Establishing the utility of multi-platform liquid biopsy by integrating the CSF methylome and proteome in CNS tumours.

BACKGROUND: Liquid biopsy represents a major development in cancer research, with significant translational potential. Similarly, it is increasingly recognized that multi-omic molecular approaches are a powerful avenue through which to understand complex and heterogeneous disease biology. We hypothesize that merging these two promising frontiers of cancer research will improve the discriminatory capacity of current models and allow for improved clinical utility. METHODS: We have compiled a cohort of patients with glioblastoma, brain metastasis, and primary central nervous system lymphoma. Cell-free methylated DNA immunoprecipitation (cfMeDIP) and shotgun proteomic profiling was obtained from the cerebrospinal fluid (CSF) of each patient and used to build tumour-specific classifiers. RESULTS: We show that the DNA methylation and protein profiles of cerebrospinal fluid can be integrated to fully discriminate lymphoma from its diagnostic counterparts with perfect AUC of 1 (95% confidence interval 1-1) and 100% specificity, significantly outperforming single-platform classifiers. CONCLUSIONS: We present the most specific and accurate CNS lymphoma classifier to date and demonstrates the synergistic capability of multi-platform liquid biopsies. This has far-reaching translational utility for patients with newly diagnosed intra-axial brain tumours.

Spherically symmetric teleparallel geometries.

We are interested in the development of spherically symmetric geometries in F(T) teleparallel gravity which are of physical importance. We first express the general forms for the spherically symmetric frame and the zero curvature, metric compatible, spin connection. We then analyse the antisymmetric field equations (the solutions of which split into two cases, which we subsequently consider separately), and derive and analyse the resulting symmetric field equations. In order to further study the applications of spherically symmetric teleparallel models, we study 3 subcases in which there is an additional affine symmetry so that the resulting field equations reduce to a system of ordinary differential equations. First, we study static spherical symmetric geometries and solve the antisymmetric field equations and subsequently derive the full set of symmetric field equations. In particular, we investigate vacuum spacetimes and obtain a number of new solutions. Second, we consider an additional affine frame symmetry in order to expand the affine frame symmetry group to that of a spatially homogeneous Kantowski-Sachs geometry. Third, we study the special case of spherical symmetry with an additional fourth similarity affine vector.

Generalized teleparallel de Sitter geometries.

Theories of gravity based on teleparallel geometries are characterized by the torsion, which is a function of the coframe, derivatives of the coframe, and a zero curvature and metric compatible spin-connection. The appropriate notion of a symmetry in a teleparallel geometry is that of an affine symmetry. Due to the importance of the de Sitter geometry and Einstein spaces within General Relativity, we shall describe teleparallel de Sitter geometries and discuss their possible generalizations. In particular, we shall analyse a class of Einstein teleparallel geometries which have a 4-dimensional Lie algebra of affine symmetries, and display two one-parameter families of explicit exact solutions.

Bedside Point-of-Care Ultrasound of an Adult with Diffuse Intermittent Abdominal Pain.

A 29-year-old woman with a history of obesity status post Roux-en-Y gastric bypass greater than five years prior presented to the emergency department with four hours of sudden-onset stabbing left-sided abdominal pain associated with nausea and non-bloody emesis. She denied melaena and hematochezia, but did report two weeks of diarrhoea that was unchanged with this new onset abdominal pain.

Infant growth outcomes from birth to 12 months of age: findings from the Delta Healthy Sprouts randomized comparative impact trial.

OBJECTIVE: Multicomponent lifestyle modification interventions designed for gestational and early postnatal periods may be key to preventing obesity in children. The primary objective of the study was to determine if infant growth outcomes differed between treatment arms of an 18-month, maternal, infant and early childhood home visiting project. METHODS: Pregnant women at least 18 years of age, less than 19 weeks pregnant and residing in a lower Mississippi Delta county were recruited between March 2013 and December 2014. Postnatal data were collected from 24 experimental and 30 control participants between September 2013 and May 2016. Infant growth outcomes were modelled as time-to-event data using Kaplan-Meier survival curves with log-rank tests to determine if survival curves differed between treatment arms. RESULTS: Retention rates for the experimental and control arms were 88% (21/24) and 83% (25/30), respectively. Approximately three-fourths of infants in both treatment arms were classified as overweight and experienced rapid weight gain during the first 12 months of life. No differences between median times neither to classification as overweight (3-4 months) nor to experiencing rapid weight gain (6-7 months) were observed between treatment arms. CONCLUSIONS: As compared with a standard educational (control) curriculum, an educational curriculum enhanced with diet and physical activity components was not effective at improving infant growth outcomes.

Formative research to identify community partnerships and foster relationships for health promotion research in South Mississippi.

OBJECTIVES: The purpose of this short communication is to describe the trust building and collaboration, fostering phases of a community-academic partnership between churches and academic researchers using a community-based participatory research approach. STUDY DESIGN AND METHODS: An academic-community partnership with church leaders was initiated using survey administration and was further developed using focus groups. A coalition was developed, and it guided a subsequent focus group with church members. RESULTS: Most churches surveyed did not have a health ministry in place but were agreeable that a variety of health topics were appropriate for the church setting. Church leaders felt that church members were key to engage in health programs in the church, whereas church members viewed pastoral support as important. Church leaders felt that working with a university brings credibility to their own health programs. CONCLUSION: This early work provides a valuable example of how community collaborations may be initiated and developed using formative research methods, serving both community and research agendas.

Association of academic performance of premedical students to satisfaction and engagement in a short training program: a cross sectional study presenting gender differences.

BACKGROUND: It is important that students have a high academic engagement and satisfaction in order to have good academic achievement. No study measures association of these elements in a short training program. This study aimed to measure the correlation between academic achievement, satisfaction and engagement dimensions in a short training program among premedical students. METHODS: We carried out a cross sectional study, in August 2013, at Cercle d'Etudiants, Ingénieurs, Médecins et Professeurs de Lycée pour le Triomphe de l'Excellence (CEMPLEX) training center, a center which prepares students for the national common entrance examination into medical schools in Cameroon. We included all students attending this training center during last examination period. They were asked to fill out a questionnaire on paper. Academic engagement was measured using three dimensions: vigor, dedication and absorption. Satisfaction to lessons, for each learning subject was collected. Academic achievement was calculated using mean of the score of all learning subjects affected with their coefficient. Pearson coefficient (r) and multiple regression models were used to measure association. A p value < 0.05 was statistically significant. RESULTS: In total, 180 students were analyzed. In univariate linear analysis, we found correlation with academic achievement for vigor (r = 0.338, p = 0.006) and dedication (r = 0.287, p = 0.021) only in male students. In multiple regression linear analysis, academic engagement and satisfaction were correlated to academic achievement only in male students (R2 = 0.159, p = 0.035). No correlation was found in female students and in all students. The independent variables (vigor, dedication, absorption and satisfaction) explained 6.8-24.3% of the variance of academic achievement. CONCLUSION: It is only in male students that academic engagement and satisfaction to lessons are correlated to academic achievement in this short training program for premedical students and this correlation is weak.

Innovation in the occupational health physician profession requires the development of a work collective to improve the efficiency of MSD prevention.

Given the ageing population of occupational health physicians and the deteriorating situation of employee health, reforms targeting the multi-disciplinary nature of occupational health are currently being drawn up. These are of great concern to doctors in terms of the future of occupational health, notably with regard to changing medical practices. The objective of this study is to explore the actual practices of occupational health physicians within the framework of MSD prevention in France. By analysing the activity of occupational health physicians, we could gain a better understanding of the coordination between those involved in OHS with the ultimate goal being to improve prevention. Based on an analysis of peer activity, this method made it possible to push beyond pre-constructed discourse. According to activity theories, it is through others that the history and controversies of a profession can be grasped and skills developed. The results produced by these collective discussions on activity analysis contributed to establish a collective point of view about the important aspects of their profession that need defending and the variations in professional genre in relation to the current reforms, notably.

Providing humanistic care: dentists' experiences in deprived areas.

Communication barriers severely reduce the effectiveness of oral health care provision to people living in poverty. Our objective was to identify specific approaches and skills developed by dentists for more effective treatment of people living in poverty and addressing their needs. We conducted qualitative research based on in-depth interviews with eight dentists practicing in disadvantaged communities of Montreal, Canada. Analyses consisted of interview debriefing, transcript coding, and data interpretation. Results revealed that, over years of practice, these dentists had developed a five-faceted socio-humanistic approach that involved: (1) understanding patients' social context; (2) taking time and showing empathy; (3) avoiding moralistic attitudes; (4) overcoming social distances; and (5) favoring direct contact with patients. This approach is original, and, even though participants found it successful, it should be evaluated in terms of its impact for access to services and patients' experience of care.

Sustainable MSD prevention: management for continuous improvement between prevention and production. Ergonomic intervention in two assembly line companies.

To increase output and meet customers' needs, companies have turned to the development of production management systems: Kaizen, one piece flow, Kanban, etc. The aim of such systems is to accelerate decisions, react to environmental issues and manage various productions. In the main, this type of management system has led to the continuous improvement of production performance. Consequently, such production management systems can have unexpected negative effects on operators' health and safety. Conversely, regulation and control systems focusing on work-related risks have obliged firms to implement health and safety management systems such as OHSAS 18001. The purpose of this type of system, also based on continuous improvement, is to reduce risks, facilitate work-related activities and identify solutions in terms of equipment and tools. However, the prevention actions introduced through health and safety systems often result in other unexpected and unwanted effects on production. This paper shows how companies can improve the way they are run by taking into account both types of management system.

Dentists' experience with low-income patients benefiting from a public insurance program.

France has a system of public coverage that guarantees low-income earners full payment of basic dental health costs. In spite of this coverage and major needs for care, deprived populations have lower access to dental care. The aim of this qualitative study was to explore dentists' experience with low-income patients benefiting from the French universal healthcare coverage system. This study is based on 17 one-on-one semistructured interviews carried out with French private dentists. Dentists distinguished two categories of low-income patients: 'good patients', described as being regular attenders; and 'bad patients', whose main characteristic is irregular attendance. Dentists explained that they have difficulties in dealing with patients who do not keep their appointments. First, dentists feel that they fail in conducting their mission of being a care provider (therapeutic failure). The absence of the patient is also seen as a lack of recognition (relationship failure). Furthermore, dentists do not earn money when patients miss their appointments (financial failure). In this context, many dentists feel discouraged and powerless (personal failure). Moreover, dentists do not understand why patients renounce the dental-care opportunities offered under the system of public coverage (failure of the system). Dentists who repeatedly experience failures related to irregular attendance tend to adopt exclusion strategies.

Selective activation of nuclear factor kappa B in the cochlea by sensory and inflammatory stress.

Damage response pathways triggered by mechanical stress might reasonably be expected to be conserved throughout evolution. However, using a nuclear factor kappa B (NF-kappaB) reporter mouse we show here that this phylogenetically recent transcription factor plays a major role in the response to mechanosensory stress in the mammalian inner ear. The protective action of NF-kappaB is exerted in neither sensory nor non-sensory epithelial cells, but rather in connective tissue cells within the spiral ligament and spiral limbus. In the spiral ligament, predominantly type I fibrocytes are activated following noise exposure, whereas type II fibrocytes are activated following systemic inflammatory stress. Immune-mediated and acoustic trauma-mediated hearing loss syndromes in humans may in part result from the vulnerability of type II and type I fibrocytes to systemic inflammatory stress and acoustic trauma, respectively. Unexpected cell-specific and stress-specific NF-kappaB activation found in the inner ear in this in vivo study suggest that this approach may have wide applications in demonstrating similar specializations of stress responses in other tissues, including the brain.

MAST3: a novel IBD risk factor that modulates TLR4 signaling.

Inflammatory bowel disease (IBD) is a chronic disorder caused by multiple factors in a genetically susceptible host. Significant advances in the study of genetic susceptibility have highlighted the importance of the innate immune system in this disease. We previously completed a genome-wide linkage study and found a significant locus (IBD6) on chromosome 19p. We were interested in identifying the causal variant in IBD6. We performed a two-stage association mapping study. In stage 1, 1530 single-nucleotide polymorphisms (SNPs) were selected from the HapMap database and genotyped in 761 patients with IBD. Among the SNPs that passed the threshold for replication, 26 were successfully genotyped in 754 additional patients (stage 2). One intronic variant, rs273506, located in the microtubule-associated serine/threonine-protein kinase gene-3 (MAST3), was found to be associated in both stages (pooled P=1.8 x 10(-4)). We identified four MAST3 coding variants, including a non-synonymous SNP rs8108738, correlated to rs273506 and associated with IBD. To test whether MAST3 was expressed in cells of interest, we performed expression assays, which showed abundant expression of MAST3 in antigen-presenting cells and in lymphocytes. The knockdown of MAST3 specifically decreased Toll-like receptor-4-dependent NF-kappaB activity. Our findings are additional proofs of the pivotal role played by modulators of NF-kappaB activity in IBD pathogenesis.

Discoidin domain receptor 2 impairs insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation and glucose uptake in 3T3-L1 adipocytes.

Differentiation of preadipocytes into functional adipocytes depends on early proliferative events (mitotic clonal expansion) and extracellular matrix interactions. We report that discoidin domain receptor (DDR) 2, a novel adhesion receptor, is expressed in 3T3-L1 preadipocytes and is downregulated during the early phase of adipogenesis. DDR2 overexpression (DDR2-L1 preadipocytes) reduced subconfluent proliferation by 56% (p<0.001) and insulin-stimulated tyrosine phosphorylation of insulin receptor substrate (IRS)-1 by 34% (p<0.05). The mitotic clonal expansion phase of differentiating confluent DDR2-L1 preadipocytes was impaired by approximately 25% (p<0.05). Although induction of peroxisome proliferator-activated receptor gamma, fatty acid synthase, and adiponectin was not altered, the resulting adipocytes were 55% larger (p<0.05), and contained 66% more triacylglycerol (p<0.01). The induction of CCAAT/enhancer binding protein alpha was reduced by 37% (p<0.05), correlating with a similar reduction in insulin-stimulated IRS-1 tyrosine phosphorylation and glucose transport in DDR2-L1 adipocytes (decreases of 22% and 27%, respectively; p<0.05 for both). Our data show that DDR2 is expressed in adipose cells and that its overexpression leads to insulin resistance.

3D ultrasound analysis of carotid plaque volume and surface morphology.

Morphological characterization of carotid plaques has been used for risk stratification and evaluation of response to therapy, evaluation of new risk factors, genetic research, and for quantifying effects of new anti-atherosclerotic therapies. We developed a 3D US system that allows detailed studies of carotid plaques in 3D. Our software includes 3D reconstruction, viewing, manual and semi-automated segmentation of carotid plaques, and surface morphology analysis to be used for quantitative tracking of plaque changes. We evaluated our plaque quantification software by examining plaque volume measurement accuracy, variability, and plaque surface morphology. We used vascular test phantoms to study segmentation accuracy, and used 48 3D US carotid plaques of patients ranging in size from 13.2 mm(3) to 544.0 mm(3) to study plaque volume measurement variability. We compared results from the semi-automated plaque measurements to the results obtained from manual measurements, which were used as the "gold" standard. We developed a surface plaque morphology quantification technique based on the segmented plaque surface curvature and used it to analyze plaques. Accuracy of plaque volume measurements for the simulated plaques ranged from 4.2% to 1.5% for volumes ranging from 68.5 mm(3) to 286 mm(3). The variability study showed that coefficients of variation in the measurement of plaque volume decreased with increasing plaque size for both inter- (90.8-3.9%) and intra-observer (70.2-3.1%) measurements over the plaque sizes measured. Surface morphology analysis showed that 1 mm ulceration could be quantified and monitored for changes over time. The automated plaque quantification approach showed a little higher intra-observer variability than the manual technique, and its performance was better for segmenting the wall than the lumen. Our results indicate that our approach is sensitive tool and can be used in studies of plaque progression and regression as it relates to atherosclerosis treatment effects and can be used effectively in longitudinal studies for direct measurement carotid plaque volume.

Macrophage-conditioned medium inhibits the differentiation of 3T3-L1 and human abdominal preadipocytes.

AIMS/HYPOTHESIS: In obesity, a limited adipogenic capacity may promote adipocyte hypertrophy and increase the risk of insulin resistance and type 2 diabetes. Recent data indicate that macrophages reside within adipose tissue in obese rodents and humans. We hypothesised that secreted macrophage factors may inhibit adipogenesis. MATERIALS AND METHODS: Conditioned media from cultured murine J774 or human THP-1 macrophages were collected, and added to either murine 3T3-L1 preadipocytes or human abdominal stromal preadipocytes from subcutaneous or omental fat depots. RESULTS: Macrophage-conditioned medium (MacCM) strongly inhibited 3T3-L1 adipogenesis. Dose-response studies with J774-MacCM revealed that 80 and 100% of J774-MacCM completely suppressed triacylglycerol accumulation as well as the induction of fatty acid synthase, peroxisome proliferator-activated receptor gamma, CCAAT/enhancer binding protein alpha, and adiponectin. Similar inhibitory effects on 3T3-L1 preadipocytes were observed with THP-1-MacCM. Differentiation of human abdominal subcutaneous stromal preadipocytes was moderately reduced (subcutaneous>omental) by J744-MacCM. In contrast, the differentiation of both subcutaneous and omental stromal preadipocytes was completely inhibited by THP-1-MacCM, as determined on the basis of morphology and triacylglycerol accumulation, as well as fatty acid synthase and adiponectin protein expression. CONCLUSIONS/INTERPRETATION: Secreted macrophage products inhibit the differentiation of 3T3-L1 preadipocytes as well as human abdominal stromal preadipocytes.

Health and reproductive profiles of malaria antigen-producing transgenic goats derived by somatic cell nuclear transfer.

Nuclear transfer (NT) using transfected primary cells is an efficient approach for the generation of transgenic goats. However, reprogramming abnormalities associated with this process might result in compromised animals. We examined the health, reproductive performance, and milk production of four transgenic does derived from somatic cell NT. Goats were derived from two fetal cell lines, each transfected with a transgene expressing a different version of the MSP-1(42) malaria antigen, either glycosylated or non-glycosylated. Two female kids were produced per cell line. Health and growth of these NT animals were monitored and compared with four age-matched control does. There were no differences in birth and weaning weights between NT and control animals. The NT does were bred and produced a total of nine kids. The control does delivered five kids. The NT does expressing the glycosylated antigen lactated only briefly, probably as a result of over-expression of the MSP-1(42) protein. However, NT does expressing the non-glycosylated antigen had normal milk yields and produced the recombinant protein. These data demonstrated that the production of healthy transgenic founder goats by somatic cell NT is readily achievable and that these animals can be used successfully for the production of a candidate Malaria vaccine.

Evaluation of [(99m)Tc] liposomes as lymphoscintigraphic agents: comparison with [(99m)Tc] sulfur colloid and [(99m)Tc] human serum albumin.

This study investigates the use of [(99m)Tc] liposomes for the detection of sentinel lymph nodes. A variety of [(99m)Tc] liposome formulations were compared with common lymphoscintigraphic agents including [(99m)Tc] regular-sulfur colloid (SC), [(99m)Tc] 0.22 microfiltered-SC, [(99m)Tc] reduced heating time 0.22 microfiltered-SC, and [(99m)Tc] human serum albumin (HSA) in rabbits. Images were acquired for the first 60 minutes and at 24 hours, followed by tissue biodistribution study. All agents except [(99m)Tc] regular SC demonstrated good migration from the injection site. Agents were retained in the popliteal node at 24 hours to varying degrees as follows: both [(99m)Tc] filtered SC preparations > [(99m)Tc] regular SC > [(99m)Tc] liposomes > [(99m)Tc] HSA. [(99m)Tc] liposome imaging can be used to develop novel liposome compositions with improved lymph node diagnostic and drug delivery characteristics.

First Report of Tomato yellow leaf curl virus in Louisiana.

Tomato yellow leaf curl virus (TYLCV) is a begomovirus (Geminiviridae) that causes a serious disease of tomato throughout the world. In 1997, the strain from Israel of TYLCV (TYLCV-IS) was found infecting tomatoes in Florida for the first time in the United States (1). During late spring of 2000, approximately 90% of the tomato plants (Lycopersicon esculentum) in a farm near New Orleans exhibited severe stunting, leaf cupping, and chlorosis. Symptoms were similar to those caused by TYLCV. Whiteflies (Bemisia tabaci biotype B) were present in the field but in relatively low numbers. The effect on yield reduction varied from negligible (late infections) to 100% (early infections). Six selected plants showing symptoms were assayed by polymerase chain reaction (PCR) using begomovirus-specific primers. Capsicum frutescens infected with an isolate of Texas pepper virus from Costa Rica was used as positive control. DNA was extracted using Plant DNAzol Reagent (GIBCO BRL). PCR was conducted using degenerate primers AV494/AC1048 that amplify the core coat protein region of most begomoviruses (2). PCR yielded a DNA fragment of approximately 550 bp, suggesting that a begomovirus was associated with the disease. The amplified DNA of one field isolate was cloned and the nucleotide (nt) sequence determined. Sequence comparisons with other begomoviruses in the GenBank Database indicated that the Louisiana isolate shared 100% nt identity with TYLCV-IS (GenBank Accession X76319). Successful transmission (100%) to Bonny Best tomato were obtained with four groups of 10 whiteflies each (B. tabaci biotype B) that fed on TYLCV-IS infected tomato plants. Acquisition and transmission feedings were for 2 days. In all cases, the virus was diagnosed by the ability to reproduce typical TYLCV-like symptoms in tomato and PCR. The virus was also successfully graft-transmitted to tomato cv. Bonny Best, Nicotiana benthamiana, and tomatillo (Physalis ixocarpa) using scions from tomato plants infected with a whitefly transmitted virus isolate. This is the first report of TYLCV-IS in Louisiana. References: (1) J. E. Polston et al. Plant Dis. 83:984-988, 1999. (2) S. D. Wyatt and J. K. Brown. Phytopathology 86:1288-1293, 1996.