our results showed, for the first time, that human muscle-specific A-kinase anchoring protein polymorphisms might alter the susceptibility of individuals to develop cardiovascular diseases with known underlying molecular mechanisms.
Myocardial infarction remodeling that progresses to heart failure: a signaling misunderstanding
Authors: Mouton Alan J. , Rivera Osvaldo J. , Lindsey Merry L.
Published: March 2018

After myocardial infarction, remodeling of the left ventricle involves a wound-healing orchestra involving a variety of cell types. In order for wound healing to be optimal, appropriate communication must occur; these cells all need to come in at the right time, be activated at the right time in the right amount, and know when to exit at the right time. When this occurs, a new homeostasis is obtained within the infarct, such that infarct scar size and quality are sufficient to maintain left ventricular size and shape. The ideal scenario does not always occur in reality. Often, miscommunication can occur between infarct and remote spaces, across the temporal wound-healing spectrum, and across organs. When miscommunication occurs, adverse remodeling can progress to heart failure. This review discusses current knowledge gaps and recent development of the roles of inflammation and the extracellular matrix in myocardial infarction remodeling. In particular, the macrophage is one cell type that provides direct and indirect regulation of both the inflammatory and scar-forming responses. We summarize current research efforts focused on identifying biomarker indicators that reflect the status of each component of the wound-healing process to better predict outcomes.
Influence of myocardial oxygen demand on the coronary vascular response to arterial blood gas changes in humans
Authors: Vermeulen Tyler D. , Boulet Lindsey M. , Stembridge Mike , Williams Alexandra M. , Anholm James D. , Subedi Prajan , Gasho Chris , Ainslie Philip N. , Feigl Eric O. , Foster Glen E.
Published: March 2018

It remains unclear if the human coronary vasculature is inherently sensitive to changes in arterial Po2 and Pco2 or if coronary vascular responses are the result of concomitant increases in myocardial O2 consumption/demand ([Formula: see text]). We hypothesized that the coronary vascular response to Po2 and Pco2 would be attenuated in healthy men when [Formula: see text] was attenuated with β1-adrenergic receptor blockade. Healthy men (age: 25 ± 1 yr, n = 11) received intravenous esmolol (β1-adrenergic receptor antagonist) or volume-matched saline in a double-blind, randomized crossover study and were exposed to poikilocapnic hypoxia, isocapnic hypoxia, and hypercapnic hypoxia. Measurements made at baseline and after 5 min of steady state at each gas manipulation included left anterior descending coronary blood velocity (LADV; Doppler echocardiography), heart rate, and arterial blood pressure. LADV values at the end of each hypoxic condition were compared between esmolol and placebo. The rate-pressure product (RPP) and left ventricular mechanical energy (MELV) were calculated as indexes of [Formula: see text]. All gas manipulations augmented RPP, MELV, and LADV, but only RPP and MELV were attenuated (4–18%) after β1-adrenergic receptor blockade ( P < 0.05). Despite attenuated RPP and MELV responses, β1-adrenergic receptor blockade did not attenuate the mean LADV vasodilatory response compared with placebo during poikilocapnic hypoxia (29.4 ± 2.2 vs. 27.3 ± 1.6 cm/s) and isocapnic hypoxia (29.5 ± 1.5 vs. 30.3 ± 2.2 cm/s). Hypercapnic hypoxia elicited a feedforward coronary dilation that was blocked by β1-adrenergic receptor blockade. These results indicate a direct influence of arterial Po2 on coronary vascular regulation that is independent of [Formula: see text].

NEW & NOTEWORTHY In humans, arterial hypoxemia led to an increase in epicardial coronary artery blood velocity. β1-Adrenergic receptor blockade did not diminish the hypoxemic coronary response despite reduced myocardial O2 demand. These data indicate hypoxemia can regulate coronary blood flow independent of myocardial O2 consumption. A plateau in the mean left anterior descending coronary artery blood velocity-rate-pressure product relationship suggested β1-adrenergic receptor-mediated, feedforward epicardial coronary artery dilation. In addition, we observed a synergistic effect of Po2 and Pco2 during hypercapnic hypoxia.
Specific circulating microRNAs display dose-dependent responses to variable intensity and duration of endurance exercise
Authors: Ramos Anna E. , Lo Claire , Estephan Leonard E. , Tai Yi-Yin , Tang Ying , Zhao Jingsi , Sugahara Masataka , Gorcsan John , Brown Marcel G. , Lieberman Daniel E. , Chan Stephen Y. , Baggish Aaron L.
Published: March 2018

Circulating microRNAs (c-miRNAs), plasma-based noncoding RNAs that control posttranscriptional gene expression, mediate processes that underlie phenotypical plasticity to exercise. The relationship and biological relevance between c-miRNA expression and variable dose exercise exposure remains uncertain. We hypothesized that certain c-miRNAs respond to changes in exercise intensity and/or duration in a dose-dependent fashion. Muscle release of such c-miRNAs may then deplete intracellular stores, thus facilitating gene reprogramming and exercise adaptation. To address these hypotheses, healthy men participated in variable intensity ( n = 12, 30 × 1 min at 6, 7, and 8 miles/h, order randomized) and variable duration ( n = 14, 7 × 1 mile/h for 30, 60, and 90 min, order randomized) treadmill-running protocols. Muscle-enriched c-miRNAs (i.e., miRNA-1 and miRNA-133a) and others with known relevance to exercise were measured before and after exercise. c-miRNA responses followed three profiles: 1) nonresponsive (miRNA-21 and miRNA-210), 2) responsive to exercise at some threshold but without dose dependence (miRNA-24 and miRNA-146a), and 3) responsive to exercise with dose dependence to increasing intensity (miRNA-1) or duration (miRNA-133a and miRNA-222). We also studied aerobic exercise-trained mice, comparing control, low-intensity (0.5 km/h), or high-intensity (1 km/h) treadmill-running protocols over 4 wk. In high- but not low-intensity-trained mice, we found increased plasma c-miR-133a along with decreased intracellular miRNA-133a and increased serum response factor, a known miR-133a target gene, in muscle. Characterization of c-miRNAs that are dose responsive to exercise in humans and mice supports the notion that they directly mediate physiological adaptation to exercise, potentially through depletion of intracellular stores of muscle-specific miRNAs.

NEW & NOTEWORTHY In this study of humans and mice, we define circulating microRNAs in plasma that are dose responsive to exercise. Our data support the notion that these microRNAs mediate physiological adaptation to exercise potentially through depletion of intracellular stores of muscle-specific microRNAs and releasing their inhibitory effects on target gene expression.
SMAD4 Gene Mutation Renders Pancreatic Cancer Resistance to Radiotherapy through Promotion of Autophagy
Authors: Wang Feng , Xia Xiaojun , Yang Chunying , Shen Jianliang , Mai Junhua , Kim Han-Cheon , Kirui Dickson , Kang Ya'an , Fleming Jason B. , Koay Eugene J. , Mitra Sankar , Ferrari Mauro , Shen Haifa
Published: March 2018

Purpose: Understanding the mechanism of radioresistance could help develop strategies to improve therapeutic response of patients with PDAC. The SMAD4 gene is frequently mutated in pancreatic cancer. In this study, we investigated the role of SMAD4 deficiency in pancreatic cancer cells' response to radiotherapy.

Experimental Design: We downregulated SMAD4 expression with SMAD4 siRNA or SMAD4 shRNA and overexpressed SMAD4 in SMAD4 mutant pancreatic cancer cells followed by clonogenic survival assay to evaluate their effects on cell radioresistance. To study the mechanism of radioresistance, the effects of SMAD4 loss on reactive oxygen species (ROS) and autophagy were determined by flow cytometry and immunoblot analysis, respectively. Furthermore, we measured radioresistance by clonogenic survival assay after treatment with autophagy inhibitor (Chloroquine) and ROS inhibitor (N-acetyl-l-cysteine) in SMAD4-depleted pancreatic cancer cells. Finally, the effects of SMAD4 on radioresistance were also confirmed in an orthotopic tumor model derived from SMAD4-depleted Panc-1 cells.

Results: SMAD4-depleted pancreatic cancer cells were more resistant to radiotherapy based on clonogenic survival assay. Overexpression of wild-type SMAD4 in SMAD4-mutant cells rescued their radiosensitivity. Radioresistance mediated by SMAD4 depletion was associated with persistently higher levels of ROS and radiation-induced autophagy. Finally, SMAD4 depletion induced in vivo radioresistance in Panc-1-derived orthotopic tumor model (P = 0.038). More interestingly, we observed that the protein level of SMAD4 is inversely correlated with autophagy in orthotopic tumor tissue samples.

Conclusions: Our results demonstrate that defective SMAD4 is responsible for radioresistance in pancreatic cancer through induction of ROS and increased level of radiation-induced autophagy. Clin Cancer Res; 24(13); 3176–85. ©2018 AACR.
A Review of Promising Natural Chemopreventive Agents for Head and Neck Cancer
Authors: Crooker Kyle , Aliani Rana , Ananth Megha , Arnold Levi , Anant Shrikant , Thomas Sufi Mary
Published: March 2018

Head and neck squamous cell carcinoma (HNSCC) accounts for 300,000 deaths per year worldwide, and overall survival rates have shown little improvement over the past three decades. Current treatment methods including surgery, chemotherapy, and radiotherapy leave patients with secondary morbidities. Thus, treatment of HNSCC may benefit from exploration of natural compounds as chemopreventive agents. With excellent safety profiles, reduced toxicities, antioxidant properties, and general acceptance for use as dietary supplements, natural compounds are viewed as a desirable area of investigation for chemoprevention. Though most of the field is early in development, numerous studies display the potential utility of natural compounds against HNSCC. These compounds face additional challenges such as low bioavailability for systemic delivery, potential toxicities when consumed in pharmacologic doses, and acquired resistance. However, novel delivery vehicles and synthetic analogues have shown to overcome some of these challenges. This review covers 11 promising natural compounds in the chemoprevention of HNSCC including vitamin A, curcumin, isothiocyanate, green tea, luteolin, resveratrol, genistein, lycopene, bitter melon, withaferin A, and guggulsterone. The review discusses the therapeutic potential and associated challenges of these agents in the chemopreventive efforts against HNSCC. Cancer Prev Res; 11(8); 441–50. ©2018 AACR.