bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of sofosbuvir/simeprevir plus flat dose ribavirin in genotype 1 elderly cirrhotic patients: A real‐life study
Authors: Pellicelli Adriano M. , Pace Palitti Valeria , Vignally Pascal , Ceccherini‐Silberstein Francesca , Siciliano Massimo , Giannelli Valerio , Moretti Alessandra , Tarquini Pierluigi , Scifo Gaetano , Messina Vincenzo , Ascione Antonio , Izzi Antonio , Marignani Massimo , D'Ambrosio Cecilia , Fondacaro Lucia , Ettorre Giuseppe M. , Ialongo Pasquale , Sacco Rodolfo , Perno Carlo F. , Barbarini Giorgio ,   the CLEO Group
Published: December 2016

Background & Aims

The proportion of HCV‐infected patients over age 65 years in Western countries is increasing. This growth and the advent of new antiviral therapy bring into the question the real‐world efficacy and safety of the combination of sofosbuvir (SOF) and simeprevir (SMV) plus a flat dose of 800 mg/d ribavirin (RBV) in elderly patients with cirrhosis compared to younger patients.

Methods

Retrospective observational multicentre real‐life investigation study of SOF/SMV/RBV for a duration of 12 weeks in HCV genotype 1‐infected patients with cirrhosis.

Results

Of the 270 patients enrolled in this study, with compensated cirrhosis, 133 (49.2%) were ≥65 years of age. Sustained virological response at 12 weeks (SVR12) was achieved by 94.2% (129/137) of those aged <65 years and 97.7% (130/133) of those ≥65 years. Diabetes was the most common comorbidity in patients ≥65 years compared to younger patients (26.3% vs 12.4% P<.003). The most common adverse event (AE) in elderly patients was a grade 2 anaemia (35.3% vs 19.9% P<.004).

Conclusions

Sofosbuvir/simeprevir plus a daily flat dose of RBV 800 mg for 12 weeks was highly effective and safe in genotype 1 elderly patients with compensated cirrhosis.
Wisteria floribunda agglutinin‐positive human Mac‐2 binding protein predicts the risk of HBV‐related liver cancer development
Authors: Kim Seung Up , Heo Ja Yoon , Kim Beom Kyung , Park Jun Yong , Kim Do Young , Han Kwang‐Hyub , Ahn Sang Hoon , Kim Hyon‐Suk
Published: December 2016

Background & Aims

Wisteria floribunda agglutinin‐positive human Mac‐2 binding protein (WFA+‐M2BP) can be used to assess the degree of liver fibrosis, but few studies have investigated its prognostic utility. We evaluated whether serum WFA+‐M2BP can predict the development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients.

Methods

A total of 1323 CHB patients with WFA+‐M2BP test results between 2009 and 2011 were included in this retrospective analysis.

Results

The mean age of patients (793 men) was 51.0 years. During the follow‐up period (median 60.3 months), 52 (3.9%) patients developed HCC. Age, the proportion of male gender, the presence of diabetes and cirrhosis, and levels of aspartate aminotransferase, alpha‐foetoprotein, and WFA+‐M2BP were significantly greater in patients with HCC than in those without HCC, whereas serum albumin levels and platelet counts were significantly lower in patients with HCC than in those without HCC (all P<.05). In multivariate analysis, WFA+‐M2BP level was an independent predictor of HCC development (adjusted hazard ratio 1.143, 95% CI: 1.139‐1.829), along with male gender and diabetes (all P<.05). In patients without cirrhosis (n=1087), WFA+‐M2BP levels ≥1.8 were associated with a higher risk of HCC development (P<.001 by log‐rank test), whereas WFA+‐M2BP levels ≥1.8 tended to be associated with a higher risk of HCC development in patients with cirrhosis (n=236) (P=.073 by log‐rank test).

Conclusions

WFA+‐M2BP level can independently predict HCC development. Further studies should investigate whether WFA+‐M2BP level could be incorporated into surveillance strategies for CHB patients.
Improving the quality of nurse‐influenced patient care in the intensive care unit
Authors: Sutton Lynsey J. , Jarden Rebecca J.
Published: December 2016

Background

Quality of care is a major focus in the intensive care unit (ICU).

Aim

To describe a nurse‐initiated quality improvement (QI) project that improved the care of critically ill patients in a New Zealand tertiary ICU.

Design

A framework for QI was developed and implemented as part of a practice change initiative.

Methods

Audit data were collected, analysed and reported across seven nurse‐influenced patient care standards. The seven standards were enteral nutrition delivered within 24 h of admission, timely administration of antibiotics, sedation holds for eligible patients, early mobilization and three pressure ulcer prevention strategies.

Results

Comparison of audit data collected in 2014 and 2015 demonstrated improvements in five of the seven standards. Those standards with the largest practice improvements were related to the following standards: all eligible patients have enteral nutrition commenced within the first 24 h of ICU admission (3% increase); all eligible patients receive antibiotics within 30 min of prescription time (6% increase); all eligible patients have a daily sedation interruption (DSI; 24% increase); and all eligible patients are mobilized daily in their ICU stay (11% increase in percentage of patients mobilized daily).

Conclusions

The nursing‐initiated QI project demonstrated improved ICU patient care in relation to early enteral nutrition commencement, DSIs and early and daily mobilizing.

Relevance to clinical practice

The use of a nursing QI framework incorporating audit and feedback is one method of evaluating and enhancing the quality of care and improving patient outcomes. This initiative demonstrated the improved quality of nursing care for ICU patients, particularly in relation to early enteral nutrition commencement, timely antibiotics, DSIs and daily mobilizing. It is thus highly relevant to critical care nursing teams, particularly those working to create a culture where change is safe, achievable and valued.
Tracing archipelagic connections through mainland islands
Authors: Rankin Jonathan R.
Published: December 2016

Biogeographers use the language of islands to theorise insular communities, extending the term beyond coastal environments to include so‐called ‘mainland’ islands. This paper suggests a similar approach is needed within cultural geography to account for places that are connected to archipelagos despite being unenclosed by water. The paper begins with a critique of materialist definitions of islands and the methodological assumptions underpinning them. It then speculates on an alternative theory of islands, which views them as autonomous objects and dynamic systems for reordering times and spaces within and beyond their watery margins. Auckland's Waitākere Ranges are considered as an example.
Enhanced regeneration potential of mobilized dental pulp stem cells from immature teeth
Authors: Nakayama H , Iohara K , Hayashi Y , Okuwa Y , Kurita K , Nakashima M
Published: December 2016

Objectives

We have previously demonstrated that dental pulp stem cells (DPSCs) isolated from mature teeth by granulocyte colony‐stimulating factor (G‐CSF)‐induced mobilization method can enhance angiogenesis/vasculogenesis and improve pulp regeneration when compared with colony‐derived DPSCs. However, the efficacy of this method in immature teeth with root‐formative stage has never been investigated. Therefore, the aim of this study was to examine the stemness, biological characteristics, and regeneration potential in mobilized DPSCs compared with colony‐derived DPSCs from immature teeth.

Materials and methods

Mobilized DPSCs isolated from immature teeth were compared to colony‐derived DPSCs using methods including flow cytometry, migration assays, mRNA expression of angiogenic/neurotrophic factor, and induced differentiation assays. They were also compared in trophic effects of the secretome. Regeneration potential was further compared in an ectopic tooth transplantation model.

Results

Mobilized DPSCs had higher migration ability and expressed more angiogenic/neurotrophic factors than DPSCs. The mobilized DPSC secretome produced a higher stimulatory effect on migration, immunomodulation, anti‐apoptosis, endothelial differentiation, and neurite extension. In addition, vascularization and pulp regeneration potential were higher in mobilized DPSCs than in DPSCs.

Conclusions

G‐CSF‐induced mobilization method enhances regeneration potential of colony‐derived DPSCs from immature teeth.
An update on the implications of cyclin D1 in oral carcinogenesis
Authors: Ramos‐García P , Gil‐Montoya JA , Scully C , Ayén A , González‐Ruiz L , Navarro‐Triviño FJ , González‐Moles MA
Published: December 2016

Cyclin D1 promotes cell cycle progression during G1 phase, a key event in G1‐S transition. The protein is encoded by gene CCND1, located in chromosomal band 11q13. Cyclin D1 plays key roles in cell biology, including cell proliferation and growth regulation, mitochondrial activity modulation, DNA repair, and cell migration control. CCND1 gene and its protein cyclin D1 are frequently altered by different molecular mechanisms, including amplification, chromosomal translocations, mutations, and activation of the pathways involved in cyclin D1 expression, alterations which appear to be essential in the development of human cancers, including oral carcinoma. This is the first published review of the specific features of cyclin D1 overexpression in oral oncogenesis. Starting with the physiological regulation of cyclin D1, there is an evaluation of its functions, overexpression mechanisms, and the implications of the oncogenic activation of CCND1/cyclin D1 in oral squamous cell carcinoma. The potential diagnostic and prognostic value of cyclin D1 is reviewed. The influence of CCND1/cyclin D1 on tumor size and clinical stage is reported, and an update is provided on the utilization of cyclin D1 as therapeutic target and on the combination of cyclin D1 inhibitors with cytotoxic agents. Future research lines in this field are also proposed.
What is (Dis)Agreement?
Authors: Rowbottom Darrell P.
Published: December 2016

When do we agree? The answer might once have seemed simple and obvious; we agree thatpwhen we each believe thatp. But from a formal epistemological perspective, where degrees of belief are more fundamental than beliefs, this answer is unsatisfactory. On the one hand, there is reason to suppose that it is false; degrees of belief aboutpmight differ when beliefs simpliciter onpdo not. On the other hand, even if it is true, it is too vague; for what it is to believe simpliciter ought to be explained in terms of degrees of belief.

This paper presents several possible notions of agreement, and corresponding notions of disagreement. It indicates how the findings are fruitful for the epistemology of disagreement, with special reference to the notion of epistemic peerhood.
Coxiella burnetii: Serological reactions and bacterial shedding in primiparous dairy cows in an endemically infected herd—impact on milk yield and fertility
Authors: Freick M , Enbergs H , Walraph J , Diller R , Weber J , Konrath A
Published: December 2016

Contents

Coxiella burnetii (C. burnetii) is the causative agent of Q fever both in humans and animals. The objectives of this study were to investigate seropositivity and bacterial shedding in heifers and primiparous cows in an endemically infected herd and to assess the effects on post‐partum diseases, fertility and milk production. At the age of 9 months, 96 Holstein heifers were included. Sampling was performed reproduction‐orientated: at the beginning of the study, at detection of first pregnancy, 3 weeks before expected calving date (blood serum), at parturition and after 21, 42, 100 and 150 days in milk (DIM) (blood serum, vaginal swabs and milk). Serum samples were investigated by a commercial ELISA for the presence of specific antibodies and vaginal swabs and milk samples by PCR to detect C. burnetii DNA. Individual animal data (calving ease, stillbirth, retained foetal membranes, puerperal metritis, endometritis after 42 DIM, presence of corpus luteum after 42 DIM, interval calving‐first service, interval calving‐conception, number of inseminations until 150 DIM, proportion of pregnant cows until 100 and 150 DIM, proportion of pregnant cows after first service and data of the dairy herd improvement test) were documented. All heifers were seronegative at the age of 9 months and 3 weeks before the expected calving date. Subsequently, the proportion of seropositive animals and the antibody score increased significantly towards 42 and 100 DIM, respectively. Vaginal C. burnetii shedding was highest at parturition (30.9%), while the most positive milk samples were detected after 100 DIM (15.3%). Coxiella burnetii seropositivity and shedding had no impact on parameters of reproduction. However, milk fat yield was declined in puerperal vaginal shedders and cows which seroconverted during their first 42 DIM, respectively.
Efficiency of uterine fluid cytology in the diagnosis of subclinical endometritis in the water buffalo (Bubalus bubalis)
Authors: Gahlot SC , Kumar S , Kumaresan A , Chand S , Baithalu RK , Lathika S , Patbandha TK , Lathwal SS , Mohanty TK
Published: December 2016

Contents

This study compared endometrial cytology vis‐a‐vis uterine fluid cytology for assessment of uterine health in clinically normal and subclinical endometritis (SE)‐affected buffaloes. Uterine fluid samples and endometrial samples were collected from the buffaloes (n = 38) at oestrus using blue sheath and cytobrush, respectively. The smears were stained with Field stain for 3 minutes, and a minimum of 400 cells were counted in each smear for determination of the percentage of polymorphonuclear (PMN) leucocyte. The incidence of subclinical endometritis, based on the cytobrush cytology, was 23.08%. The correlation between cytobrush cytology with uterine fluid cytology was positive and significant (r = .37; p = .02). The ratio of PMN leucocyte in cytobrush cytology to uterine fluid cytology was 1:2.4. ROC analysis revealed that the threshold value of 6.16% PMN leucocyte in uterine fluid cytology showed a diagnostic sensitivity and specificity of 100% in differentiating normal from SE‐affected buffaloes. In conclusion, collection of uterine fluid was easier compared to collection of endometrial samples using cytobrush and the percentage of PMN leucocyte in uterine fluid cytology can be used as a tool for diagnosis of subclinical endometritis in buffaloes.
Affects, Bodies and Desire: ‘Queering’ Methods and Methodologies to Research Queer Migration
Authors: Di Feliciantonio Cesare , Gadelha Kaciano B.
Published: December 2016

In this paper we discuss the main methodological issues raised by a research project we carried out between 2012 and 2013 about Italian queer ‘creative’ migration in Berlin, focusing on the tensions among mobility/movement, desire, bodies, affects and fieldwork. Following an increasing international debate on the topic, the contribution discusses the (im)possibility to develop a queer method or methodology. We stress how ‘queering’ methodologies and methods is not an ontological position pre‐assumed when conducting research with queer‐identified subjects, but is a process of dismantling taken‐for‐granted, stable, monolithic categories and identities. In order to do so, the paper discusses positionalities, situated knowledge and the different interactions – with both human and non‐human actors – shaping the field. Through analysing body performances in the terms introduced by Taylor, ‘a politics of becoming’ emerges as a way to consider the relation between sexualities and spaces. The ‘objects’ of our research, that is, queer migrants, can thus be reframed following Braidotti's conceptualisation of the ‘nomadic subject’ and Deleuze and Guattari's ‘desiring machines’. Since they are shaped by affects, personal trajectories are exceptional and unique, composing new territorial materialities.
Evaluation of the Lactate Plus monitor for plasma lactate concentration measurement in dogs
Authors: Nye Carolyn J. , Musulin Sarah E. , Hanel Rita M. , Mariani Christopher L.
Published: December 2016

Objective

To compare the Lactate Plus handheld monitor to a reference blood gas analyzer for determining plasma lactate concentrations in canine whole blood.

Design

Prospective observational study.

Setting

University teaching hospital.

Animals

Ninety‐four dogs hospitalized or admitted through the emergency service provided 125 blood samples. Only dogs that required a venous or arterial blood gas evaluation as a part of their diagnostic assessment or ongoing management were included.

Interventions

None.

Measurements and Main Results

Canine whole blood samples were assayed for plasma lactate concentration with a reference blood gas analyzer and the Lactate Plus monitor. Correlation and Bland–Altman analyses were used to compare results between the 2 methods. A subset of blood samples was repeatedly analyzed with the Lactate Plus to assess monitor precision. Plasma lactate measurements from the Lactate Plus monitor showed excellent correlation with those from the reference analyzer (ρ = 0.98, P < 0.0001). Bland–Altman analysis revealed a small bias (0.1296). Agreement between the 2 methods was less consistent for lactate concentrations >5 mmol/L. The coefficient of variation ranged from 0–26.2% (median, 3.7%) and was <15% for 50/53 samples.

Conclusions

The Lactate Plus provides a fast and affordable method to measure plasma lactate concentration in dogs. Results showed excellent agreement with the reference analyzer and precision of the instrument was acceptable.
Managing haemovigilance at hospital and national level
Authors: Hindawi S.
Published: December 2016

Background

The haemovigilance system is an adverse event monitoring system established at the beginning of the last decade (1990s) in Europe. It then became a crucial part in quality system of blood transfusion in developed countries. However, there have been difficulties in taking farther steps in the direction of haemovigilance in developing countries up until now. In each country, a proposal of clear simple plan should be submitted to an official national body responsible of transfusion services in the country to get approval and support. The proposal should include aim and objective of having such system. The aim was to prevent the risk and/or to reduce the severity of adverse events, a written policy and standard to be followed, working group or committee to be responsible for the process of implementation, funds to cover system requirement and the running cost of the system. The decision must be taken to apply the haemovigilance system as voluntary or mandatory process according to the need of the country. At national level, the ministry of health (MOH) or the National Blood Authority (NBA) should ensure that bidirectional traceability is maintained from donor to patient and vice versa. In addition, they should ensure that mechanisms are in place for data collection, monitoring, analysis, reporting, evaluation and assessment.

Conclusion

Haemovigilance should be part of quality management systems of blood centres and healthcare institutions and should result in improved policies, procedures and practices in the blood transfusion chain.
The Epidemiology and Characteristics of Q fever and Co‐infections with Scrub Typhus, Murine Typhus or Leptospirosis in Taiwan: A Nationwide Database Study
Authors: Lai C.‐H. , Sun W. , Lee C.‐H. , Lin J.‐N. , Liao M.‐H. , Liu S.‐S. , Chang T.‐Y. , Tsai K.‐F. , Chang Y.‐C. , Lin H.‐H. , Chen Y.‐H.
Published: December 2016

Q fever (QF) is a worldwide zoonosis associated with outbreaks. Only a few nationwide studies regarding the surveillance and epidemiology of human QF have been reported. Although QF is endemic in Taiwan, a nationwide database investigation of the epidemiology and characteristics of QF and its associations with scrub typhus (ST), murine typhus (MT) and leptospirosis (LS) has never been reported. We analysed nationwide databases of suspected QF, ST, MT and LS cases from October 2007 to December 2014 obtained from the Centers for Disease Control, Taiwan. A total of 468 (4.2%) QF cases were identified among 11 109 suspected QF cases. QF cases were mainly distributed in the southern and Kaohsiung–Pingtung regions but rarely in the eastern region. Compared to non‐QF cases, QF cases had significantly higher percentages of males (88.7 versus 66.2%) and high‐risk occupations (farming, animal husbandry or veterinary medicine) (16.2 versus 10.5%). But the percentages of specific animal contact, including cattle (0.6 versus 0.8%) and goats (0.9 versus 1.0%), were low in both. The majority of suspected QF cases (89.4%) were simultaneously suspected with ST, MT or LS, and the combinations of suspected diseases differed between regions. The number of suspected QF cases from the eastern region decreased since 2009, which was not observed in other regions. A total of 1420 (12.8%) cases had confirmed diseases, including QF (453, 4.1%), QF+ST (7, 0.06%), QF+MT (4, 0.04%), QF+LS (4, 0.04%), MT (186, 1.7%), ST (545, 4.9%), ST+LS (11, 0.1%) and LS (210, 1.9%). Compared to cases of unknown disease, QF cases had larger percentages of high‐risk occupations (16.2 versus 9.6%) but similar histories of animal contact (29.8 versus 25.1%). QF is an endemic disease in southern Taiwan. It is difficult to differentiate QF from ST, MT or LS only by high‐risk occupations and history of animal contact, and co‐infection of QF with these diseases should be considered.
In Canada, case spurs concern over misconduct secrecy
Authors: Komnenic Ana
Published: December 2016

Government, universities should name offenders, critics say.
Large gem diamonds from metallic liquid in Earth’s deep mantle
Authors: Smith Evan M. , Shirey Steven B. , Nestola Fabrizio , Bullock Emma S. , Wang Jianhua , Richardson Stephen H. , Wang Wuyi
Published: December 2016

Diamonds rock their metal roots

Massive diamonds are rare, expensive, and captivating. These diamonds now appear to be distinctive not only in their size but also in their origin. Smith
et al.
probed mineral inclusions from these very large diamonds and found abundant slivers of iron metal surrounded by reducing gases. This suggests that the large diamonds grew from liquid metal in Earth's mantle. The inclusions also provide direct evidence of a long-suspected metal precipitation reaction that requires a more reducing mantle.

Science
, this issue p.
1403
Long-term maintenance of human naïve T cells through in situ homeostasis in lymphoid tissue sites
Authors: Thome Joseph J. C. , Grinshpun Boris , Kumar Brahma V. , Kubota Masaru , Ohmura Yoshiaki , Lerner Harvey , Sempowski Gregory D. , Shen Yufeng , Farber Donna L.
Published: December 2016

Human naïve T cells are maintained in lymph nodes for decades and clonally expand in situ after cessation of thymopoiesis.
Cardiovascular health, growth and gonadal function in children and adolescents with congenital adrenal hyperplasia
Authors: Mooij Christiaan F , Webb Emma A , Claahsen van der Grinten Hedi L , Krone Nils
Published: December 2016

After the introduction of replacement therapy with glucocorticoids and mineralocorticoids in the 1950s, congenital adrenal hyperplasia (CAH) is no longer a life-limiting condition. However, due to the successful introduction of medical steroid hormone replacement, CAH has become a chronic condition, with associated comorbidities and long-term health implications. The aim of treatment is the replacement of mineralocorticoids and glucocorticoids and the normalisation of elevated androgen concentrations. Long-term consequences of the condition and current treatment regimens include unfavourable changes in the cardiovascular risk profile, impaired growth, testicular adrenal rest tumours (TART) in male and subfertility in both male and female patients with CAH. Optimising replacement therapy in patients with CAH remains challenging. On one hand, treatment with supraphysiological doses of glucocorticoids might be required to normalise androgen concentrations and decrease size or presence of TARTs. On the other hand, treatment with supraphysiological doses of glucocorticoids is associated with an increased prevalence of unfavourable cardiovascular and metabolic risk profiles as well as impaired longitudinal growth and gonadal function. Therefore, treatment of children and adults with CAH requires an individualised approach. Careful monitoring for early signs of complications is already warranted during paediatric healthcare provision to prevent and reduce the impact of comorbidities in later life.
Rare cause of neck pain: tumours of the posterior elements of the cervical spine
Authors: Katsuura Yoshihiro , Cason Garrick , Osborn James
Published: December 2016

Here we present two cases of primary bone tumours of the cervical spine in patients who had persistent neck pain—in one case, lasting 8 years. In each case, there was a delay in diagnosis and referral to a spine specialist was prolonged. Primary bone tumours of the spine are rare, which is in contrast to the wide prevalence of cervical neck pain. Many primary care providers may go an entire career without encountering a symptomatic primary cervical spine tumour. In this paper, we discuss the clinical course and treatment of each patient and review the current literature on primary bone tumours of the spine. Owing to the subtle roentgenographic findings of primary cervical tumours, we highlight the importance of advanced imaging in the clinical work-up of simple axial neck pain lasting >6 weeks to avoid misdiagnosis of serious pathology.
Unusual case of bilateral maxillary fungus ball
Authors: Vinciguerra Alessandro , Saibene Alberto Maria , Lozza Paolo , Maccari Alberto
Published: December 2016

An otherwise healthy 34-year-old man was referred to our ear, nose and throat (ENT) clinic for a bilateral maxillary radiologic opacity. This condition was accidentally discovered with a panoramic radiography performed during a follow-up visit after a bilateral endodontic treatment. The patient did not report any specific sinonasal symptom such as purulent nasal discharge, loss of smell and cough, apart from an unspecific sinus pressure. The CT scans showed a bilateral inflammatory process into the maxillary-ethmoidal sinuses and an iron-like density within the maxillary sinuses, while nasal endoscopy showed purulent discharge in the ostiomeatal complex. The patient underwent functional endoscopic sinus surgery under general anaesthesia and the inflammatory material collected was histologically diagnosed as a rare case of bilateral fungus ball. The patient was dismissed the following day with no complications; there were not any sign of recurrence or symptoms during a 4 month follow-up.
Hand-related physical function in rheumatic hand conditions: a protocol for developing a patient-reported outcome measurement instrument
Authors: Klokker Louise , Terwee Caroline B , Wæhrens Eva Ejlersen , Henriksen Marius , Nolte Sandra , Liegl Gregor , Kloppenburg Margreet , Westhoven Rene , Wittoek Ruth , Kjeken Ingvild , Haugen Ida K , Schalet Ben , Gershon Richard , Bliddal Henning , Christensen Robin
Published: December 2016

Introduction

There is no consensus about what constitutes the most appropriate patient-reported outcome measurement (PROM) instrument for measuring physical function in patients with rheumatic hand conditions. Existing instruments lack psychometric testing and vary in feasibility and their psychometric qualities. We aim to develop a PROM instrument to assess hand-related physical function in rheumatic hand conditions.

Methods and analysis

We will perform a systematic search to identify existing PROMs to rheumatic hand conditions, and select items relevant for hand-related physical function as well as those items from the Patient Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) item bank that are relevant to patients with rheumatic hand conditions. Selection will be based on consensus among reviewers. Content validity of selected items will be established through the use of focus groups. If patients deem necessary, we will develop new items based on the patients' input. We will examine whether it is valid to score all selected and developed items on the same scale as the original items from the PROMIS PF item bank. Our analyses will follow the methods used for calibrating the original PROMIS PF item bank in US samples, which were largely based on the general PROMIS approach.

Ethics and dissemination

This study will be carried out in accordance with the Helsinki Declaration. Ethics approvals will be obtained where necessary, and signed informed consent will be obtained from all participants. We aim to disseminate the results of the study through publication in international peer-reviewed journals and at international conferences.
Leading a global veterinary community
Authors: Ingwersen Walt
Published: December 2016

Canadian veterinarian Walt Ingwersen was recently elected as president of the World Small Animal Veterinary Association. Here, he describes the route his career has taken and why he became involved in the WSAVA
Energy spectrum of black holes: A new view
Authors: Majhi Abhishek
Published: December 2016

Energy of a black hole is usually quantized by invoking some area quantization scheme after expressing the energy in terms of the horizon area. However, in this approach one has to quantize the local and asymptotic energy of the black hole separately and the two results do not manifest any physical correspondence with each other. Here, as opposed to this practice, we find the unique energy spectrum of black holes by adopting a top-down approach. The physical links among the underlying quantum theory, statistical mechanics and thermodynamics of the black hole horizon play the central role in determining the energy spectrum. The energy spectrum that we obtain explicitly reveals the correspondence between asymptotic and local observations through the presence of the surface gravity of the horizon as a parameter in the spectrum, rather than being expressed as a function of area and consequently getting quantized in the usual approach. Thus, our result presents a new view as far as black hole energy quantization is concerned. The calculations are performed using the quantum geometric description of black hole horizons as laid down by loop quantum gravity.
Permian conodont biostratigraphy
Authors: Henderson Charles M.
Published: December 2016

Forty Permian conodont biozones are summarized and 35 additional regional zones are correlated. The Lower Permian is largely zoned on the basis of partial range lineage interval zones of species of
Streptognathodus
,
Sweetognathus
,
Neostreptognathodus
and
Mesogondolella
. The Middle and Upper Permian are zoned, respectively, on the basis of partial range lineage interval zones of species of
Jinogondolella
and
Clarkina
. The ranges of all key taxa to develop this zonation are depicted in relation to the geochronological ages of Permian stages. The lowest Permian succession has been astronomically tuned with 400 kyr cyclothems linked to interpolated ages in the Uralian succession.
Characteristics of breathing rate control mediated by a subregion within the pontine parabrachial complex
Authors: Zuperku Edward J. , Stucke Astrid G. , Hopp Francis A. , Stuth Eckehard A. E.
Published: December 2016

The role of the dorsolateral pons in the control of expiratory duration (Te) and breathing frequency is incompletely understood. A subregion of the pontine parabrachial-Kölliker-Fuse (PB-KF) complex of dogs was identified via microinjections, in which localized pharmacologically induced increases in neuronal activity produced increases in breathing rate while decreases in neuronal activity produced decreases in breathing rate. This subregion is also very sensitive to local and systemic opioids. The purpose of this study was to precisely characterize the relationship between the PB-KF subregion pattern of altered neuronal activity and the control of respiratory phase timing as well as the time course of the phrenic nerve activity/neurogram (PNG). Pulse train electrical stimulation patterns synchronized with the onset of the expiratory (E) and/or phrenic inspiratory (I) phase were delivered via a small concentric bipolar electrode while the PNG was recorded in decerebrate, vagotomized dogs. Step frequency patterns during the E phase produced a marked frequency-dependent decrease in Te, while similar step inputs during the I phase increased inspiratory duration (Ti) by 14 ± 3%. Delayed pulse trains were capable of pacing the breathing rate by terminating the E phase and also of triggering a consistent stereotypical inspiratory PNG pattern, even when evoked during apnea. This property suggests that the I-phase pattern generator functions in a monostable circuit mode with a stable E phase and a transient I phase. Thus the I-pattern generator must contain neurons with nonlinear pacemaker-like properties, which allow the network to rapidly obtain a full on-state followed by relatively slow inactivation. The activated network can be further modulated and supplies excitatory drive to the neurons involved with pattern generation.

NEW & NOTEWORTHY A circumscribed subregion of the pontine medial parabrachial nucleus plays a key role in the control of breathing frequency primarily via changes in expiratory duration. Excitation of this subregion triggers the onset of the inspiratory phase, resulting in a stereotypical ramplike phrenic activity pattern independent of time within the expiratory phase. The ability to pace the I-burst rate suggests that the in vivo I-pattern generating network must contain functioning pacemaker neurons.
Role of Mitochondria-Associated Endoplasmic Reticulum Membrane in Inflammation-Mediated Metabolic Diseases
Authors: Thoudam Themis , Jeon Jae-Han , Ha Chae-Myeong , Lee In-Kyu
Published: December 2016

Inflammation is considered to be one of the most critical factors involved in the development of complex metabolic diseases such as type 2 diabetes, cancer, and cardiovascular disease. A few decades ago, the discovery of mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) was followed by the identification of its roles in regulating cellular homeostatic processes, ranging from cellular bioenergetics to apoptosis. MAM provides an excellent platform for numerous signaling pathways; among them, inflammatory signaling pathways associated with MAM play a critical role in cellular defense during pathogenic infections and metabolic disorders. However, induction of MAM causes deleterious effects by amplifying mitochondrial reactive oxygen species generation through increased calcium transfer from the ER to mitochondria, thereby causing mitochondrial damage and release of mitochondrial components into the cytosol as damage-associated molecular patterns (DAMPs). These mitochondrial DAMPs rapidly activate MAM-resident inflammasome components and other inflammatory factors, which promote inflammasome complex formation and release of proinflammatory cytokines in pathological conditions. Long-term stimulation of the inflammasome instigates chronic inflammation, leading to the pathogenesis of metabolic diseases. In this review, we summarize the current understanding of MAM and its association with inflammation-mediated metabolic diseases.
Molecular Imaging of Stem Cell Transplantation for Liver Diseases: Monitoring, Clinical Translation, and Theranostics
Authors: Wang Ping , Petrella Francesco , Nicosia Luca , Bellomi Massimo , Rizzo Stefania
Published: December 2016

Stem cell transplantation has been investigated to rescue experimental liver failure and is promising to offer an alternative therapy to liver transplantation for liver diseases treatment. Several clinical studies in this field have been carried out, but the therapeutic benefit of this treatment is still controversial. A major obstacle to developing stem cell therapies in clinic is being able to visualize the cells in vivo. Imaging modalities allow optimization of delivery, detecting cell survival and functionality by in vivo monitoring these transplanted graft cells. Moreover, theranostic imaging is a brand new field that utilizes nanometer‐scale materials to glean diagnostic insight for simultaneous treatment, which is very promising to improve stem cell‐based therapy for treatment of liver diseases. The aim of this review was to summarize the various imaging tools that have been explored with advanced molecular imaging probes. We also outline some recent progress of preclinical and clinical studies of liver stem cells transplantation. Finally, we discuss theranostic imaging for stem cells transplantation for liver dysfunction and future opportunities afforded by theranostic imaging.
Burkholderia contaminansBiofilm Regulating Operon and Its Distribution in Bacterial Genomes
Authors: Voronina Olga L. , Kunda Marina S. , Ryzhova Natalia N. , Aksenova Ekaterina I. , Semenov Andrey N. , Romanova Yulia M. , Gintsburg Alexandr L.
Published: December 2016

Biofilm formation byBurkholderiaspp. is a principal cause of lung chronic infections in cystic fibrosis patients. A “lacking biofilm production” (LBP) strainB. contaminansGIMC4587:Bct370-19 has been obtained by insertion modification of clinical strain with plasposon mutagenesis. It has an interrupted transcriptional response regulator (RR) gene. The focus of our investigation was a two-component signal transduction system determination, including this RR.B. contaminansclinical and LBP strains were analyzed by whole genome sequencing and bioinformatics resources. A four-component operon (BiofilmReg) has a key role in biofilm formation. The relative location (i.e., by being separated by another gene) of RR and histidine kinase genes is unique in BiofilmReg. Orthologs were found in other members of the Burkholderiales order. Phylogenetic analysis of strains containing BiofilmReg operons demonstrated evidence for earlier inheritance of a three-component operon. During further evolution one lineage acquired a fourth gene, whereas others lost the third component of the operon. Mutations in sensor domains have created biodiversity which is advantageous for adaptation to various ecological niches. Different speciesBurkholderiaandAchromobacterstrains all demonstrated similar BiofilmReg operon structure. Therefore, there may be an opportunity to develop a common drug which is effective for treating all these causative agents.
Hepatitis E Virus in Industrialized Countries: The Silent Threat
Authors: Clemente-Casares Pilar , Ramos-Romero Carlota , Ramirez-Gonzalez Eugenio , Mas Antonio
Published: December 2016

Hepatitis E virus (HEV) is the main cause of acute viral hepatitis worldwide. Its presence in developing countries has been documented for decades. Developed countries were supposed to be virus-free and initially only imported cases were detected in those areas. However, sporadic and autochthonous cases of HEV infection have been identified and studies reveal that the virus is worldwide spread. Chronic hepatitis and multiple extrahepatic manifestations have also been associated with HEV. We review the data from European countries, where human, animal, and environmental data have been collected since the 90s. In Europe, autochthonous HEV strains were first detected in the late 90s and early 2000s. Since then, serological data have shown that the virus infects quite frequently the European population and that some species, such as pigs, wild boars, and deer, are reservoirs. HEV strains can be isolated from environmental samples and reach the food chain, as shown by the detection of the virus in mussels and in contaminated pork products as sausages or meat. All these data highlight the need of studies directed to control the sources of HEV to protect immunocompromised individuals that seem the weakest link of the HEV epidemiology in industrialized regions.
Immobilization of NTPDase-1 fromTrypanosoma cruziand Development of an Online Label-Free Assay
Authors: Calil Felipe Antunes , Lima Juliana Maria , de Oliveira Arthur Henrique Cavalcante , Mariotini-Moura Christiane , Fietto Juliana Lopes Rangel , Cardoso Carmen Lucia
Published: December 2016

The use of IMERs (Immobilized Enzyme Reactors) as a stationary phase coupled to high performance chromatographic systems is an interesting approach in the screening of new ligands. In addition, IMERs offer many advantages over techniques that employ enzymes in solution. The enzyme nucleoside triphosphate diphosphohydrolase (NTPDase-1) fromTrypanosoma cruziacts as a pathogen infection facilitator, so it is a good target in the search for inhibitors. In this paper, immobilization of NTPDase-1 afforded ICERs (Immobilized Capillary Enzyme Reactors). A liquid chromatography method was developed and validated to monitor the ICER activity. The conditions for the application of these bioreactors were investigated, and excellent results were obtained. The enzyme was successfully immobilized, as attested by the catalytic activity detected in theTcNTPDase-1-ICER chromatographic system. Kinetic studies on the substrate ATP gaveKMof 0.317 ± 0.044 mmol·L−1, which still presented high affinity compared to in solution. Besides that, the ICER was stable for 32 days, enough time to investigate samples of possible inhibitors, including especially the compound Suramin, that inhibited 51% the enzyme activity at 100 µmol·L−1, which is in accordance with the data for the enzyme in solution.
Abstract A06: Identification of tumor-specific antibodies using phage display selections on pancreatic ductal organoids
Authors: Oni Tobiloba E. , Bautista Carmelita , Nelson Bryce , Tuveson David A.
Published: December 2016

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a five year survival rate at 6%. The high mortality of this disease is associated with its late diagnosis. Developing accurate means of early detection will allow for curative surgery and significantly improve patient outcomes. Monoclonal antibodies against tumor-associated neoepitopes are promising tools for identifying novel biomarkers due to their exquisite specificity.

To generate antibodies specific to pancreatic tumor cells, we have adapted previously established screening methods with synthetic phage displayed Fab libraries to the pancreatic ductal organoid system, a recently developed ex vivo platform for culturing both normal and malignant pancreatic tissue. This antibody screen employs negative selection of Fabs binding normal organoids to eliminate those cell surface markers elevated during normal ductal cell proliferation, a state similar to the proliferation observed in the pancreas during inflammatory conditions. This is significant because the ability of novel biomarkers to accurately detect pancreatic cancer depends on their capacity to distinguish PDAC from benign diseases of the pancreas.

Using this method, we have isolated five unique Fabs that preferentially bind cell surface antigens on tumor but not normal organoids derived from human PDAC and non-diseased patients respectively. Characterization of the cognate antigens of these antibodies and validation of their binding to human tissue are ongoing. We demonstrate that pancreatic ductal organoids provide a systematic platform to screen antibody libraries for the discovery of biomarkers specific to the neoplastic state.

Citation Format: Tobiloba E. Oni, Carmelita Bautista, Bryce Nelson, David A. Tuveson.{Authors}. Identification of tumor-specific antibodies using phage display selections on pancreatic ductal organoids. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A06.
Abstract A25: Pancreatic cancer cells scavenge complex lipids from stroma in the hypoxic tumor microenvironment
Authors: Jong Petrus R. de , Campos Alejandro D. , Shanahan Sean-Luc , Richardson Adam , Powis Garth
Published: December 2016

Pancreatic ductal adenocarcinoma (PDAC) is non-resectable in 85% of cases and highly resistant to chemotherapy, resulting in a poor 5-year survival (5-7%). Understanding the metabolic vulnerabilities of PDAC in the harsh tumor microenvironment (TME) may lead to novel therapeutic approaches with improved clinical efficacy. The pancreatic TME is characterized by widespread desmoplasia represented by alpha-smooth muscle actin-positive fibroblasts, pancreatic stellate cells and extracellular matrix components, among others. Up to 90% of the pancreatic tumor mass consists of non-neoplastic cells, and high interstitial pressures and poor perfusion both result in severe hypoxia, leading to a more malignant PDAC phenotype. We hypothesized that these conditions lead to specific metabolic constrains in oncogene-driven, rapidly proliferating PDAC cells that experience high levels of stress, in contrast to the surrounding quiescent stromal cells. We used co-culturing of PDAC (MIAPaCa2) and stromal (NIH/3T3) cells in transwell systems as a robust and reproducible model of cell contact-independent interactions in the pancreatic TME. A commercial metabolic profiling platform (Metabolon) and 13C-based flux assays were used to study changes in metabolite levels in both cell types in normoxia or hypoxia (1% O2). We found that hypoxia induced similar metabolic changes in the PDAC and stromal cells, suggesting that hypoxia-regulated metabolic rewiring is independent of cell-type. Interestingly, the metabolic effects of co-culturing were predominantly observed in the stromal compartment, e.g. enhanced glycogenolysis, metabolite changes indicative of gluconeogenesis, and increased dipeptide levels, all reminiscent of a ‘starvation’ phenotype. In contrast, the tumor cells maintained a mixed anabolic and catabolic phenotype, as shown by elevated intracellular levels of essential amino acids and ribonucleotide triphosphates, representative of a ‘feeding’ phenotype. Importantly, a unique dependence on complex lipid species was observed in cancer cells with reciprocal changes in stromal cells. These data suggest that pancreatic cancer cells reprogram stromal cells to ‘feed off’ the metabolic capacity of non-neoplastic cells in the tumor microenvironment, thereby inducing the release of diffusable metabolites to satisfy their specific catabolic needs.

Citation Format: Petrus R. de Jong, Alejandro D. Campos, Sean-Luc Shanahan, Adam Richardson, Garth Powis.{Authors}. Pancreatic cancer cells scavenge complex lipids from stroma in the hypoxic tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A25.