The Standard of Care in Type 2 Diabetes: Re-evaluating the Treatment Paradigm.
There is currently a worldwide epidemic of type 2 diabetes (T2D) that is predicted to increase substantially in the next few years. With 80% of the global T2D population living in low to middle-income countries, there are issues with cost and of access to appropriate medicines. The objective of this symposium was to provide an overview of the efficacy and safety of glucose-lowering drugs, focussing in particular on sulfonylureas (SUs) in patients with T2D using data taken from both randomised controlled trials (RCTs) and real-world studies, the application of strategies to ensure optimal patient adherence and clinical outcomes, and the optimal use of SUs in terms of dose adjustment and agent choice to ensure the best clinical outcome. The symposium began by exploring a profile of the typical patient seen in diabetes clinical practice and the appropriate management of such a patient in the real world, before moving on to an overview of the risks associated with T2D and how the currently available agents, including newer antidiabetic medications, mitigate or exacerbate those risks. The final presentation provided an overview of real-world studies, the gap between RCTs and the real world, and the use of available glucose-lowering agents in daily clinical practice. Clinical evidence was presented demonstrating that tight glucose control improved both microvascular and macrovascular outcomes, but that aggressive treatment in patients with a very high cardiovascular risk could lead to adverse outcomes. Real-world data suggest that older agents such as SUs and metformin are being used in a large proportion of patients with T2D with demonstrable effectiveness, indicating that they still have a place in modern T2D management. The symposium, while acknowledging the need for newer antidiabetic drugs in specific situations and patient groups, recommended the continuation of SUs and metformin as the primary oral antidiabetic agents in resource-constrained regions of the world.Funding:Servier.


The prevalence of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) in skin abscesses presenting to the pediatric emergency department.
Community-acquired methicillin resistant Staphylococcus aureus (CA-MRSA) infections have been increasing. The most common of these infections present as skin abscesses. The objectives of this study were to prospectively determine the prevalence of CA-MRSA in abscesses in the population of a pediatric emergency department, to determine antibiotic sensitivity patterns of the CA-MRSA isolates, and to describe the patient population that presented with skin abscesses. We conducted a prospective study of children under the age of 18 years who presented to our pediatric emergency department with a skin abscess that required incision and drainage. Pus from these abscesses was sent for culture to determine the causative agent, and antibiotic sensitivities were reported. Characteristics of the patient population that presented with these abscesses were examined. Sixty-eight patients were enrolled over an 18-month period. Of these, 60 (88%) had cultures positive for Staphylococcus aureus (S. Aureus). Of these 60 patients, 51 (85%) were identified as CA-MRSA by their resistance patterns. All of the CA-MRSA isolates were sensitive to trimethoprim/sulfamethoxisole; 6 (10%) were either resistant or intermittently resistant to clindamycin. The study was conducted on a convenience sample of patients and enrolled a relatively small number of patients. CA-MRSA is responsible for the vast majority of skin abscesses presenting to the pediatric emergency department. CA-MRSA isolates are likely to be sensitive to trimethoprim/sulfamethoxisole or clindamycin, although there is some resistance to clindamycin.


The Economy of Shark Conservation in the Northeast Pacific: The Role of Ecotourism and Citizen Science.
Historically sharks have been seen either as a source of income through harvesting, or as a nuisance and danger. The economic value of sharks has traditionally been measured as the total value of sharks caught for liver oil, fins, or meat for consumption. Sharks have also been killed to near extinction in cases where they were seen as a threat to fisheries on other species. This is illustrated by the mass extermination of Basking Sharks (Cetorhinus maximus) in British Columbia. They were seen as a nuisance to fishermen as they got entangled in gill nets during the salmon fishing season. However with the development of the SCUBA diving industry, and ecotourism in general, increased awareness of the role sharks play in marine ecosystems has resulted in changes in how they are perceived and utilized. Despite an ongoing harvest of sharks such as the North Pacific Spiny Dogfish (Squalus suckleyi), sharks now generate economic value through SCUBA diving enthusiasts who travel the globe to see, swim with, and photograph them. The use of digital cameras and other digital media has brought sharks into households around the world and increased awareness of the conservation issues facing many species. This renewed appreciation has led to a better understanding of sharks by the public, resulting in advocates calling for better protections and conservation. In particular, a growing part of the SCUBA diving community wants to contribute to conservation and research projects, which has led to participation in citizen science projects. These projects provide scientific data but also gain ground as ecotourism activities, thus adding to both economic value of tourism and conservation efforts.


Using Linguistic Ethnography to Study Video Consultations: A Call to Action and Future Research Agenda.
Video consultations are a rapidly growing service model, particularly in secondary care. Studies, mainly using trials and post-hoc surveys, have routinely documented that they can be a safe and effective means to deliver care at a distance. While video offers new opportunities to provide health services, it also constrains how patients and clinicians can interact, raising questions about feasibility, quality, and safety-questions that cannot be adequately addressed with prevailing methods and approaches. To support successful and appropriate implementation, use and spread of video consultations, we need to investigate how video changes the interaction. In this article, we use two worked examples to demonstrate how Linguistic Ethnography, a methodological approach combining ethnographic with linguistic analysis, enables a detailed understanding of how communication in video consultations works, providing an evidence base to support patients and clinicians with using this service model.


Gender differences in attitudes and attributes of people using therapeutic shoes for diabetic foot complications.
Therapeutic shoes can prevent diabetic foot reulcerations but their use is complicated by the fact that shoes have psychological and social meanings, which is believed to put a larger burden on women than men. The aim was to compare attitudes and attributes of women and men using therapeutic shoes for diabetic foot complications. A questionnaire was posted to 1230 people with diabetes who had been fitted with therapeutic shoes. Women's and men's answers were compared using t-tests, Mann-Whitney U tests and chi-square tests with Fischer's exact tests. P-values < 0.05 were considered statistically significant. Questionnaires from 443 (36.0%) respondents (294 men, 149 women, mean age 69.2 years) were analyzed. More men than women (p < 0.05) had paid employment (20.4% vs 9.4%), had someone who reminded them to wear their therapeutic shoes (27.6% vs 10.0%), and had a history of foot ulcers (62.9% vs 46.3%) or minor amputation (17.7% vs 6.7%). More women than men received disability pension (18.8% vs 10.2%). Women reported worse general health, lower internal locus of control regarding ulcer prevention, and more negative attitudes to the appearance and price of therapeutic shoes and how they felt about wearing them in public. Other comparisons were non-significant: other shoe attributes, education, diabetes type, current foot ulcers, major amputations, satisfaction with shoe services, understanding of neuropathy as a risk factor, locus of control regarding ulcer healing, belief in the shoes' efficacy to prevent and heal ulcers, worries about ulcer healing and new ulcerations, self-efficacy, depression, shoe use/adherence, paying a fee for therapeutic shoes, and social support. Men had worse foot complications. Women had worse general health, lower internal locus of control regarding ulcer prevention, and more negative attitudes toward therapeutic shoes. Clinicians should pay more attention to their female patients' concerns. Future research and development should focus on improving the weight and appearance of therapeutic shoes, particularly for women. Research is also needed on how to facilitate the adaption and reevaluation process where patients change from viewing shoes purely as items of clothing to also viewing them as medical interventions.


Bacteriologic and serologic findings in experimental pyelonephritis caused by Ureaplasma urealyticum.
A challenge procedure based on reflux of Ureaplasma urealyticum to the rat kidney was used to examine the disease-causing potential of this species for the upper urinary tract. Renal infection was detected 8 days after challenge in 90 to 100% of animals exposed to 10(7) ureaplasmas but was not detected in animals exposed to fewer than 10(6) microorganisms. Viable microorganisms were recoverable from more than 60% of infected animals throughout a 24-week follow-up period of study. Animals with persistent infection exhibited a humoral response involving immunoglobulin M and immunoglobulin G antibody. These results show that U. urealyticum is capable of giving rise to chronic infection in the kidneys of rats following challenge via the ascending route.


Lesion Index-Guided Ablation Facilitates Continuous, Transmural, and Durable Lesions in a Porcine Recovery Model.
The Lesion Index (LSI) is a proprietary algorithm from Abbott Medical combining contact force, radiofrequency application duration, and radiofrequency current. It can be displayed during ablation with the TactiCath contact force catheter. The LSI Index was designed to provide real-time lesion formation feedback and is hypothesized to estimate the lesion diameter. Before ablation, animals underwent cardiac computed tomography to assess atrial tissue thickness. Ablation lines (n=2-3 per animal) were created in the right atrium of 7 Göttingen mini pigs with point lesions (25 W). Within each line of ablation, the catheter tip was moved a prescribed distance (D/mm) according to 1 of 3 strategies: D=LSI+0 mm; D=LSI+2 mm; or D=LSI+4 mm. Two weeks after ablation, serial sections of targeted atrial tissue were examined histologically to identify gaps in transmural ablation. LSI-guided lines had a lower incidence of histological gaps (4 gaps in 69 catheter moves, 5.8%) than LSI+2 mm lines (7 gaps in 33 catheter moves, 21.2%) and LSI+4 mm lines (15 gaps in 23 catheter moves, 65.2%, P<0.05 versus D=LSI). ΔLSI was calculated retrospectively as the distance between 2 adjacent lesions above the mean LSI of the 2 lesions. ΔLSI values of ≤1.5 were associated with no gaps in transmural ablation. In this model of chronic atrial ablation, delivery of uninterrupted transmural linear lesions may be facilitated by using LSI to guide catheter movement. When ΔLSI between adjacent lesions is ≤1.5 mm, no gaps in atrial linear lesions should be expected.


The impact of smoking different tobacco types on the subgingival microbiome and periodontal health: a pilot study.
Smoking is a risk factor for periodontal disease, and a cause of oral microbiome dysbiosis. While this has been evaluated for traditional cigarette smoking, there is limited research on the effect of other tobacco types on the oral microbiome. This study investigates subgingival microbiome composition in smokers of different tobacco types and their effect on periodontal health. Subgingival plaques were collected from 40 individuals, including smokers of either cigarettes, medwakh, or shisha, and non-smokers seeking dental treatment at the University Dental Hospital in Sharjah, United Arab Emirates. The entire (~ 1500 bp) 16S rRNA bacterial gene was fully amplified and sequenced using Oxford Nanopore technology. Subjects were compared for the relative abundance and diversity of subgingival microbiota, considering smoking and periodontal condition. The relative abundances of several pathogens were significantly higher among smokers, such as Prevotella denticola and Treponema sp. OMZ 838 in medwakh smokers, Streptococcus mutans and Veillonella dispar in cigarette smokers, Streptococcus sanguinis and Tannerella forsythia in shisha smokers. Subgingival microbiome of smokers was altered even in subjects with no or mild periodontitis, probably making them more prone to severe periodontal diseases. Microbiome profiling can be a useful tool for periodontal risk assessment. Further studies are recommended to investigate the impact of tobacco cessation on periodontal disease progression and oral microbiome.


Epidemiology and control of an outbreak of vancomycin-resistant enterococci in the intensive care units.
This study was aimed to describe a vancomycin-resistant enterococci (VRE) outbreak across three intensive care units (ICUs) of a Korean hospital from September 2006 to January 2007 and the subsequent control strategies. We simultaneously implemented multifaceted interventions to control the outbreak, including establishing a VRE cohort ward, active rectal surveillance cultures, daily extensive cleaning of environmental surfaces and environmental cultures, antibiotic restriction, and education of hospital staff. We measured weekly VRE prevalence and rectal acquisition rates and characterized the VRE isolates by polymerase chain reaction (PCR) of the vanA gene and Sma1-pulsed-field gel electrophoresis (PFGE). During the outbreak, a total of 50 patients infected with VRE were identified by clinical and surveillance cultures, and 46 had vancomycin-resistant Enterococcus faecium (VREF). PFGE analysis of VREF isolates from initial two months disclosed 6 types and clusters of two major types. The outbreak was terminated 5 months after implementation of the interventions: The weekly prevalence rate decreased from 9.1/100 patients-day in September 2006 to 0.6/100 by the end of January 2007, and the rectal acquisition rates also dropped from 6.9/100 to 0/100 patients-day. Our study suggests that an aggressive multifaceted control strategy is a rapid, effective approach for controlling a VRE outbreak.


Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study.
Ataxia-telangiectasia (A-T) is an autosomal recessive neurodegenerative disorder with multisystem involvement and cancer predisposition, caused by mutations in the A-T mutated (ATM) gene. To study genotype-phenotype correlations, we evaluated the clinical and laboratory data of 51 genetically proven A-T patients, and additionally measured ATM protein expression and kinase activity. Patients without ATM kinase activity showed the classical phenotype. The presence of ATM protein, correlated with slightly better immunological function. Residual kinase activity correlated with a milder and essentially different neurological phenotype, absence of telangiectasia, normal endocrine and pulmonary function, normal immunoglobulins, significantly lower X-ray hypersensitivity in lymphocytes, and extended lifespan. In these patients, cancer occurred later in life and generally consisted of solid instead of lymphoid malignancies. The genotypes of severely affected patients generally included truncating mutations resulting in total absence of ATM kinase activity, while patients with milder phenotypes harbored at least one missense or splice site mutation resulting in expression of ATM with some kinase activity. Overall, the phenotypic manifestations in A-T show a continuous spectrum from severe classical childhood-onset A-T to a relatively mild adult-onset disorder, depending on the presence of ATM protein and kinase activity. Each patient is left with a tremendously increased cancer risk.


Comparative structural analysis provides new insights into the function of R2-like ligand-binding oxidase.
R2-like ligand-binding oxidase (R2lox) is a ferritin-like protein that harbours a heterodinuclear manganese-iron active site. Although R2lox function is yet to be established, the enzyme binds a fatty acid ligand coordinating the metal centre and catalyses the formation of a tyrosine-valine ether cross-link in the protein scaffold upon O2 activation. Here, we characterized the ligands copurified with R2lox by mass spectrometry-based metabolomics. Moreover, we present the crystal structures of two new homologs of R2lox, from Saccharopolyspora erythraea and Sulfolobus acidocaldarius, at 1.38 Å and 2.26 Å resolution, respectively, providing the highest resolution structure for R2lox, as well as new insights into putative mechanisms regulating the function of the enzyme.


Gentamicin resistance genes in environmental bacteria: prevalence and transfer.
A comprehensive multiphasic survey of the prevalence and transfer of gentamicin resistance (Gm(r)) genes in different non-clinical environments has been performed. We were interested to find out whether Gm(r) genes described from clinical isolates can be detected in different environmental habitats and whether hot spots can be identified. Furthermore, this study aimed to evaluate the impact of selective pressure on the abundance and mobility of resistance genes. The study included samples from soils, rhizospheres, piggery manure, faeces from cattle, laying and broiler chickens, municipal and hospital sewage water, and coastal water. Six clusters of genes coding for Gm-modifying enzymes (aac(3)-I, aac(3)-II/VI, aac(3)-III/IV, aac(6')-II/Ib, ant(2'')-I, aph(2'')-I) were identified based on a database comparison and primer systems for each gene cluster were developed. Gm-resistant bacteria isolated from the different environments had a different taxonomic composition. In only 34 of 207 isolates, mainly originating from sewage, faeces and coastal water polluted with wastewater, were known Gm(r) genes corresponding to five of the six clusters detected. The strains belonged to genera in which the genes had previously been detected (Enterobacteriaceae, Pseudomonas, Acinetobacter) but also to phylogenetically distant bacteria, such as members of the CFB group, alpha- and beta-Proteobacteria. Gm(r) genes located on mobile genetic elements (MGE) could be captured in exogenous isolations into recipients belonging to alpha-, beta- and gamma-Proteobacteria from all environments except for soil. A high proportion of the MGE, conferring Gm resistance isolated from sewage, were identified as IncPbeta plasmids. Molecular detection of Gm(r) genes, and broad host range plasmid-specific sequences (IncP-1, IncN, IncW and IncQ) in environmental DNA indicated a habitat-specific dissemination. A high abundance and diversity of Gm(r) genes could be shown for samples from faeces (broilers, layers, cattle), from sewage, from seawater, collected close to a wastewater outflow, and from piggery manure. In the latter samples all six clusters of Gm(r) genes could be detected. The different kinds of selective pressure studied here seemed to enhance the abundance of MGE, while an effect on Gm(r) genes was not obvious.


Segmentation of dental cone-beam CT scans affected by metal artifacts using a mixed-scale dense convolutional neural network.
In order to attain anatomical models, surgical guides and implants for computer-assisted surgery, accurate segmentation of bony structures in cone-beam computed tomography (CBCT) scans is required. However, this image segmentation step is often impeded by metal artifacts. Therefore, this study aimed to develop a mixed-scale dense convolutional neural network (MS-D network) for bone segmentation in CBCT scans affected by metal artifacts. Training data were acquired from 20 dental CBCT scans affected by metal artifacts. An experienced medical engineer segmented the bony structures in all CBCT scans using global thresholding and manually removed all remaining noise and metal artifacts. The resulting gold standard segmentations were used to train an MS-D network comprising 100 convolutional layers using far fewer trainable parameters than alternative convolutional neural network (CNN) architectures. The bone segmentation performance of the MS-D network was evaluated using a leave-2-out scheme and compared with a clinical snake evolution algorithm and two state-of-the-art CNN architectures (U-Net and ResNet). All segmented CBCT scans were subsequently converted into standard tessellation language (STL) models and geometrically compared with the gold standard. CBCT scans segmented using the MS-D network, U-Net, ResNet and the snake evolution algorithm demonstrated mean Dice similarity coefficients of 0.87 ± 0.06, 0.87 ± 0.07, 0.86 ± 0.05, and 0.78 ± 0.07, respectively. The STL models acquired using the MS-D network, U-Net, ResNet and the snake evolution algorithm demonstrated mean absolute deviations of 0.44 mm ± 0.13 mm, 0.43 mm ± 0.16 mm, 0.40 mm ± 0.12 mm and 0.57 mm ± 0.22 mm, respectively. In contrast to the MS-D network, the ResNet introduced wave-like artifacts in the STL models, whereas the U-Net incorrectly labeled background voxels as bone around the vertebrae in 4 of the 9 CBCT scans containing vertebrae. The MS-D network was able to accurately segment bony structures in CBCT scans affected by metal artifacts.


Using Balanced Time Perspective to Explain Well-Being and Planning in Retirement.
The notion of whether people focus on the past, present or future, and how it shapes their behavior is known as Time Perspective. Fundamental to the work of two of its earliest proponents, Zimbardo and Boyd (2008), was the concept of balanced time perspective and its relationship to wellness. A person with balanced time perspective can be expected to have a flexible temporal focus of mostly positive orientations (past-positive, present-hedonistic, and future) and much less negative orientations (past-negative and present-fatalistic). This study measured deviation from balanced time perspective (DBTP: Zhang et al., 2013) in a sample of 243 mature adults aged 45 to 91 years and explored relationships to Retirement Planning, Depression, Anxiety, Stress, Positive Mood, and Negative Mood. Results indicate that DBTP accounts for unexplained variance in the outcome measures even after controlling for demographic variables. DBTP was negatively related to Retirement Planning and Positive Mood and positively related to Depression, Anxiety, Stress, and Negative Mood. Theoretical and practical implications regarding balanced time perspective are discussed.


White blood cell count and clinical outcomes after intracerebral hemorrhage: The INTERACT2 trial.
Increased inflammatory reaction can aggravate brain injury after acute intracerebral hemorrhage, but the clinical effect of such response is not fully understood. The aim of this study was to determine associations of peripheral white blood cell (WBC) count on clinical outcome among participants of the INTERACT2 study. INTERACT2 was a randomized controlled trial of early intensive (target systolic level<140 mm Hg) compared to guideline-recommended (target systolic level < 180 mm Hg) blood pressure (BP) lowering in 2839 patients with acute ICH (<6h) and elevated systolic BP (150-220 mm Hg). Blood samples were collected on admission and WBC count was measured at local laboratories. The primary outcome was death or major disability, defined by scores 3-6 on the modified Rankin Scale at 90 days. Secondary outcome was death at 90 days. Associations of baseline WBC count and outcomes were evaluated in logistic regression models. INTERACT2 is registered with http://www.clinicaltrials.gov NCT00716079. There were 2630 participants with relevant data who were classified into quartiles of WBC counts (≤ 6.22, 6.24-7.89, 7.90-10.17, and ≥ 10.20 × 10(9)/L, respectively). Increased WBC count was associated with younger age, elevated body temperature, increased glucose level, stroke severity, larger baseline hematoma volume, and intraventricular extension. Risks of death or major disability at 90 days increased progressively with higher WBC count: frequencies of 49.9%, 52.0%, 52.3% and 58.1% for quartile groups, respectively (P=0.004 for trend). However, after adjustment for baseline clinical and imaging variables including age, sex, region, lipid lowering therapy, body temperature, glucose, systolic BP, heart rate, high NIHSS scores, volume and location of hematoma, intraventricular extension, time from onset to CT scan, and randomized treatment, the association between WBC count and primary outcome was no longer significant (P=0.426 for trend). Patients with increased WBC count had significantly higher risk of death (P=0.0003 for trend), but again the association was no longer significant after adjustment for baseline clinical and imaging variables. Elevated WBC count on admission is not an independent prognostic variable in patients with acute ICH.


Experimental and feasibility assessment of biogas production by anaerobic digestion of fruit and vegetable waste from Joburg Market.
Substrate-induced instability of anaerobic digestion from fruit and vegetable waste (FVW) results in low biogas yield. In this study, substrate management through fruit to vegetable mix ratio in a two-stage semi-continuous digester was investigated as a pathway for optimality of yield. The experiment conducted over 105 days with 62.52 kg of FVWs sourced from Joburg Market, South Africa showed that a stable process was achieved at a fruit to vegetable waste mix ratio of 2.2:2.8. At this ratio, optimal organic loading rate ranged between 2.68 and 2.97 kg VS/m3-d which resulted in a specific biogas yield of 0.87 Nm3/kg VS with 57.58% methane on average. The results of the experimental study were used as a feasibility assessment for a full-scale 45 tonnes/d plant for Joburg Market considering three energy pathways. The plant will produce 1,605,455 Nm3/y of biogas with the potential for offsetting 15.2% of the Joburg Market energy demand. Conversion of all biogas to biomethane was the most economically attractive energy pathway with a net present value of $2,428,021, an internal rate of return of 16.90% and a simple payback period of 6.17 years. This route avoided the greenhouse gas emission of 12,393 tonnes CO2, eq. The study shows that the anaerobic digestion of FVWs as sole substrate is possible with financial and environmental attractiveness.


Synthesis of globin RNA in enucleated differentiating murine erythroleukemia cells.
In an earlier report (Volloch, V., 1986, Proc. Natl. Acad. Sci. USA., 83:1208-1212) we had presented evidence for the occurrence of the cytoplasmic synthesis of globin mRNA and of RNA complementary to globin mRNA which differed from DNA-dependent transcription by its insensitivity to actinomycin D. In this paper, we describe the use of enucleated differentiating mouse erythroleukemia cells to demonstrate directly the occurrence of cytoplasmic synthesis of both positive- and negative-strand globin RNA. For this purpose, we developed an enucleation procedure which yielded pure cytoplasts from differentiated mouse erythroleukemia cells in the absence of cytochalasin B and selectively permeabilized the cytoplasts to small molecules by treatment with dextran sulfate and saponin. The permeabilized cytoplasts incorporated [3H]dUTP into positive- and negative-strand globin RNA and experiments with mercurated nucleotide substrate suggested that this process involved de novo RNA synthesis rather than limited terminal nucleotide addition. Globin RNA synthesis required Mg++, was inhibited by Mn++, and was unaffected by the addition of Zn++. Studies of its response to inhibitors of DNA-dependent RNA synthesis showed that it differed from that process in its insensitivity to actinomycin D and alpha-amanitin, but that like many other macromolecular biosynthetic reactions it was inhibited by rifamycin AF/ABDP and aurintricarboxylic acid. These observations provide additional evidence for the occurrence of cytoplasmic RNA-dependent RNA synthesis in differentiated cells and show permeabilized enucleated cells to be a useful experimental system for further studies of the characteristics of that process.