bluuebunny/crossref_metadata_2025_split huggingface dataset:
Simulating sequential multiple assignment randomized trials to generate optimal personalized warfarin dosing strategies
Authors: Rich Benjamin , Moodie Erica EM , Stephens David A 
Published: January 2014

Background Due to the cost and complexity of conducting a sequential multiple assignment randomized trial (SMART), it is desirable to pre-define a small number of personalized regimes to study. Purpose We proposed a simulation-based approach to studying personalized dosing strategies in contexts for which a therapeutic agent’s pharmacokinetic and pharmacodynamics properties are well understood. We take dosing of warfarin as a case study, as its properties are well understood. We consider a SMART in which there are five intervention points in which dosing may be modified, following a loading phase of treatment. Methods Realistic SMARTs are simulated, and two methods of analysis, G-estimation and Q-learning, are used to assess potential personalized dosing strategies. Results In settings where outcome modelling may be complex due to the highly non-linear nature of the pharmacokinetic and pharmacodynamics mechanisms of the therapeutic agent, G-estimation provides for which the more promising method of estimating an optimal dosing strategy. Used in combination with the simulated SMARTs, we were able to improve simulated patient outcomes and suggest which patient characteristics were needed to best individually tailor dosing. In particular, our simulations suggest that current dosing should be determined by an individual’s current coagulation time as measured by the international normalized ratio (INR), their last measured INR, and their last dose. Tailoring treatment only based on current INR and last warfarin dose provided inferior control of INR over the course of the trial. Limitations The ability of the simulated SMARTs to suggest optimal personalized dosing strategies relies on the pharmacokinetic and pharmacodynamic models used to generate the hypothetical patient profiles. This approach is best suited to therapeutic agents whose effects are well studied. Conclusion Prior to investing in a complex randomized trial that involves sequential treatment allocations, simulations should be used where possible in order to guide which dosing strategies to evaluate.
IKK-dependent activation of NF-κB contributes to myeloid and lymphoid leukemogenesis by BCR-ABL1
Authors: Hsieh Mo-Ying , Van Etten Richard A. 
Published: January 2014

Key Points
Inhibitors of NF-κB activation attenuate lymphoid and myeloid leukemogenesis by BCR-ABL1 and decrease leukemic stem cells in vivo. These results validate IKKs and NF-κB signaling as pharmacological targets for therapy of CML and Ph+ B-ALL.
Gender differences in adiponectin levels and body composition in older adults: Hallym aging study
Authors: Song Hong Ji , Oh Sohee , Quan Shanai , Ryu Ohk-Hyun , Jeong Jin-Young , Hong Kyung-Soon , Kim Dong-Hyun 
Published: January 2014

Abstract

Background
Body composition changes with ageing can influence the adiponectin concentration. However, the component of body composition that is associated with adiponectin concentrations in older adults remains unclear.

Methods
There were 152 males and 168 females aged 65 years or older that participated in the 2010 Hallym Aging Study (HAS). Body composition (assessed by dual energy X-ray absorptiometry; DXA), anthropometric parameters and adiponectin were obtained from all participants. Multivariate linear regression models assessed the association of body fat percentage, regional muscle and bone mineral contents of body composition and waist/height ratio with adiponectin concentration. Age, albumin, testosterone concentration and metabolic parameters were considered as confounding factors.

Results
In correlation analysis, age was positively associated with adiponectin in males (P < 0.01), but not in females. Fasting glucose, albumin, arm skeletal muscle mass and bone mineral content were negatively associated with adiponectin in males (P < 0.05). Testosterone and leg bone mineral content were negatively associated with adiponectin in females (P < 0.05). In multivariate linear regression models, body fat percentage and albumin (P < 0.05) were negatively associated with adiponectin, and high-density lipoprotein cholesterol (HDL-C) (P < 0.001) and age (P < 0.01) were positively associated with adiponectin in older males. In older females, the only factors that correlated significantly with adiponectin concentration were the homeostasis model assessment of insulin resistance (P < 0.001) and HDL-C (P < 0.05). The waist/height ratio and bone mineral content were not associated with adiponectin in either gender.

Conclusion
Plasma adiponectin levels correlated negatively with body fat percentage in older males but not in older females. The differential results between older males and females suggest that certain gender-specific mechanisms may affect the association between adiponectin and age-related body composition changes.
Hypoxia increases membrane metallo-endopeptidase expression in a novel lung cancer ex vivo model – role of tumor stroma cells
Authors: Leithner Katharina , Wohlkoenig Christoph , Stacher Elvira , Lindenmann Jörg , Hofmann Nicole A , Gallé Birgit , Guelly Christian , Quehenberger Franz , Stiegler Philipp , Smolle-Jüttner Freyja-Maria , Philipsen Sjaak , Popper Helmut H , Hrzenjak Andelko , Olschewski Andrea , Olschewski Horst 
Published: January 2014

Abstract

Background
Hypoxia-induced genes are potential targets in cancer therapy. Responses to hypoxia have been extensively studied in vitro, however, they may differ in vivo due to the specific tumor microenvironment. In this study gene expression profiles were obtained from fresh human lung cancer tissue fragments cultured ex vivo under different oxygen concentrations in order to study responses to hypoxia in a model that mimics human lung cancer in vivo.

Methods
Non-small cell lung cancer (NSCLC) fragments from altogether 70 patients were maintained ex vivo in normoxia or hypoxia in short-term culture. Viability, apoptosis rates and tissue hypoxia were assessed. Gene expression profiles were studied using Affymetrix GeneChip 1.0 ST microarrays.

Results
Apoptosis rates were comparable in normoxia and hypoxia despite different oxygenation levels, suggesting adaptation of tumor cells to hypoxia. Gene expression profiles in hypoxic compared to normoxic fragments largely overlapped with published hypoxia-signatures. While most of these genes were up-regulated by hypoxia also in NSCLC cell lines, membrane metallo-endopeptidase (MME, neprilysin, CD10) expression was not increased in hypoxia in NSCLC cell lines, but in carcinoma-associated fibroblasts isolated from non-small cell lung cancers. High MME expression was significantly associated with poor overall survival in 342 NSCLC patients in a meta-analysis of published microarray datasets.

Conclusions
The novel ex vivo model allowed for the first time to analyze hypoxia-regulated gene expression in preserved human lung cancer tissue. Gene expression profiles in human hypoxic lung cancer tissue overlapped with hypoxia-signatures from cancer cell lines, however, the elastase MME was identified as a novel hypoxia-induced gene in lung cancer. Due to the lack of hypoxia effects on MME expression in NSCLC cell lines in contrast to carcinoma-associated fibroblasts, a direct up-regulation of stroma fibroblast MME expression under hypoxia might contribute to enhanced aggressiveness of hypoxic cancers.
Pathology of bladder cancer among diabetic patients undergoing radical cystectomy with a history of pioglitazone (Actos) use
Authors: Romero Victoriano , Peyton Charles , Gray Ian , Hemal Ashok , Terlecki Ryan 
Published: January 2014

Abstract

Background
Prospective studies suggested an association between pioglitazone (Actos) use and the development of bladder cancer. Cancer pathology among pioglitazone users has not been characterized. We chose to compare the surgical pathology among diabetic users and non-users, as well as non-diabetic patients who underwent radical cystectomy for bladder cancer.

Methods
Our single-center, prospectively-maintained bladder cancer database was reviewed. Patient demographics, surgical pathology, and outcomes were evaluated. Information regarding diabetic history and use of pioglitazone was determined from chart analysis and patient interview.

Results
From April 2005 to October 2011, 204 patients undergoing radical cystectomy were identified. Of these, 33 (16.2%) were diabetic and 171 (83.8%) had no history of diabetes. Among diabetic patients, 9 (27.3%) had a history of pioglitazone use. Median duration of therapy was 14 (6–120) months. Pathology in non-diabetic patients was T1 in 17 (9.9%), T2 in 38 (22.2%), T3 in 44 (25.7%), and T4 in 31 (18.1%). Pathology among diabetic non-users was T1 in 1 (4.2%), T2 in 7 (29.2%), T3 in 7 (29.2%), and T4 in 4 (16.7%). Pathologic stage among diabetic users was T1 in 1 (11.1%), T2 in 3 (33.3%), T3 in 3 (33.3%), and T4 in 1 (11.1%). Lymph node involvement in non-diabetics, diabetic non-users, and diabetic users was 25.7%, 33.3%, and 33.3%, respectively. Cancer-specific death was seen in 60.3% of non-diabetics, 58.3% of diabetic non-users, and 75% of diabetic users.

Conclusions
Diabetics have similar stage distribution regardless of pioglitazone use. Lymph node metastases rates and cancer specific death were similar across all groups. Additional studies will serve to better characterize this relationship.
Treatment seeking behaviour in southern Chinese elders with chronic orofacial pain: a qualitative study
Authors: Au Teresa SY , Wong May CM , McMillan Anne S , Bridges Susan , McGrath Colman 
Published: January 2014

Abstract

Background
Chronic orofacial pain (OFP) is common in general adult populations worldwide. High levels of psychological distress and impaired coping abilities are common among Western people with chronic OFP but limited information was found in southern Chinese people. This study aimed to explore the perceptions and experiences of community dwelling elderly people with chronic OFP symptoms and their treatment seeking behaviour in Hong Kong.

Methods
An exploratory qualitative interview study was conducted. Elderly people experiencing chronic OFP symptoms were invited to take part in an individual semi-structured interview. A total of 25 semi-structured interviews were performed for 25 participants.

Results
Pertinent issues relating to the treatment seeking behaviour emerged from the interviews, many of which were inter-related and overlapping. They were organized into three major themes: (i) Impact of chronic OFP on daily life; (ii) Personal knowledge and feeling of chronic OFP; (iii) Management of chronic OFP. The participants were found to have the intention to seek professional treatment, but there were barriers which discouraged them continuing to seek professional treatment. They also received complementary treatment for chronic OFP, such as acupuncture, massage and “chi kung”. Moreover, a wide range self-management techniques were also mentioned. On the other hand, those who did not seek professional treatment for the chronic OFP claimed that they had accepted or adapted to the pain as part of their lives.

Conclusions
This qualitative study observed that elderly people affected by chronic OFP symptoms in Hong Kong sought many different ways to manage their pain including traditional and complementary approaches. The role of the dentist in dealing with chronic OFP is unclear. Multiple barriers exist to accessing care for chronic OFP. The findings may be used to inform future chronic OFP management strategies in Hong Kong.
Assessment of the nursing skill mix in Mozambique using a task analysis methodology
Authors: Dgedge Martinho , Mendoza Angel , Necochea Edgar , Bossemeyer Debora , Rajabo Maharifa , Fullerton Judith 
Published: January 2014

AbstractBackgroundThe density of the nursing and maternal child health nursing workforce in Mozambique (0.32/1000) is well below the WHO minimum standard of 1 nurse per 1000. Two levels of education were being offered for both nurses and maternal child health nurses, in programmes ranging from 18 to 30 months in length. The health care workforce in Mozambique also includes Medical Technicians and Medical Agents, who are also educated at either basic or mid-level. The Ministry of Health determined the need to document the tasks that each of the six cadres was performing within various health facilities to identify gaps, and duplications, in order to identify strategies for streamlining workforce production, while retaining highest educational and competency standards. The methodology of task analysis (TA) was used to achieve this objective. This article provides information about the TA methodology, and selected outcomes of the very broad study.MethodsA cross-sectional descriptive task analysis survey was conducted over a 15 month period (2008–2009). A stratified sample of 1295 individuals was recruited from every type of health facility in all of Mozambique’s 10 provinces and in Maputo City. Respondents indicated how frequently they performed any of 233 patient care tasks. Data analysis focused on identifying areas where identical tasks were performed by the various cadres. Analyses addressed frequency of performance, grouped by level of educational preparation, within various types of health facilities.ResultsTask sharing ranged from 74% to 88% between basic and general nurse cadres and from 54% to 88% between maternal and child health nurse cadres, within various health facility types. Conversely, there was distinction between scope of practice for nursing and maternal/child health nursing cadres.ConclusionThe educational pathways to general nursing and maternal/child health nursing careers were consolidated into one 24 month programme for each career. The scopes of practice were affirmed based on task analysis survey data.
Surface chemistry of SnO2 nanowires on Ag-catalyst-covered Si substrate studied using XPS and TDS methods
Authors: Sitarz Michal , Kwoka Monika , Comini Elisabetta , Zappa Dario , Szuber Jacek 
Published: January 2014

Abstract
In this paper we investigate the surface chemistry, including surface contaminations, of SnO2 nanowires deposited on Ag-covered Si substrate by vapor phase deposition (VPD), thanks to x-ray photoelectron spectroscopy (XPS) in combination with thermal desorption spectroscopy (TDS). Air-exposed SnO2 nanowires are slightly non-stoichiometric, and a huge amount of C contaminations is observed at their surface. After the thermal physical desorption (TPD) process, SnO2 nanowires become almost stoichiometric without any surface C contaminations. This is probably related to the fact that C contaminations, as well as residual gases from air, are weakly bounded to the crystalline SnO2 nanowires and can be easily removed from their surface. The obtained results gave us insight on the interpretation of the aging effect of SnO2 nanowires that is of great importance for their potential application in the development of novel chemical nanosensor devices.
The value of simple microbiological studies for on-site screening of acute neonatal conjunctivitis in Angola
Authors: Alexandre Isabel , Cortes Nestor , Justel Mar , Fernández Itziar , Ortíz de Lejarazu Raul , Pastor J Carlos 
Published: January 2014

Abstract

Background
Neonatal conjunctivitis or ophthalmia neonatorum (ON) is an acute bacterial conjunctivitis contracted by newborns during delivery. In non-industrialized countries, detection of the etiological agent is difficult due to the unavailability of modern diagnostic resources. Therefore, we analyzed the effectiveness of Gram and methylene blue staining techniques, which are simple microbiological methods in suspecting the aetiology of ON in a maternity ward in Luanda, Angola.

Findings
Neonatal conjunctival smears (n = 95), maternal data, and perinatal factors were collected. Slides were air-dried and sent to the Microbiology Department of the Hospital Clinico Universitario, Valladolid, Spain, where trained personnel performed Gram and methylene blue staining methods. Findings were interpreted by two expert microbiologists. Ophthalmological examination of all children showed five newborns with clinical signs of ON. Fourteen mothers reported were suspected with vulvo-vaginitis, and 27 had a urinary infection during pregnancy. Gram staining revealed the presence of epithelial cells in 87.6% and leukocytes in 15% of the conjunctival smears. These values were significantly higher than those shown by methylene blue staining. No rods, cocci, or yeasts were identified by either staining method. Chlamydia trachomatis DNA was also undetected in a small sub-sample with clinical suspicion of ON. There was no correlation among the presence of ON, ON microbes, maternal data, or perinatal factors.

Conclusions
Basic microbiological techniques did not provide enough information for screening cases of ON in Angola. Therefore, the use of molecular biology or other techniques is warranted for this purpose.
Seq and CLIP through the miRNA world
Authors: Mittal Nitish , Zavolan Mihaela 
Published: January 2014

AbstractHigh-throughput sequencing of RNAs crosslinked to Argonaute proteins reveals not only a multitude of atypical miRNA binding sites but also of miRNA targets with atypical functions, and can be used to infer quantitative models of miRNA-target interaction strength.
Topoisomerase IIbeta is required for proper retinal development and survival of postmitotic cells
Authors: Li Ying , Hao Hailing , Tzatzalos Evangeline , Lin Ren-Kuo , Doh Sungtae , Liu Leroy F. , Lyu Yi Lisa , Cai Li 
Published: January 2014

Summary
Topoisomerase IIbeta (Top2b) is an enzyme that modulates DNA supercoiling by catalyzing the passage of DNA duplexes through one another. It is ubiquitously expressed in postmitotic cells and known to function during the development of neuromuscular junctions in the diaphragm and the proper formation of laminar structure in the cerebral cortex. However, due to the perinatal death phenotype of the traditional constitutive and brain-specific Top2b knockout mice, the precise in vivo function of Top2b, especially during postnatal neural development, remains to be determined. Using both the constitutive and retina-specific knockout mouse models, we showed that Top2b deficiency resulted in delayed neuronal differentiation, degeneration of the plexiform layers and outer segment of photoreceptors, as well as dramatic reduction in cell number in the retina. Genome-wide transcriptome analysis by RNA sequencing revealed that genes involved in neuronal survival and neural system development were preferentially affected in Top2b-deficient retinas. Collectively, our findings have indicated an important function of Top2b in proper development and the maintenance/survival of postmitotic neurons in the retina.
Systematic screen for mutants resistant to TORC1 inhibition in fission yeast reveals genes involved in cellular ageing and growth
Authors: Rallis Charalampos , López-Maury Luis , Georgescu Teodora , Pancaldi Vera , Bähler Jürg 
Published: January 2014

Summary
Target of rapamycin complex 1 (TORC1), which controls growth in response to nutrients, promotes ageing in multiple organisms. The fission yeast Schizosaccharomyces pombe emerges as a valuable genetic model system to study TORC1 function and cellular ageing. Here we exploited the combinatorial action of rapamycin and caffeine, which inhibit fission yeast growth in a TORC1-dependent manner. We screened a deletion library, comprising ∼84% of all non-essential fission yeast genes, for drug-resistant mutants. This screen identified 33 genes encoding functions such as transcription, kinases, mitochondrial respiration, biosynthesis, intra-cellular trafficking, and stress response. Among the corresponding mutants, 5 showed shortened and 21 showed increased maximal chronological lifespans; 15 of the latter mutants showed no further lifespan increase with rapamycin and might thus represent key targets downstream of TORC1. We pursued the long-lived sck2 mutant with additional functional analyses, revealing that the Sck2p kinase functions within the TORC1 network and is required for normal cell growth, global protein translation, and ribosomal S6 protein phosphorylation in a nutrient-dependent manner. Notably, slow cell growth was associated with all long-lived mutants while oxidative-stress resistance was not.
Feminization of pheromone-sensing neurons affects mating decisions in Drosophila males
Authors: Lu Beika , Zelle Kathleen M. , Seltzer Raya , Hefetz Abraham , Ben-Shahar Yehuda 
Published: January 2014

Summary
The response of individual animals to mating signals depends on the sexual identity of the individual and the genetics of the mating targets, which represent the mating social context (social environment). However, how social signals are sensed and integrated during mating decisions remains a mystery. One of the models for understanding mating behaviors in molecular and cellular terms is the male courtship ritual in the fruit fly (Drosophila melanogaster). We have recently shown that a subset of gustatory receptor neurons (GRNs) that are enriched in the male appendages and express the ion channel ppk23 play a major role in the initiation and maintenance of male courtship via the perception of cuticular contact pheromones, and are likely to represent the main chemosensory pathway that influences mating decisions by males. Here we show that genetic feminization of ppk23-expressing GRNs in male flies resulted in a significant increase in male–male sexual attraction without an apparent impact on sexual attraction to females. Furthermore, we show that this increase in male–male sexual attraction is sensory specific, which can be modulated by variable social contexts. Finally, we show that feminization of ppk23-expressing sensory neurons lead to major transcriptional shifts, which may explain the altered interpretation of the social environment by feminized males. Together, these data indicate that the sexual cellular identity of pheromone sensing GRNs plays a major role in how individual flies interpret their social environment in the context of mating decisions.
Screening Method to Evaluate Point-of-Care Human Chorionic Gonadotropin (hCG) Devices for Susceptibility to the Hook Effect by hCG β Core Fragment: Evaluation of 11 Devices
Authors: Nerenz Robert D , Song Haowei , Gronowski Ann M 
Published: January 2014

Abstract

BACKGROUND
The predominant hCG variant in urine, hCG β core fragment (hCGβcf), has been demonstrated to cause false-negative results in qualitative point-of-care (POC) hCG devices. This is a major concern for healthcare professionals using POC pregnancy tests. We developed a screening method to evaluate qualitative POC hCG devices for their susceptibility to inhibition by hCGβcf. Using this method, we evaluated the performance of 11 commonly used devices.

METHODS
A wide range of purified hCG and hCGβcf concentrations were mixed and tested on 2 POC devices. By use of those results, a screening method was defined and 9 additional POC devices were evaluated. Two solutions containing (a) 500 pmol/L (171 IU/L) intact hCG with 0 pmol/L hCGβcf and (b) 500 pmol/L intact hCG with 500 000 pmol/L hCGβcf were used to screen all POC devices.

RESULTS
The OSOM and Cen-Med Elite devices were found to be most susceptible to false-negative results due to hCGβcf. The BC Icon 20 and the Alere were the least susceptible. The remaining 7 were moderately affected. Devices that gave the strongest signal with hCGβcf alone were those that were least likely to show a hook effect.

CONCLUSIONS
The screening method put forth here can be used by device users and manufacturers to evaluate POC devices for inhibition by hCGβcf. Of 11 devices evaluated, only 2 have been identified that exhibit minimal to no susceptibility to hCGβcf.