bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting frequent hospital admission risk in Singapore: a retrospective cohort study to investigate the impact of comorbidities, acute illness burden and social determinants of health
Authors: Low Lian Leng , Liu Nan , Wang Sijia , Thumboo Julian , Ong Marcus Eng Hock , Lee Kheng Hock
Published: October 2016

Objectives

To evaluate the impact of comorbidities, acute illness burden and social determinants of health on predicting the risk of frequent hospital admissions.

Design

Multivariable logistic regression was used to associate the predictive variables extracted from electronic health records and frequent hospital admission risk. The model's performance of our predictive model was evaluated using a 10-fold cross-validation.

Setting

A single tertiary hospital in Singapore.

Participants

All adult patients admitted to the hospital between 1 January 2013 and 31 May 2014 (n=25 244).

Main outcome measure

Frequent hospital admissions, defined as 3 or more inpatient admissions within 12 months of discharge. Area under the receiver operating characteristic curve (AUC) of the predictive model, and the sensitivity, specificity and positive predictive values for various cut-offs.

Results

4322 patients (17.1%) met the primary outcome. 11 variables were observed as significant predictors and included in the final regression model. The strongest independent predictor was treatment with antidepressants in the past 1 year (adjusted OR 2.51, 95% CI 2.26 to 2.78). Other notable predictors include requiring dialysis and treatment with intravenous furosemide during the index admission. The predictive model achieved an AUC of 0.84 (95% CI 0.83 to 0.85) for predicting frequent hospital admission risk, with a sensitivity of 73.9% (95% CI 72.6% to 75.2%), specificity of 79.1% (78.5% to 79.6%) and positive predictive value of 42.2% (95% CI 41.1% to 43.3%) at the cut-off of 0.235.

Conclusions

We have identified several predictors for assessing the risk of frequent hospital admissions that achieved high discriminative model performance. Further research is necessary using an external validation cohort.
Supervisors' perspective on medical thesis projects and dropout rates: survey among thesis supervisors at a large German university hospital
Authors: Can Elif , Richter Felicitas , Valchanova Ralitsa , Dewey Marc
Published: October 2016

Objectives

To identify underlying causes for failure of medical thesis projects and the constantly high drop-out rate in Germany from the supervisors' perspective and to compare the results with the students' perspective.

Setting

Cross-sectional survey. Online questionnaire for survey of medical thesis supervisors among the staff of Charité—Universitätsmedizin Berlin, Germany. Published, earlier longitudinal survey among students for comparison.

Participants

1069 thesis supervisors participated.

Data extraction and synthesis

Data are presented using descriptive statistics, and the χ2test served to compare the results among supervisors with the earlier data from the longitudinal survey of doctoral students.

Primary and secondary outcomes

Not applicable. This survey is an observational study.

Results

Of 3653 potential participants, 1069 (29.3%) supervising 3744 doctoral candidates participated in the study. Supervisors considered themselves to be highly motivated and to offer adequate supervision. On the other hand, 87% stated that they did not feel well prepared for thesis supervision. Supervisors gave lack of timeliness of doctoral students and personal differences (p=0.024 and p=0.001) as the main reasons for terminating thesis projects. Doctoral students predominantly mentioned methodological problems and difficult subjects as critical issues (p=0.001 and p<0.001). Specifically, students felt ill prepared for the statistical part of their research—49.5% stated that they never received statistical assistance, whereas 97% of supervisors claimed to help their students with statistical analysis.

Conclusions

The authors found that both thesis supervisors and medical students feel ill prepared for their roles in the process of a medical dissertation. Contradictory reasons for terminating medical thesis projects based on supervisors' and students' self-assessment suggest a lack of communication and true scientific collaboration between supervisors and doctoral students as the major underlying issue that requires resolution.
Finding consensus on frailty assessment in acute care through Delphi method
Authors: Soong John T Y , Poots Alan J , Bell Derek
Published: October 2016

Objective

We seek to address gaps in knowledge and agreement around optimal frailty assessment in the acute medical care setting. Frailty is a common term describing older persons who are at increased risk of developing multimorbidity, disability, institutionalisation and death. Consensus has not been reached on the practical implementation of this concept to assess clinically and manage older persons in the acute care setting.

Design

Modified Delphi, via electronic questionnaire. Questions included ranking items that best recognise frailty, optimal timing, location and contextual elements of a successful tool. Intraclass correlation coefficients for overall levels of agreement, with consensus and stability tested by 2-way ANOVA with absolute agreement and Fisher's exact test.

Participants

A panel of national experts (academics, front-line clinicians and specialist charities) were invited to electronic correspondence.

Results

Variables reflecting accumulated deficit and high resource usage were perceived by participants as the most useful indicators of frailty in the acute care setting. The Acute Medical Unit and Care of the older Persons Ward were perceived as optimum settings for frailty assessment. ‘Clinically meaningful and relevant’, ‘simple (easy to use)’ and ‘accessible by multidisciplinary team’ were perceived as characteristics of a successful frailty assessment tool in the acute care setting. No agreement was reached on optimal timing, number of variables and organisational structures.

Conclusions

This study is a first step in developing consensus for a clinically relevant frailty assessment model for the acute care setting, providing content validation and illuminating contextual requirements. Testing on clinical data sets is a research priority.
Comparison of foam swabs and toothbrushes as oral hygiene interventions in mechanically ventilated patients: a randomised split mouth study
Authors: Marino Paola J , Hannigan Ailish , Haywood Sean , Cole Jade M , Palmer Nicki , Emanuel Charlotte , Kinsella Tracey , Lewis Michael A O , Wise Matt P , Williams David W
Published: October 2016

Introduction

During critical illness, dental plaque may serve as a reservoir of respiratory pathogens. This study compared the effectiveness of toothbrushing with a small-headed toothbrush or a foam-headed swab in mechanically ventilated patients.

Methods

This was a randomised, assessor-blinded, split-mouth trial, performed at a single critical care unit. Adult, orally intubated patients with >20 teeth, where >24 hours of mechanical ventilation was expected were included. Teeth were cleaned 12-hourly using a foam swab or toothbrush (each randomly assigned to one side of the mouth). Cleaning efficacy was based on plaque scores, gingival index and microbial plaque counts.

Results

High initial plaque (mean=2.1 (SD 0.45)) and gingival (mean=2.0 (SD 0.54)) scores were recorded for 21 patients. A significant reduction compared with initial plaque index occurred using both toothbrushes (mean change=−1.26, 95% CI −1.57 to −0.95; p<0.001) and foam swabs (mean change=−1.28, 95% CI −1.54 to −1.01; p<0.001). There was significant reduction in gingival index over time using toothbrushes (mean change=−0.92; 95% CI −1.19 to −0.64; p<0.001) and foam swabs (mean change=−0.85; 95% CI −1.10 to −0.61; p<0.001). Differences between cleaning methods were not statistically significant (p=0.12 for change in gingival index; p=0.24 for change in plaque index). There was no significant change in bacterial dental plaque counts between toothbrushing (mean change 3.7×104colony-forming units (CFUs); minimum to maximum (−2.5×1010CFUs, 8.7×107CFUs)) and foam swabs (mean change 9×104CFUs; minimum to maximum (−3.1×1010CFUs, 3.0×107CFUs)).

Conclusions

Patients admitted to adult intensive care had poor oral health, which improved after brushing with a toothbrush or foam swab. Both interventions were equally effective at removing plaque and reducing gingival inflammation.

Trial registration number

NCT01154257; Pre-results.
Accuracy and cost-effectiveness of dynamic contrast-enhanced CT in the characterisation of solitary pulmonary nodules—the SPUtNIk study
Authors: Qureshi N R , Rintoul R C , Miles K A , George S , Harris S , Madden J , Cozens K , Little L A , Eichhorst K , Jones J , Moate P , McClement C , Pike L , Sinclair D , Wong W L , Shekhdar J , Eaton R , Shah A , Brindle L , Peebles C , Banerjee A , Dizdarevic S , Han S , Poon F W , Groves A M , Kurban L , Frew A J , Callister M E , Crosbie P , Gleeson F V , Karunasaagarar K , Kankam O , Gilbert F J
Published: October 2016

Introduction

Solitary pulmonary nodules (SPNs) are common on CT. The most cost-effective investigation algorithm is still to be determined. Dynamic contrast-enhanced CT (DCE-CT) is an established diagnostic test not widely available in the UK currently.

Methods and analysis

The SPUtNIk study will assess the diagnostic accuracy, clinical utility and cost-effectiveness of DCE-CT, alongside the current CT and 18-flurodeoxyglucose-positron emission tomography) (18FDG-PET)-CT nodule characterisation strategies in the National Health Service (NHS). Image acquisition and data analysis for18FDG-PET-CT and DCE-CT will follow a standardised protocol with central review of 10% to ensure quality assurance. Decision analytic modelling will assess the likely costs and health outcomes resulting from incorporation of DCE-CT into management strategies for patients with SPNs.

Ethics and dissemination

Approval has been granted by the South West Research Ethics Committee. Ethics reference number 12/SW/0206. The results of the trial will be presented at national and international meetings and published in an Health Technology Assessment (HTA) Monograph and in peer-reviewed journals.

Trial registration number

ISRCTN30784948; Pre-results.
UK end-of-life care services in dementia, initiatives and sustainability: results of a national online survey
Authors: Amador Sarah , Goodman Claire , Robinson Louise , Sampson Elizabeth L
Published: October 2016

Background

People living and dying with non-cancer diagnoses, including dementia, have poorer access to generalist and specialist palliative care than people with cancer, and experience worse outcomes in terms of pain and symptom control, and quality and experience of care. In the UK, the National Council for Palliative Care (NCPC) ran a national survey of services for end-of-life care for people with dementia (2008) in which 16 services were identified, and reported on case studies and examples of good practice. We updated the NCPC survey to review progress in previously identified services, identify factors that lead to sustainable services and identify new initiatives in this area of care.

Methods

An online survey was developed and piloted before use. Initiatives were contacted via targeted (N=63) and open call invitations. The survey was made up of 5 sections. Quantitative data were analysed using descriptive statistics.

Results

15 services responded. They engaged in a wide range of activities predominately providing direct care (80%) and workforce development/advisory or educational activities (87%). Results suggest that sustainability of services is reliant on clinicians with a leadership role and wider system support through funding mechanisms and a minimum level of integration within normal service provision.

Conclusions

Recent initiatives are largely built on the expertise of the nursing profession (with or without input from medical consultants), and driven mainly by the charity and hospice sector. This has generated a potential new model of care provision in end of life dementia care, ‘Hospice-enabled Dementia Care’.
Molecular classification of Crohn's disease reveals two clinically relevant subtypes
Authors: Weiser Matthew , Simon Jeremy M , Kochar Bharati , Tovar Adelaide , Israel Jennifer W , Robinson Adam , Gipson Gregory R , Schaner Matthew S , Herfarth Hans H , Sartor R Balfour , McGovern Dermot P B , Rahbar Reza , Sadiq Timothy S , Koruda Mark J , Furey Terrence S , Sheikh Shehzad Z
Published: October 2016

Objective

The clinical presentation and course of Crohn's disease (CD) is highly variable. We sought to better understand the cellular and molecular mechanisms that guide this heterogeneity, and characterise the cellular processes associated with disease phenotypes.

Design

We examined both gene expression and gene regulation (chromatin accessibility) in non-inflamed colon tissue from a cohort of adult patients with CD and control patients. To support the generality of our findings, we analysed previously published expression data from a large cohort of treatment-naïve paediatric CD and control ileum.

Results

We found that adult patients with CD clearly segregated into two classes based on colon tissue gene expression—one that largely resembled the normal colon and one where certain genes showed expression patterns normally specific to the ileum. These classes were supported by changes in gene regulatory profiles observed at the level of chromatin accessibility, reflective of a fundamental shift in underlying molecular phenotypes. Furthermore, gene expression from the ilea of a treatment-naïve cohort of paediatric patients with CD could be similarly subdivided into colon-like and ileum-like classes. Finally, expression patterns within these CD subclasses highlight large-scale differences in the immune response and aspects of cellular metabolism, and were associated with multiple clinical phenotypes describing disease behaviour, including rectal disease and need for colectomy.

Conclusions

Our results strongly suggest that these molecular signatures define two clinically relevant forms of CD irrespective of tissue sampling location, patient age or treatment status.
Human oral microbiome and prospective risk for pancreatic cancer: a population-based nested case-control study
Authors: Fan Xiaozhou , Alekseyenko Alexander V , Wu Jing , Peters Brandilyn A , Jacobs Eric J , Gapstur Susan M , Purdue Mark P , Abnet Christian C , Stolzenberg-Solomon Rachael , Miller George , Ravel Jacques , Hayes Richard B , Ahn Jiyoung
Published: October 2016

Objective

A history of periodontal disease and the presence of circulating antibodies to selected oral pathogens have been associated with increased risk of pancreatic cancer; however, direct relationships of oral microbes with pancreatic cancer have not been evaluated in prospective studies. We examine the relationship of oral microbiota with subsequent risk of pancreatic cancer in a large nested case–control study.

Design

We selected 361 incident adenocarcinoma of pancreas and 371 matched controls from two prospective cohort studies, the American Cancer Society Cancer Prevention Study II and the National Cancer Institute Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. From pre-diagnostic oral wash samples, we characterised the composition of the oral microbiota using bacterial 16S ribosomal RNA (16S rRNA) gene sequencing. The associations between oral microbiota and risk of pancreatic cancer, controlling for the random effect of cohorts and other covariates, were examined using traditional and L1-penalised least absolute shrinkage and selection operator logistic regression.

Results

Carriage of oral pathogens,Porphyromonas gingivalisandAggregatibacter actinomycetemcomitans, were associated with higher risk of pancreatic cancer (adjusted OR for presence vs absence=1.60 and 95% CI 1.15 to 2.22; OR=2.20 and 95% CI 1.16 to 4.18, respectively). PhylumFusobacteriaand its genusLeptotrichiawere associated with decreased pancreatic cancer risk (OR per per cent increase of relative abundance=0.94 and 95% CI 0.89 to 0.99; OR=0.87 and 95% CI 0.79 to 0.95, respectively). Risks related to these phylotypes remained after exclusion of cases that developed within 2 years of sample collection, reducing the likelihood of reverse causation in this prospective study.

Conclusions

This study provides supportive evidence that oral microbiota may play a role in the aetiology of pancreatic cancer.
PIK3CAandAKT1mutations in hidradenoma papilliferum
Authors: Goto Keisuke , Maeda Daichi , Kudo-Asabe Yukitsugu , Hibiya Takashi , Hayashi Akimasa , Fukayama Masashi , Ohashi Kenichi , Goto Akiteru
Published: October 2016

Aims

Hidradenoma papilliferum (HP) is a benign vulvar neoplasm that arises from anogenital mammary-like glands, and its morphology is similar to mammary intraductal papilloma. The aim of this study was to investigate oncogenic mutations involved in the tumourigenesis of HP. We focused specifically onPIK3CAandAKT1mutations, which are both reported to be detected in 33% of mammary intraductal papillomas.

Methods

In total, seven HP cases were analysed. Clinicopathological analyses and immunohistochemistry for oestrogen receptor, p63, smooth muscle actin (SMA), p53 and β-catenin were performed. Furthermore,PIK3CA,AKT1, BRAFandKRAShot spot mutations were examined by Sanger sequencing.

Results

Morphologically, all HPs had a papillary and tubular architecture with a biphasic pattern of epithelial and myoepithelial cells. Immunohistochemistry revealed that oestrogen receptor expression was restricted to epithelial cells, whereas p63 and SMA were exclusively expressed in myoepithelial cells. The patterns of p53 and β-catenin immunostaining suggested wild-type genotypes. Direct sequencing revealed the presence of somaticPIK3CAmutations (Ex9. c.1633G>A, p.E545K and Ex20. c.3140A>G, p.H1047R) in two of the HPs and anAKT1(c.49G>A, p.E17K) mutation in one.BRAFandKRASmutations were not found in any of the HP cases.

Conclusions

PIK3CAandAKT1are frequently mutated in HP tumours (29% and 14%, respectively). PIK3CA/AKT1 pathway alterations in HP further support the hypothesis that HP is the vulvar (anogenital mammary-like gland) analogue of breast intraductal papilloma.
Establishing a Gradient between Partial Pressure of Arterial Carbon Dioxide and End-Tidal Carbon Dioxide in Patients with Acute Respiratory Distress Syndrome
Authors: Yousuf Tariq , Brinton Taylor , Murtaza Ghulam , Wozniczka Daniel , Ahmad Khansa , Iskandar Joy , Mehta Raju , Keshmiri Hesam , Hanif Tabassum
Published: October 2016

End-tidal carbon dioxide (ETCO2) monitoring is useful in many situations. However, ETCO2 monitoring is unreliable in patients with acute respiratory distress syndrome (ARDS) due to widespread lung inflammation. In our study, we attempt to establish the gradient between the arterial pressure of carbon dioxide (PaCO2) and ETCO2 in patients with ARDS, which we defined as the PaETCO2 gradient. The main objective of the study was to establish a PaETCO2 gradient in each severity of ARDS. We analyzed 35 patients with ARDS and a total of 88 arterial blood gases were included. PaCO2, PaO2/FiO2 and ETCO2 were measured. Patients were stratified into mild, moderate and severe ARDS as classified by the Berlin ARDS criteria. PaCO2 and ETCO2 were compared at each severity stratification. The mean PaCO2 was 50.0, the mean ETCO2 was 26.6 and the gradient among all samples was 23.24 (±12.02). The mean gradient for each severity is as follows: mild: 19.3 (±9.9), moderate: 27.9 (±13.2) and severe: 23.9 (±7.8). The difference between the PaETCO2 gradient of the mild to moderate (p=0.001) and mild to severe groups (p=0.01) reached statistical significance. However, the difference between the moderate to severe groups did not reach statistical significance (p=0.48). We found the gradient between PaCO2 and ETCO2 in patients with ARDS is vast and tends to worsen with increasing severity of ARDS. This indicates that the gradient between the 2 may be used as an indicator of increasing severity of ARDS.
Coiling of wide-necked carotid artery aneurysms assisted by a temporary bridging device (Comaneci): preliminary experience
Authors: Fischer S , Weber A , Carolus A , Drescher F , Götz F , Weber W
Published: October 2016

Background

Endovascular treatment of wide-necked aneurysms remains challenging without the use of adjunctive devices to preserve the parent artery.

Objective

To present our initial experience with a temporary bridging device, the Comaneci (Rapid Medical, Israel). The compliant remodeling mesh protects the parent artery during coil occlusion without flow arrest in the distal vasculature. Permanent dual antiplatelet therapy is not required since the device is fully removed at the end of the procedure.

Methods

All intracranial aneurysms treated by coil occlusion with the Comaneci device between December 2014 and November 2015 were included. Angiographic and clinical results were retrospectively analysed, including follow-up examinations. All aneurysms were unruptured.

Results

18 aneurysms of the internal carotid artery were included. Successful coil occlusion assisted by the Comaneci device as intended was possible in 14 cases (77.8%). Insufficient coverage of the aneurysmal neck was observed in four cases (22.2%), with modification of the treatment to stent-assisted coiling or remodeling. One clinically relevant complication occurred (5.6%).

Conclusions

Our initial experience shows that use of the Comaneci device is straightforward for the treatment of selected wide-necked aneurysms. Further studies with long-term follow-up data are needed to identify the significance of the presented technique in the neurointerventional armamentarium.
High prevalence of antithyroid peroxidase and antiparietal cell antibodies among patients with type 1 diabetes mellitus attending a tertiary diabetes centre in South Africa
Authors: Paruk Imran M , Ganie Yasmeen , Maharaj Sureka , Pirie Fraser J , Naidoo Vasudevan G , Nkwanyana Ntombifikile M , Dinnematin Hilary L , Ramdial Pratistadevi K , Motala Ayesha A
Published: October 2016

Objective

Data on the prevalence of autoimmune thyroid disease (AITD) and gastric autoimmunity in type 1 diabetes mellitus (T1DM) in Africa are limited. The aim of this study was to assess the prevalence of antithyroid peroxidase (TPO-A) and antiparietal cell antibody (PCA) in patients with T1DM at a tertiary diabetes clinic in Durban, South Africa.

Research design and methods

This was a cross-sectional observational study among subjects attending the adult T1DM clinic at Inkosi Albert Luthuli Hospital. Information about history and clinical examination was collected. Blood tests included glutamic acid decarboxylase antibody (GADA), TPO-A, PCA, vitamin B12, folate, ferritin, thyroid stimulating hormone (TSH), free thyroxine, lipids and HbA1c.

Results

A total of 202 (M:F, 90:112) patients were recruited. The ethnic composition was African (black) (56.4%; n=114), Indian (31.7%; n=64), white (4.5%; n=9) and coloured (mixed race) (7.4%; n=15). Mean age and mean duration of diabetes were 26.4±11.4 and 10.7±9.1 years, respectively. Mean body mass index was 21.6±6.3 kg/m2. GADA was positive in 63.37% (n=128). The prevalence of TPO-A was 18.9% (n=39) and PCA 8.9% (n=17). The prevalence of overt hypothyroidism, subclinical hypothyroidism and Graves’ disease was 10.9%, 2.5% and 1.5%, respectively; vitamin B12 deficiency was noted in 3.5% (n=7) and iron deficiency in 19.3% (n=39).

Conclusions

Among patients with T1DM in this study, there was a high prevalence of coexistent AITD and gastric autoimmunity. Screening for hypothyroidism and thyroid autoimmunity should be undertaken in all patients at initial presentation. However, to assess the feasibility and optimal timing of subsequent testing in the African setting with limited resources, more collaborative research with longitudinal studies is required.
MicroRNAs interfere with DNA methylation in rheumatoid arthritis synovial fibroblasts
Authors: Gaur Niharika , Karouzakis Emmanuel , Glück Selene , Bagdonas Edvardas , Jüngel Astrid , Michel Beat A , Gay Renate E , Gay Steffen , Frank-Bertoncelj Mojca , Neidhart Michel
Published: October 2016

Background

The DNA of rheumatoid arthritis synovial fibroblasts (RASF) is globally hypomethylated; this contributes to an aggressive behaviour. In an attempt to remethylate these cells, we supplemented with methyl donors. We investigated the possible interference of microRNAs (miRs).

Material and methods

RASF were treated with L-methionine or betaine. Transcripts of de novo methyltransferases (DNMTs) and miRs were measured by real-time PCR, and a transcription PCR array was performed. Levels of homocysteine, matrix metalloproteinase-1 (MMP-1) and global DNA methylation were determined. Transfection with lipofectamine was performed with specific pre-miRs and anti-miRs, such as miR29 and let7f.

Results

L-methionine was more efficient to increase DNA methylation than betaine. This was associated with a reduced expression of DNMT3A mRNA in betaine-treated RASF. Betaine increases the expression of miR29 in RASF which targets DNMT3A, thereby limiting the remethylation process. Nevertheless, betaine inhibited the expression of multiple transcription factors, decreased the release of MMP-1, biosynthesis of homocysteine and cell migration.

Conclusion

Alterations in cellular miRs profiles, in particular the upregulation of miR29, which targets DNMT3A, may limit the efficiency of betaine if it is used as DNA remethylating agent. However, L-methionine also has similar impact on miR29 expression. On the other hand, betaine has multiple other beneficial effects on the activated phenotype of RASF; it is not excluded that the effect of betaine on DNMT3A is, at least in part, indirect. Clinical trials with betaine could be promising.
Integration of facies architecture, ooid granulometry and morphology for prediction of reservoir quality, Lower Triassic Khuff Formation, Saudi Arabia
Authors: Eltom Hassan A. , Abdullatif Osman M. , Babalola Lameed O. , Bashari Mazin A. , Yassin Mohamed , Osman Mutasim S. , Abdulraziq Asaad M.
Published: October 2016

Prediction of the reservoir quality of oolitic carbonates is one of the main challenges for petroleum geology due to the inherited heterogeneity in pore systems. This study investigated and characterized the sedimentological, stratigraphic, morphological and granulometric data of oolitic outcrop strata of the Khartam Member of the Khuff Formation in Saudi Arabia, including the giant hydrocarbon reservoirs (Khuff reservoirs), and the results have implications for exploration and development. Linking ooid morphology to sequence stratigraphy revealed that the distribution of the oolitic beds and their pore systems are mainly controlled by stratigraphic position, morphology (controlled by primary mineralogy) and grain size. The systematic distribution of ooids with distinct original mineral compositions allows for the prediction of the porosity distribution and occurrence within analogous reservoirs. The ooids in the studied interval were aragonitic (lower interval), bimineralic (middle interval) and aragonitic (upper interval). Linking ooid grain size with depositional environments indicated that the ooid grain size increases with water energy and follows the upwards-shallowing pattern of the studied succession. These results can be used to improve the understanding and prediction of the reservoir quality of oolitic carbonates.
A geometrical model for shale smear: implications for upscaling in faulted geomodels
Authors: Grant Neil T.
Published: October 2016

A new 1D bed-scale model has been built to help model shale smear in interbedded sand–shale sequences using the shale smear factor (SSF). A smear envelope is generated by mapping each potential shale smear onto the fault plane employing five different shale smear geometries. Graphical outputs then focus on the cumulative length of the resultant smears and the remaining sand–sand juxtaposition windows in the predicted shale smear envelope. The smears are evaluated stochastically with lengths that are a randomized function of the estimated Vclay content of the source shale layers, allowing the smear pattern to change with each realization. A new fragmented smear mode is developed that allows discontinuous smears to be distributed randomly on the fault plane and can be used to modify the smear pattern as fault displacement increases. The model has been tested using well data. Results show that windows in the smear envelope are commonly present, and that their frequency and location are dependent on the smear placement model and sand–shale stacking pattern. Smear fragmentation leads to more windows being preserved. The 1D model can also assess the impact of geocellular upscaling on fault seal analysis. Upscaling reduces cross-fault sand connectivity due to the elimination of thin beds. Shale smear envelopes are also reduced in length as fewer shale beds are involved, even though layers are thicker. A fault may or may not appear more sealing dependent on the layer configuration and net-to-gross ratio (NTG). The model offers results that can inform input to fault seal evaluations and allows the effect of geomodel upscaling to be more closely interrogated.
Softening of organic matter in shales at reservoir temperatures
Authors: Emmanuel Simon , Eliyahu Moshe , Day-Stirrat Ruarri J. , Hofmann Ronny , Macaulay Calum I.
Published: October 2016

The elastic modulus of organic matter can strongly influence the mechanical behaviour of source rocks. Although recent advances have shed crucial light on the mechanical properties of natural organic matter under ambient conditions, the elastic properties of kerogen and bitumen at reservoir temperatures remain poorly constrained. In this paper, we use a novel atomic force microscope technique to measure the changes to organic matter during the heating of an organic-rich shale. Our measurements show that bitumen becomes more compliant with heating and in an experiment during which the temperature was increased from 25 to 225°C, the reduced elastic modulus dropped from 6.3 to 0.8 GPa. In contrast to bitumen, we were unable to discern any significant changes to the elastic modulus of kerogen with increasing temperature. Our results suggest that the temperature dependence of the elastic properties could be used as an additional method to differentiate between bitumen and kerogen in shales. Moreover, our analysis indicates that temperature should be taken into account when modelling the elastic properties of bitumen under reservoir conditions.
Do deformation bands matter for flow? Insights from permeability measurements and flow simulations in porous carbonate rocks
Authors: Rotevatn Atle , Fossmark Heidi S. , Bastesen Eivind , Thorsheim Elin , Torabi Anita
Published: October 2016

We investigate the permeability and flow effects of deformation bands in porous granular carbonate rocks in Malta and use results from flow simulations to discuss the practical implications of deformation bands in carbonate and siliciclastic reservoirs rocks in general. Image- and laboratory-based analyses of deformation bands show permeabilities that are 1 – 2 orders of magnitude lower than the adjacent host rocks. Small-scale outcrop-based flow models (1 × 1 m) focus on the effect of deformation band on flow at the scale of individual bands. Two-phase flow simulations (water displacing oil) show that at the local scale a decrease in deformation band permeability led to increasing flow complexity, reduced and irregular waterfront propagation and reduction in sweep efficiency. A reduction in host rock permeability is associated with increased sensitivity to deformation bands. In low-permeable host rocks, a single magnitude-order reduction of deformation band permeability significantly delays flow, whereas in higher-permeable host rocks the effect is less pronounced. Hence, in some cases, deformation bands may represent a significant impediment to flow already when they are only 1 – 2 orders of magnitude less permeable than host rock. Consequently, deformation bands may have greater practical implications than previously thought, particularly in reservoir rocks with moderate to low host rock permeability.
History-matching surface-based property models using the ensemble Kalman filter
Authors: Trani Mario , Graham Gavin H.
Published: October 2016

Hydrocarbon reservoirs often contain thin and irregularly shaped low-permeability heterogeneities at the interface between sedimentary bodies that can act as barriers or baffles where they are aligned perpendicular to the flow. These heterogeneities are often not explicitly captured in simulation models because they occur over lengthscales smaller than a single simulation grid block and, as such, are ubiquitously captured in flow simulations using transmissibility multipliers. This parameterization implies that the properties of the fine-scale heterogeneities are a direct function of the properties in the adjacent grid cells. A new methodology is proposed where fine-scale heterogeneities are modelled using properties attached to surfaces and updated independently from other uncertain reservoir properties present during assisted history matching. This method is validated via a synthetic reservoir simulation model, using the ensemble Kalman filter to assimilate production history. The update of geometrical and petrophysical parameters related to fine-scale heterogeneity improves the history match and production forecast in comparison to traditional implicit techniques that do not honour the characteristics of the heterogeneity. The results indicate that, for history matching, it can be important to capture fine-scale heterogeneities independently from other uncertain reservoir properties even if the fine-scale heterogeneities do not exert a large control on reservoir response.
Nerve growth factor is critical requirement for in vitro angiogenesis in gastric endothelial cells
Authors: Ahluwalia Amrita , Jones Michael K. , Brzozowski Tomasz , Tarnawski Andrzej S.
Published: October 2016

Angiogenesis is critical for the healing of gastric mucosal injury and is considered to be primarily regulated by vascular endothelial growth factor (VEGF), the fundamental proangiogenic factor. The role of nerve growth factor (NGF) in gastric angiogenesis is unknown. We examined the expression of NGF and its TrkA receptor in endothelial cells (ECs) isolated from gastric mucosa of rats (GMECs), the effect of NGF treatment on in vitro angiogenesis in GMECs, and, the mechanisms underlying NGF's proangiogenic actions. Isolated GMECs from Fisher rats were treated with vehicle, NGF (10-1,000 ng/ml), VEGF (20 ng/ml), or NGF+VEGF. To determine whether and to what extent NGF is critical for angiogenesis in GMECs, we silenced NGF expression using specific siRNA and examined in vitro angiogenesis with and without treatment with exogenous NGF and/or VEGF. Treatment of GMECs with NGF significantly increased in vitro angiogenesis similar to that seen in GMECs treated with VEGF. Silencing of NGF in GMECs abolished angiogenesis, and this effect was reversed only by exogenous NGF but not VEGF, which indicates a direct proangiogenic action of NGF on GMECs that is, at least in part, distinct and independent of VEGF. NGF's proangiogenic action on GMECs was mediated via PI3-K/Akt signaling. This study showed for the first time that gastric mucosal ECs express NGF and its receptor TrkA and that NGF is critical for angiogenesis in these cells.
Emerging concepts in smooth muscle contributions to airway structure and function: implications for health and disease
Authors: Prakash Y. S.
Published: October 2016

Airway structure and function are key aspects of normal lung development, growth, and aging, as well as of lung responses to the environment and the pathophysiology of important diseases such as asthma, chronic obstructive pulmonary disease, and fibrosis. In this regard, the contributions of airway smooth muscle (ASM) are both functional, in the context of airway contractility and relaxation, as well as synthetic, involving production and modulation of extracellular components, modulation of the local immune environment, cellular contribution to airway structure, and, finally, interactions with other airway cell types such as epithelium, fibroblasts, and nerves. These ASM contributions are now found to be critical in airway hyperresponsiveness and remodeling that occur in lung diseases. This review emphasizes established and recent discoveries that underline the central role of ASM and sets the stage for future research toward understanding how ASM plays a central role by being both upstream and downstream in the many interactive processes that determine airway structure and function in health and disease.
Lysyl Oxidase Is a Strong Determinant of Tumor Cell Colonization in Bone
Authors: Reynaud Caroline , Ferreras Laura , Di Mauro Paola , Kan Casina , Croset Martine , Bonnelye Edith , Pez Floriane , Thomas Clémence , Aimond Géraldine , Karnoub Antoine E. , Brevet Marie , Clézardin Philippe
Published: October 2016

Lysyl oxidase (LOX) is a secreted copper-dependent amine oxidase whose primary function is to drive collagen crosslinking and extracellular matrix stiffness. LOX in colorectal cancer synergizes with hypoxia-inducible factor-1 (HIF-1) to promote tumor progression. Here we investigated whether LOX/HIF1 endows colorectal cancer cells with full competence for aggressive colonization in bone. We show that a high LOX expression in primary tumors from patients with colorectal cancer was associated with poor clinical outcome, irrespective of HIF-1. In addition, LOX was expressed by tumor cells in the bone marrow from colorectal cancer patients with bone metastases. In vivo experimental studies show that LOX overexpression in colorectal cancer cells or systemic delivery of the conditioned medium from LOX-overexpressing colorectal cancer cells promoted tumor cell dissemination in the bone marrow and enhanced osteolytic lesion formation, irrespective of HIF-1. Conversely, silencing or pharmacologic inhibition of LOX activity blocked dissemination of colorectal cancer cells in the bone marrow and tumor-driven osteolytic lesion formation. In vitro, tumor-secreted LOX supported the attachment and survival of colorectal cancer cells to and in the bone matrix, and inhibited osteoblast differentiation. LOX overexpression in colorectal cancer cells also induced a robust production of IL6. In turn, both LOX and IL6 were acting in concert to promote RANKL-dependent osteoclast differentiation, thereby creating an imbalance between bone resorption and bone formation. Collectively, our findings show that LOX supports colorectal cancer cell dissemination in the bone marrow and they reveal a novel mechanism through which LOX-driven IL6 production by colorectal cancer cells impairs bone homeostasis. Cancer Res; 77(2); 268–78. ©2016 AACR.
The Stem Cell Factor HMGA2 Is Expressed in Non-HPV–Associated Head and Neck Squamous Cell Carcinoma and Predicts Patient Survival of Distinct Subsites
Authors: Günther Kathrin , Foraita Ronja , Friemel Juliane , Günther Frauke , Bullerdiek Jörn , Nimzyk Rolf , Markowski Dominique Nadine , Behrens Thomas , Ahrens Wolfgang
Published: October 2016

Background: The transcription factor high-mobility AT-hook 2 (HMGA2) is involved in stem cell renewal and is expressed in many tumor tissues. Head and neck squamous cell carcinomas (HNSCC) comprise tumors of the upper aerodigestive tract and are characterized by high recurrence rates that represent a challenge to patient management. The study addresses the potential of HMGA2 as a molecular biomarker for HNSCC patient survival.

Methods: Patients with HNSCC of the larynx, pharynx, tonsils, or oral cavity were recruited in a hospital-based case–control study (n = 202). Quantitative expression of HMGA2 in tumor tissues was measured by RT-PCR. In a 6- to 10-year follow-up, secondary cancers, vital status, and cause of death were ascertained. The HR and 95% confidence intervals (CI) for overall, tumor-specific, and progression-free survival were estimated by Cox proportional hazards with HMGA2 expression level as the independent variable.

Results: High HMGA2 expression in tumor tissues of HNSCC patients was significantly correlated with negative HPV status (P = 0.01), and associated with shorter overall survival time. In Cox regression modeling, HMGA2 expression yielded a risk increase for overall and tumor-specific death in subsets of HNSCC patients, that is, laryngeal cancer patients (overall survival: HR = 4.00; 95% CI, 1.18–13.62) and in oral cancer patients (tumor-specific survival: HR = 2.88; 95% CI, 1.06–7.84), but not in patients with pharyngeal and tonsillar HNSCC.

Conclusions: HMGA2 expression is associated with a risk increase for adverse outcomes in patients with HNSCC of the larynx and oral cavity.

Impact: The understanding of stem cell signaling in HNSCC may offer new strategies for cancer treatment. Cancer Epidemiol Biomarkers Prev; 26(2); 197–205. ©2016 AACR.
Toxicity and Efficacy Probability Interval Design for Phase I Adoptive Cell Therapy Dose-Finding Clinical Trials
Authors: Li Daniel H. , Whitmore James B. , Guo Wentian , Ji Yuan
Published: October 2016

Recent trials of adoptive cell therapy (ACT), such as the chimeric antigen receptor (CAR) T-cell therapy, have demonstrated promising therapeutic effects for cancer patients. A main issue in the product development is to determine the appropriate dose of ACT. Traditional phase I trial designs for cytotoxic agents explicitly assume that toxicity increases monotonically with dose levels and implicitly assume the same for efficacy to justify dose escalation. ACT usually induces rapid responses, and the monotonic dose–response assumption is unlikely to hold due to its immunobiologic activities. We propose a toxicity and efficacy probability interval (TEPI) design for dose finding in ACT trials. This approach incorporates efficacy outcomes to inform dosing decisions to optimize efficacy and safety simultaneously. Rather than finding the maximum tolerated dose (MTD), the TEPI design is aimed at finding the dose with the most desirable outcome for safety and efficacy. The key features of TEPI are its simplicity, flexibility, and transparency, because all decision rules can be prespecified prior to trial initiation. We conduct simulation studies to investigate the operating characteristics of the TEPI design and compare it to existing methods. In summary, the TEPI design is a novel method for ACT dose finding, which possesses superior performance and is easy to use, simple, and transparent. Clin Cancer Res; 23(1); 13–20. ©2016 AACR.
FCGR Polymorphisms Influence Response to IL2 in Metastatic Renal Cell Carcinoma
Authors: Erbe Amy K. , Wang Wei , Goldberg Jacob , Gallenberger Mikayla , Kim KyungMann , Carmichael Lakeesha , Hess Dustin , Mendonca Eneida A. , Song Yiqiang , Hank Jacquelyn A. , Cheng Su-Chun , Signoretti Sabina , Atkins Michael , Carlson Alexander , Mier James W. , Panka David J. , McDermott David F. , Sondel Paul M.
Published: October 2016

Purpose: Fc-gamma receptors (FCGRs) are expressed on immune cells, bind to antibodies, and trigger antibody-induced cell-mediated antitumor responses when tumor-reactive antibodies are present. The affinity of the FCGR/antibody interaction is variable and dependent upon FCGR polymorphisms. Prior studies of patients with cancer treated with immunotherapy indicate that FCGR polymorphisms can influence antitumor response for certain immunotherapies that act via therapeutically administered mAbs or via endogenous tumor-reactive antibodies induced from tumor antigen vaccines. The previously published “SELECT” trial of high-dose aldesleukin (HD-IL2) for metastatic renal cell carcinoma resulted in an objective response rate of 25%. We evaluated the patients in this SELECT trial to determine whether higher-affinity FCGR polymorphisms are associated with outcome.

Experimental Design: SNPs in FCGR2A, FCGR3A, and FCGR2C were analyzed, individually and in combination, for associations between genotype and clinical outcome.

Results: When higher-affinity genotypes for FCGR2A, FCGR3A, and FCGR2C were considered together, they were associated with significantly increased tumor shrinkage and prolonged survival in response to HD-IL2.

Conclusions: Although associations of higher-affinity FCGR genotype with clinical outcome have been demonstrated with mAb therapy and with idiotype vaccines, to our knowledge, this is the first study to show associations of FCGR genotypes with outcome following HD-IL2 treatment. We hypothesize that endogenous antitumor antibodies may engage immune cells through their FCGRs, and HD-IL2 may enhance antibody-induced tumor destruction, or antibody-enhanced tumor antigen presentation, via augmented activation of innate or adaptive immune responses; this FCGR-mediated immune activity would be augmented through immunologically favorable FCGRs. Clin Cancer Res; 23(9); 2159–68. ©2016 AACR.
Congenital Heart Defects and Indices of Placental and Fetal Growth in a Nationwide Study of 924 422 Liveborn Infants
Authors: Matthiesen Niels B. , Henriksen Tine B. , Agergaard Peter , Gaynor J. William , Bach Cathrine C. , Hjortdal Vibeke E. , Østergaard John R.
Published: October 2016

Background:

Congenital heart defects (CHDs) have been associated with placental anomalies. The nature and the consequences of this association remain poorly understood. We aimed to estimate the associations between all major subtypes of CHD and placental weight at birth, and the association between placental weight and measures of both overall and cerebral growth in fetuses with CHD, as well.

Methods:

We included all 924 422 liveborn Danish singletons, 1997 to 2011. CHD was present in 7569. We compared mean differences in placental weight
z
score between newborns with CHD and newborns without CHD by multivariable linear regression adjusted for potential confounders.

Results:

CHD was associated with a mean
z
score difference of –0.04 (95% confidence interval, –0.07 to –0.02). Some subtypes were associated with smaller placental size at birth: tetralogy of Fallot, –0.45 (95% confidence interval, –0.58 to –0.31); double-outlet right ventricle, –0.48 (95% confidence interval, –0.87 to –0.10); major ventricular septal defects, –0.41 (95% confidence interval, –0.52 to –0.29). Placental weight
z
score was associated with birth weight and head circumference
z
scores in all subtypes. In the 3 mentioned subtypes, the mean deviations from the population mean head circumference and birth weight
z
scores were reduced by up to 66% with adjustment for placental weight
z
score.

Conclusions:

Three subtypes of CHD were associated with lower placental weight, and placental weight was associated with measures of both overall growth and cerebral growth in fetuses with all subtypes of CHD. In certain subtypes, the described deviations in fetal growth were reduced by up to two-thirds after adjustment for placental weight
z
score.