Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM): a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial.
Men who are overweight or obese frequently have low serum testosterone concentrations, which are associated with increased risk of type 2 diabetes. We aimed to determine whether testosterone treatment prevents progression to or reverses early type 2 diabetes, beyond the effects of a community-based lifestyle programme. T4DM was a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial done at six Australian tertiary care centres. Men aged 50-74 years, with a waist circumference of 95 cm or higher, a serum testosterone concentration of 14·0 nmol/L or lower but without pathological hypogonadism, and impaired glucose tolerance (oral glucose tolerance test [OGTT] 2-h glucose 7·8-11·0 mmol/L) or newly diagnosed type 2 diabetes (provided OGTT 2-h glucose ≤15·0 mmol/L) were enrolled in a lifestyle programme and randomly assigned (1:1) to receive an intramuscular injection of testosterone undecanoate (1000 mg) or placebo at baseline, 6 weeks, and then every 3 months for 2 years. Randomisation was done centrally, including stratification by centre, age group, waist circumference, 2-h OGTT glucose, smoking, and first-degree family history of type 2 diabetes. The primary outcomes at 2 years were type 2 diabetes (2-h OGTT glucose ≥11·1 mmol/L) and mean change from baseline in 2-h OGTT glucose, assessed by intention to treat. For safety assessment, we did a masked monitoring of haematocrit and prostate-specific antigen, and analysed prespecified serious adverse events. This study is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12612000287831. Between Feb 5, 2013, and Feb 27, 2017, of 19 022 men who were pre-screened, 1007 (5%) were randomly assigned to the placebo (n=503) and testosterone (n=504) groups. At 2 years, 2-h glucose of 11·1 mmol/L or higher on OGTT was reported in 87 (21%) of 413 participants with available data in the placebo group and 55 (12%) of 443 participants in the testosterone group (relative risk 0·59, 95% CI 0·43 to 0·80; p=0·0007). The mean change from baseline 2-h glucose was -0·95 mmol/L (SD 2·78) in the placebo group and -1·70 mmol/L (SD 2·47) in the testosterone group (mean difference -0·75 mmol/L, -1·10 to -0·40; p<0·0001). The treatment effect was independent of baseline serum testosterone. A safety trigger for haematocrit greater than 54% occurred in six (1%) of 484 participants in the placebo group and 106 (22%) of 491 participants in the testosterone group, and a trigger for an increase of 0·75 μg/mL or more in prostate-specific antigen occurred in 87 (19%) of 468 participants in the placebo group and 109 (23%) of 480 participants in the testosterone group. Prespecified serious adverse events occurred in 37 (7·4%, 95% CI 5·4 to 10·0) of 503 patients in the placebo group and 55 (10·9%, 8·5 to 13·9) of 504 patients in the testosterone group. There were two deaths in each group. Testosterone treatment for 2 years reduced the proportion of participants with type 2 diabetes beyond the effects of a lifestyle programme. Increases in haematocrit might be treatment limiting. Longer-term durability, safety, and cardiovascular effects of the intervention remain to be further investigated. Australian National Health and Medical Research Council, Bayer, Eli Lilly, University of Adelaide, and WW (formerly Weight Watchers).


Cooperation of spike timing-dependent and heterosynaptic plasticities in neural networks: a Fokker-Planck approach.
It is believed that both Hebbian and homeostatic mechanisms are essential in neural learning. While Hebbian plasticity selectively modifies synaptic connectivity according to activity experienced, homeostatic plasticity constrains this change so that neural activity is always within reasonable physiological limits. Recent experiments reveal spike timing-dependent plasticity (STDP) as a new type of Hebbian learning with high time precision and heterosynaptic plasticity (HSP) as a new homeostatic mechanism acting directly on synapses. Here, we study the effect of STDP and HSP on randomly connected neural networks. Despite the reported successes of STDP to account for neural activities at the single-cell level, we find that, surprisingly, at the network level, networks trained using STDP alone cannot seem to generate realistic neural activities. For instance, STDP would stipulate that past sensory experience be maintained forever if it is no longer activated. To overcome this difficulty, motivated by the fact that HSP can induce strong competition between sensory experiences, we propose a biophysically plausible learning rule by combining STDP and HSP. Based on the Fokker-Planck theory and extensive numerical computations, we demonstrate that HSP and STDP operated on different time scales can complement each other, resulting in more realistic network activities. Our finding may provide fresh insight into the learning mechanism of the brain.


DNA damage in the elderly is associated with 5-MTHF levels: a pro-oxidant activity.
The aging phenomenon is associated with oxidative stress damage in biomolecules, especially DNA. 5-Methyltetrahydrofolate (5-MTHF), the active folate form, plays a pivotal role in maintaining genomic integrity. However, recently it was associated with cancer development. In Brazil, there are folic acid enriched foods, such as flour, making the general population chronically exposed to folates. Therefore, the aim of this study was to investigate whether erythrocytes 5-MTHF levels were associated with age-related DNA damage in two groups (elderly and young subjects). Additionally, a study in Caenorhabditis elegans, an in vivo alternative model, was performed to verify if 5-MTHF presents a pro-oxidant effect. A total of 50 elderly and 25 young subjects participated in this study, which analyzed whole blood DNA damage, plasma carbonyl proteins (PCO), and erythrocytes 5-MTHF levels. In addition, ROS and RNS production, survival rate, and lifespan were performed in C. elegans exposed to 5-MTHF. Blood 5-MTHF levels and DNA damage were increased in the elderly compared to the young group. A positive association was found between 5-MTHF levels and DNA damage, and between DNA damage and PCO levels, suggesting an oxidative cause of damage associated with the active folate form. In an experimental study it was observed that 5-MTHF increased ROS production in C. elegans, in a dose dependent manner, while survival rate and life span were not affected at the test doses. These findings suggest that 5-MTHF, the active folate form, may be involved in DNA damage in the elderly. This damage could be a result of oxidative stress, as observed in the in vivo alternative model; however, more studies are necessary to prove our present results.


Hypothyroidism and risks of cerebrovascular complications among patients with head and neck cancer after radiotherapy.
Hypothyroidism (HT) and carotid artery stenosis (CAS) are complications of radiotherapy (RT) in patients with head and neck cancer (HNC). The impact of post-RT HT on CAS progression remains unclear. Between 2013 and 2014, HNC patients who had ever received RT and were under regular follow-up in our hospital were initially screened. Patients were categorized into euthyroid (EU) and HT groups. Details of RT and HNC were recorded. Total plaque scores and degrees of CAS were measured during annual extracranial duplex follow-up. Patients were monitored for CAS progression to > 50 % stenosis or ischemic stroke (IS). Cumulative time to CAS progression and IS between the 2 groups were compared. Data were further analyzed based on the use or nonuse of thyroxine of the HT group. 333 HNC patients with RT history were screened. Finally, 216 patients were recruited (94 and 122 patients in the EU and HT groups). Patients of the HT group received higher mean RT doses (HT vs. EU; 7021.55 ± 401.67 vs. 6869.69 ± 425.32 centi-grays, p = 0.02). Multivariate Cox models showed comparable CAS progression (p = 0.24) and IS occurrence (p = 0.51) between the 2 groups. Moreover, no significant difference was observed in time to CAS progression (p = 0.49) or IS (p = 0.31) among patients with EU and HT using and not using thyroxine supplement. Our results did not demonstrate significant effects of HT and thyroxine supplementation on CAS progression and IS incidence in patients with HNC after RT.


Transcranial Direct Current Stimulation Effects on Semantic Processing in Healthy Individuals.
Semantic processing allows us to use conceptual knowledge about the world. It has been associated with a large distributed neural network that includes the frontal, temporal and parietal cortices. Recent studies using transcranial direct current stimulation (tDCS) also contributed at investigating semantic processing. The goal of this article was to review studies investigating semantic processing in healthy individuals with tDCS and discuss findings from these studies in line with neuroimaging results. Based on functional magnetic resonance imaging studies assessing semantic processing, we predicted that tDCS applied over the inferior frontal gyrus, middle temporal gyrus, and posterior parietal cortex will impact semantic processing. We conducted a search on Pubmed and selected 27 articles in which tDCS was used to modulate semantic processing in healthy subjects. We analysed each article according to these criteria: demographic information, experimental outcomes assessing semantic processing, study design, and effects of tDCS on semantic processes. From the 27 reviewed studies, 8 found main effects of stimulation. In addition to these 8 studies, 17 studies reported an interaction between stimulus types and stimulation conditions (e.g. incoherent functional, but not instrumental, actions were processed faster when anodal tDCS was applied over the posterior parietal cortex as compared to sham tDCS). Results suggest that regions in the frontal, temporal, and parietal cortices are involved in semantic processing. tDCS can modulate some aspects of semantic processing and provide information on the functional roles of brain regions involved in this cognitive process.


Distinction of brain tissue, low grade and high grade glioma with time-resolved fluorescence spectroscopy.
Neuropathology frozen section diagnoses are difficult in part because of the small tissue samples and the paucity of adjunctive rapid intraoperative stains. This study aims to explore the use of time-resolved laser-induced fluorescence spectroscopy as a rapid adjunctive tool for the diagnosis of glioma specimens and for distinction of glioma from normal tissues intraoperatively. Ten low grade gliomas, 15 high grade gliomas without necrosis, 6 high grade gliomas with necrosis and/or radiation effect, and 14 histologically uninvolved "normal" brain specimens are spectroscopicaly analyzed and contrasted. Tissue autofluorescence was induced with a pulsed Nitrogen laser (337 nm, 1.2 ns) and the transient intensity decay profiles were recorded in the 370-500 nm spectral range with a fast digitized (0.2 ns time resolution). Spectral intensities and time-dependent parameters derived from the time-resolved spectra of each site were used for tissue characterization. A linear discriminant analysis diagnostic algorithm was used for tissue classification. Both low and high grade gliomas can be distinguished from histologically uninvolved cerebral cortex and white matter with high accuracy (above 90%). In addition, the presence or absence of treatment effect and/or necrosis can be identified in high grade gliomas. Taking advantage of tissue autofluorescence, this technique facilitates a direct and rapid investigation of surgically obtained tissue.


Interfacial study of clathrates confined in reversed silica pores.
Storing methane in clathrates is one of the most promising alternatives for transporting natural gas (NG) as it offers similar gas densities to liquefied and compressed NG while offering lower safety risks. However, the practical use of clathrates is limited given the extremely low temperatures and high pressures necessary to form these structures. Therefore, it has been suggested to confine clathrates in nanoporous materials, as this can facilitate clathrate's formation conditions while preserving its CH4 volumetric storage. Yet, the choice of nanoporous materials to be employed as the clathrate growing platform is still rather arbitrary. Herein, we tackle this challenge in a systematic way by computationally exploring the stability of clathrates confined in alkyl-grafted silica materials with different pore sizes, ligand densities and ligand types. Based on our findings, we are able to propose key design criteria for nanoporous materials favoring the stability of a neighbouring clathrate phase, namely large pore sizes, high ligand densities, and smooth pore walls. We hope that the atomistic insight provided in this work will guide and facilitate the development of new nanomaterials designed to promote the formation of clathrates.


Differential role of melanocortins in mediating leptin's central effects on feeding and reproduction.
Leptin serves as a humoral link coupling the status of energy reserves to the functional activity of the reproductive system. Leptin is thought to act through melanocortinergic pathways in the brain to regulate ingestive behaviors; however, whether melanocortins mediate leptin's actions on the neuroendocrine-reproductive axis is unknown. We tested this hypothesis first by determining whether the effects of leptin on feeding behavior and reproduction in the ob/ob mouse could be blocked by the melanocortin receptor (MC-R) antagonist SHU9119 and second, by examining the effects of the MC-R agonist MTII on feeding and the endocrine-reproductive system. Administered by intracerebroventricular injections, leptin inhibited food intake, raised plasma gonadotropin levels, and increased seminal vesicle weights compared with controls; SHU9119 (intracerebroventricularly) attenuated leptin's effects on food intake and body weight but did not alter leptin's stimulatory effect on the reproductive axis. MTII (intracerebroventricularly and intraperitoneally) decreased food intake and increased body temperature compared with controls but had no effect on the reproductive-endocrine axis. These results suggest that although leptin acts centrally through melanocortinergic pathways to inhibit ingestive behaviors and stimulate metabolism, leptin's activational effect on the reproductive axis is likely to be mediated by other, unknown neuroendocrine circuits.


Advancement of analytical modes in a multichannel, microfluidic droplet-based sample chopper employing phase-locked detection.
In this work, we expand upon our recently developed droplet-based sample chopping concepts by introducing a multiplexed fluidic micro-chopper device (μChopper). Six aqueous input channels were integrated with a single oil input, and each of these seven channels was controlled by a pneumatic valve for automated sampling through software control. This improved design, while maintaining high precision in valve-based droplet generation at bandwidths of 0.03 to 0.05 Hz, enabled a variety of analytical modes to be employed on-chip compared to previous devices limited to sample/reference alternations. The device was analytically validated for real-time, continuous calibration with a single sample and five standards; multiplexed analysis during calibration using a mixed mode; and standard addition through spiking of six sample droplets with varying amounts of standard. Finally, the standard addition mode was applied to protein quantification in human serum samples using on-chip, homogeneous fluorescence immunoassays. Ultimately, with only ~1.2 μL of total analyzed solution volume- representing 100-fold and 75-fold reductions in reagent and serum volumes, respectively-we were able to generate full, six-point standard addition curves in only 1.5 min, and results correlated well with those from standard plate-reader equipment. This work thus exploited microfluidic valves for both their automation and droplet phase-locking capabilities, resulting in a micro-analytical tool capable of complex analytical interrogation modes on sub-microliter sample volumes while also leveraging drastic noise rejection via lock-in detection. The multichannel μChopper device should prove particularly useful in analyzing precious biological samples or for dynamic analyses at small volume scales.


Single-cell transcriptome analysis reveals coordinated ectopic gene-expression patterns in medullary thymic epithelial cells.
Expression of tissue-restricted self antigens (TRAs) in medullary thymic epithelial cells (mTECs) is essential for the induction of self-tolerance and prevents autoimmunity, with each TRA being expressed in only a few mTECs. How this process is regulated in single mTECs and is coordinated at the population level, such that the varied single-cell patterns add up to faithfully represent TRAs, is poorly understood. Here we used single-cell RNA sequencing and obtained evidence of numerous recurring TRA-co-expression patterns, each present in only a subset of mTECs. Co-expressed genes clustered in the genome and showed enhanced chromatin accessibility. Our findings characterize TRA expression in mTECs as a coordinated process that might involve local remodeling of chromatin and thus ensures a comprehensive representation of the immunological self.


An herbal formula inhibits STAT3 signaling and attenuates bone erosion in collagen-induced arthritis rats.
Receptor activator of NF-κB ligand (RANKL) facilitates differentiation of osteoclast precursors into osteoclasts, resulting in bone erosion in rheumatoid arthritis (RA) patients. Fibroblast-like synoviocytes (FLS) are the main cells for producing RANKL. Signal transducer and activator of transcription 3 (STAT3) signaling is activated in FLS of RA patients (RA-FLS), which has been linked to RANKL production. A two-herb formula (RL) comprising Rosae Multiflorae Fructus and Lonicerae Japonicae Flos is traditionally used for treating RA in China. We have found that a standardized ethanolic extract of RL (RLE for short) alleviates bone erosion in collagen-induced arthritis (CIA) rats. This study aimed to determine whether RLE inhibits RANKL production and osteoclastogenesis in cell and rat models, and to explore the involvement of the STAT3 pathway in this inhibition. A CIA rat model, interleukin-6/soluble interleukin-6 receptor (IL-6/sIL-6R)-stimulated RA-FLS and a co-culture system (IL-6/sIL-6R-stimulated RA-FLS/peripheral blood mononuclear cells) were used to evaluate the effects of RLE. Micro-computed tomography analysis was used to observe bone erosion in CIA rats. Tartrate-resistant acid phosphatase staining was used to evaluate osteoclastogenesis. Western blotting and ELISA assays were employed to examine protein levels. RT-qPCR was used to detect mRNA levels. STAT3-over-activated RA-FLS were used to investigate the involvement of STAT3 signaling in the anti-osteoclastogenic effects of RLE. RLE alleviated bone erosion in joints of CIA rats. In both synovial tissues of CIA rats and IL-6/sIL-6R-stimulated RA-FLS, RLE downregulated the protein level of RANKL. In the co-culture system, RLE significantly and dose-dependently inhibited IL-6/sIL-6R-induced osteoclastogenesis. Mechanistic studies revealed that RLE lowered the protein level of phospho-STAT3 (Tyr705) in synovial tissues of CIA rats. In IL-6/sIL-6R-stimulated RA-FLS, RLE inhibited the activation/phosphorylation of a STAT3 upstream kinase Janus kinase 2 (Tyr1007/1008) and STAT3 (Tyr705), decreased the nuclear localization of STAT3, lowered mRNA levels of STAT3-transcriptionally regulated genes IL-1β and TNF-α. RLE's inhibitory effects on RANKL production in RA-FLS gradually decreased when IL-6/sIL-6R doses increased. Over-activation of STAT3 diminished the inhibitory effects of RLE on RANKL production in IL-6/sIL-6R-stimulated RA-FLS, and attenuated the anti-osteoclastogenic effects of RLE in the co-culture system. We, for the first time, demonstrated that suppressing STAT3 signaling contributes to the inhibition of RANKL production and osteoclastogenesis, and thereby supports the mechanisms responsible for the reduction in bone erosion in RLE-treated CIA rats. This study provides further pharmacological groundwork for developing RLE as a modern anti-arthritic drug, and supports the notion that targeting STAT3 signaling is a viable strategy for managing bone erosion.


Analysis of Yersinia ruckeri strains isolated from trout farms in northwest Germany.
Enteric redmouth disease (ERM), caused by Yersinia ruckeri, is among the most important infectious diseases in rainbow trout Oncorhynchus mykiss aquaculture in Europe. Our aim was to analyse the persistence of Y. ruckeri strains in trout farms in northwest Germany and their dissemination between farms based on a detailed molecular and phenotypical characterisation scheme. The data on identification and characterisation of Y. ruckeri strains and examining the distribution of these strains in the field could serve as a basis for preventive disease monitoring plans. During the observation period from June 2011 until June 2012, we collected 48 Y. ruckeri isolates from 12 different rainbow trout hatcheries. In total, 44 (91.7%) of the isolates were non-motile; in particular, all isolates recovered during the sampling period in winter and early spring were non-motile. In several trout farms, characteristic farm-specific Y. ruckeri isolates from particular typing groups were isolated throughout the year, while in other farms, which had a trading relationship between each other, ERM outbreaks were caused by Y. ruckeri from the same typing group. Our data indicate that in some farms, the causative Y. ruckeri strains persisted in the respective trout farm. The presence of Y. ruckeri from the same typing group in farms with a trading relationship indicates a dissemination of the infection between the farms.


Activin signaling as an emerging target for therapeutic interventions.
After the initial discovery of activins as important regulators of reproduction, novel and diverse roles have been unraveled for them. Activins are expressed in various tissues and have a broad range of activities including the regulation of gonadal function, hormonal homeostasis, growth and differentiation of musculoskeletal tissues, regulation of growth and metastasis of cancer cells, proliferation and differentiation of embryonic stem cells, and even higher brain functions. Activins signal through a combination of type I and II transmembrane serine/threonine kinase receptors. Activin receptors are shared by multiple transforming growth factor-beta (TGF-beta) ligands such as myostatin, growth and differentiation factor-11 and nodal. Thus, although the activity of each ligand is distinct, they are also redundant, both physiologically and pathologically in vivo. Activin receptors activated by ligands phosphorylate the receptor-regulated Smads for TGF-beta, Smad2 and 3. The Smad proteins then undergo multimerization with the co-mediator Smad4, and translocate into the nucleus to regulate the transcription of target genes in cooperation with nuclear cofactors. Signaling through receptors and Smads is controlled by multiple mechanisms including phosphorylation and other posttranslational modifications such as sumoylation, which affect potein localization, stability and transcriptional activity. Non-Smad signaling also plays an important role in activin signaling. Extracellularly, follistatin and related proteins bind to activins and related TGF-beta ligands, and control the signaling and availability of ligands.The functions of activins through activin receptors are pleiotrophic, cell type-specific and contextual, and they are involved in the etiology and pathogenesis of a variety of diseases. Accordingly, activin signaling may be a target for therapeutic interventions. In this review, we summarize the current knowledge on activin signaling and discuss the potential roles of this pathway as a molecular target of therapy for metabolic diseases, musculoskeletal disorders, cancers and neural damages.


Income Disparities in Absolute Cardiovascular Risk and Cardiovascular Risk Factors in the United States, 1999-2014.
Large improvements in the control of risk factors for cardiovascular disease have been achieved in the United States, but it remains unclear whether adults in all socioeconomic strata have benefited equally. To assess temporal trends in 10-year predicted absolute cardiovascular risk and cardiovascular risk factors among US adults in different socioeconomic strata. A cross-sectional analysis was conducted using data on adults 40 to 79 years of age without established cardiovascular disease from the 1999 to 2014 National Health and Nutrition Examination Survey. Socioeconomic status was based on the family income to poverty ratio and participants were divided into the following 3 groups: high income (family income to poverty ratio, ≥4), middle income (>1 and <4), or at or below the federal poverty level (≤1). We assessed predicted absolute cardiovascular risk using the pooled cohort equation. We assessed the following 4 risk factors: systolic blood pressure, smoking status, diabetes, and total cholesterol. Of the 17 199 adults whose data were included in the study (8828 women and 8371 men; mean age, 54.4 years), from 1999-2014, trends in the percentage of adults with predicted absolute cardiovascular risk of 20% or more, mean systolic blood pressure, and the percentage of current smokers varied by income strata (P ≤ .02 for interaction). For adults with incomes at or below the federal poverty level, there was little evidence of a change in any of these outcomes across survey years (cardiovascular risk ≥20%, 14.9% [95% CI, 12.9%-16.8%] in 1999-2004; 16.5% [95% CI, 13.7%-19.2%] in 2011-2014; P = .41; mean systolic blood pressure, 127.6 [95% CI, 126.1-129.0] mm Hg in 1999-2004; 126.8 [95% CI, 125.2-128.5] mm Hg in 2011-2014; P = .44; and smoking, 36.5% [95% CI, 32.1%-41.0%] in 1999-2004; 36.0% [95% CI, 31.1%-40.8%] in 2011-2014; P = .87). For adults in the high-income stratum, these variables decreased across survey years (cardiovascular risk ≥20%, 12.0% [95% CI, 10.7%-13.3%] in 1999-2004; 9.5% [95% CI, 8.2%-10.7%] in 2011-2014; P = .003; systolic blood pressure, 126.0 [95% CI, 125.0-126.9] mm Hg in 1999-2004; 122.3 [95% CI, 121.3-123.3] mm Hg in 2011-2014; P < .001; and smoking, 14.1% [95% CI, 12.0%-16.2%] in 1999-2004; 8.8% [95% CI, 6.6%-11.0%] in 2011-2014; P = .001). Trends in the percentage of adults with diabetes and the mean total cholesterol level did not vary by income. Adults in each socioeconomic stratum have not benefited equally from efforts to control cardiovascular risk factors.


Cross-functional analysis of the Microviridae internal scaffolding protein.
The assembly of the viral structural proteins into infectious virions is often mediated by scaffolding proteins. These proteins are transiently associated with morphogenetic intermediates but not found in the mature particle. The genes encoding three Microviridae (phiX174, G4 and alpha3) internal scaffolding proteins (B proteins) have been cloned, expressed in vivo and assayed for the ability to complement null mutations of different Microviridae species. Despite divergence as great as 70% in amino acid sequence over the aligned length, cross-complementation was observed, indicating that these proteins are capable of directing the assembly of foreign structural proteins into infectious particles. These results suggest that the Microviridae internal scaffolding proteins may be inherently flexible. There was one condition in which a B protein could not cross-function. The phiX174 B protein cannot productively direct the assembly of the G4 capsid at temperatures above 21 degreesC. Under these conditions, assembly is arrested early in the morphogenetic pathway, before the first B protein mediated reaction. Two G4 mutants, which can productively utilize the phiX174 B protein at elevated temperatures, were isolated. Both mutations confer amino acid substitutions in the viral coat protein but differ in their relative abilities to utilize the foreign scaffolding protein. The more efficient substitution is located in a region where coat-scaffolding interactions have been observed in the atomic structure and may emphasize the importance of interactions in this region.


Fracture-related outcome study for operatively treated tibia shaft fractures (F.R.O.S.T.): registry rationale and design.
Tibial shaft fractures (TSFs) are among the most common long bone injuries often resulting from high-energy trauma. To date, musculoskeletal complications such as fracture-related infection (FRI) and compromised fracture healing following fracture fixation of these injuries are still prevalent. The relatively high complication rates prove that, despite advances in modern fracture care, the management of TSFs remains a challenge even in the hands of experienced surgeons. Therefore, the Fracture-Related Outcome Study for operatively treated Tibia shaft fractures (F.R.O.S.T.) aims at creating a registry that enables data mining to gather detailed information to support future clinical decision-making regarding the management of TSF's. This prospective, international, multicenter, observational registry for TSFs was recently developed. Recruitment started in 2019 and is planned to take 36 months, seeking to enroll a minimum of 1000 patients. The study protocol does not influence the clinical decision-making procedure, implant choice, or surgical/imaging techniques; these are being performed as per local hospital standard of care. Data collected in this registry include injury specifics, treatment details, clinical outcomes (e.g., FRI), patient-reported outcomes, and procedure- or implant-related adverse events. The minimum follow up is 12 months. Although over the past decades, multiple high-quality studies have addressed individual research questions related to the outcome of TSFs, knowledge gaps remain. The scarcity of data calls for an international high-quality, population-based registry. Creating such a database could optimize strategies intended to prevent severe musculoskeletal complications. The main purpose of the F.R.O.S.T registry is to evaluate the association between different treatment strategies and patient outcomes. It will address not only operative techniques and implant materials but also perioperative preventive measures. For the first time, data concerning systemic perioperative antibiotic prophylaxis, the influence of local antimicrobials, and timing of soft-tissue coverage will be collected at an international level and correlated with standardized outcome measures in a large prospective, multicenter, observational registry for global accessibility. ClinicalTrials.gov : NCT03598530 .


Neural response to emotional salience in schizophrenia.
Neuroimaging probes of brain regions implicated in emotion represent an important research strategy for understanding emotional dysfunction in schizophrenia. Anterior limbic structures, such as the ventral striatum and the amygdala, have been implicated in the pathophysiology of schizophrenia and the generation of emotional responses, although few studies to date have used emotion probes to target these areas in schizophrenia. With this goal in mind, emotionally salient visual images were used in a simple, nondemanding task. In all, 13 medicated, schizophrenic patients, five unmedicated patients, and 10 healthy volunteers viewed complex visual pictures and a nonsalient, blank screen while regional cerebral blood flow was measured with the [O-15] water technique. Pictures consisted of real world scenes with aversive, positive, and nonaversive content. Eye movements were recorded simultaneous with scan acquisition. Positron emission tomography images were analyzed for baseline, tonic activity, in addition to phasic changes ('activation') to salient stimuli. Lateral eye movement measures and on-line ratings showed good behavioral compliance with the task. Patients with schizophrenia showed impaired neural responses to salient stimuli in the right ventral striatum (VS), and they exhibited elevated tonic activity levels in the right VS and bilateral amygdala, inversely correlated with overall symptom severity. The patients also showed reduced modulation of visual cortex by salient stimuli. The results show that patients with schizophrenia exhibit impaired neural responses to emotionally salient stimuli in the VS, supporting a role for this structure in the pathophysiology of the illness. Reduced modulation of visual cortex by emotionally salient stimuli also suggests a failure to organize cerebral activity at a global level.


Sequence analysis of SARS-CoV-2 genome reveals features important for vaccine design.
As the SARS-CoV-2 pandemic is rapidly progressing, the need for the development of an effective vaccine is critical. A promising approach for vaccine development is to generate, through codon pair deoptimization, an attenuated virus. This approach carries the advantage that it only requires limited knowledge specific to the virus in question, other than its genome sequence. Therefore, it is well suited for emerging viruses, for which we may not have extensive data. We performed comprehensive in silico analyses of several features of SARS-CoV-2 genomic sequence (e.g., codon usage, codon pair usage, dinucleotide/junction dinucleotide usage, RNA structure around the frameshift region) in comparison with other members of the coronaviridae family of viruses, the overall human genome, and the transcriptome of specific human tissues such as lung, which are primarily targeted by the virus. Our analysis identified the spike (S) and nucleocapsid (N) proteins as promising targets for deoptimization and suggests a roadmap for SARS-CoV-2 vaccine development, which can be generalizable to other viruses.


Comparison of a new insertion element, IS1407, with established molecular markers for the characterization of Mycobacterium celatum.
Genomic analyses of 18 Mycobacterium celatum strains obtained from different patients in three countries (United States, United Kingdom, and France) were performed; the methods used in this study were restriction fragment length polymorphism (RFLP) analysis, pulsed-field gel electrophoresis (PFGE) analysis, and PCR restriction analysis (PRA) of the hsp-65 gene. A new insertion sequence, IS1407 (GenBank accession no. X97307), belonging to the IS256 family, was identified in M. celatum type 1 strains and was characterized by sequencing. When a probe for Mycobacterium xenopi IS1395-like sequences was used, the RFLP analysis of M. celatum type 1 strains revealed that they contained three or four copies of IS1407 in identical genomic positions, while this element was absent in all M. celatum type 2 strains. PFGE performed with three different endonucleases revealed a unique large restriction fragment (LRF) pattern for M. celatum type 1 strains, whereas the LRF patterns obtained for M. celatum type 2 strains were polymorphic. Moreover, PFGE of nondigested genomic DNA revealed extrachromosomal elements in M. celatum type 2. The type strain of M. celatum type 3 could not be differentiated from M. celatum type 1 strains on the basis of the results of the RFLP analysis, the PFGE analysis, and the PRA of IS1407. In this study we confirmed that M. celatum types 1 and 2 represent distinct genomic clusters and that the molecular markers in M. celatum type 2 exhibit greater polymorphism than the molecular markers in M. celatum type 1.


A phase II study of alpha-difluoromethylornithine (DFMO) for the treatment of metastatic melanoma.
Difluoromethylornithine (DFMO) is an irreversible enzyme-activated inhibitor of ornithine decarboxylase, a key enzyme in polyamine synthesis. We have screened for potential anti-cancer activity of DFMO using a clonogenic assay, which suggested that melanoma might have sensitivity to this agent. Accordingly, we have performed a phase II trial of DFMO (2 g/m2 po q 8 h) in 24 patients, 21 of whom were evaluable for response. One patient achieved a complete response of a large subcutaneous mass for 11 months. Although stabilization is frequently difficult to measure, seven patients appeared to stabilize previously active disease, with a median duration of response of eight weeks. Toxicity was significant and DFMO was discontinued in five patients due to side effects - hearing loss alone in four and hearing loss associated with thrombocytopenia in the fifth patient. Hearing changes occurred in ten patients. Other side effects were mild. These data indicate that DFMO as a single agent may be an effective therapy for melanoma. A phase II trial of DFMO in previously untreated patients using a different schedule to decrease hearing loss is warranted. Additionally, several in vitro and animal models suggest that DFMO plus interferon are synergistic, and this combination might be used for a clinical trial as well.


What are we asking for when requesting "Specialling" for the confused hospitalised older person? A concept analysis.
BACKGROUND AND/OR RATIONALE: "Specialling" is a common nursing practice in hospitals which entails the allocation of extra staff to be with an older person who is confused to maintain safety. Despite ongoing use, this practice has little evidence of effectiveness. To facilitate further investigation, a concept analysis of "specialling" was undertaken. The aim of this paper was to report on a concept analysis on the practice of "specialling" pertaining to older people who have cognitive impairment when in hospital. This study used Rodgers evolutionary approach to concept analysis to clarify the attributes, antecedents and consequences of the concept to determine a definition of "specialling." Web of Science (Core Collection and Web of Science Medline), CINAHL and SCOPUS databases were searched to identify relevant literature. Due to the scarcity of papers, the search was broadened to include all sources that could add understanding. A total of (n = 43) sources were identified. The attributes were themed to 5 categories: Labels and descriptions; the "Special" role; Patient safety; Patient care; and Communication. The antecedents to 2 themes: Patient characteristics; and Organisational risk. The consequences of "specialling" were diverse with 6 themes: the "Special" role; the Older persons experience; Costly; "Special" use and nursing beliefs; Safety outcomes; and Opportunities. The process of concept analysis provided a means to identify knowledge gaps and practice challenges. The definition determined from this analysis has provided a reflective opportunity for clinicians and researchers to consider when implementing care initiatives to support older people in hospital. Important is the lack of person-centred approaches and the opportunities in developing nurse leadership through empowerment. The findings from this analysis will inform a PhD study. Nurses have an opportunity to lead care improvements by ensuring person-centred approaches in the care of older people with cognitive impairment.


Fine mapping of leaf rust resistance gene LrZH84 using expressed sequence tag and sequence-tagged site markers, and allelism with other genes on wheat chromosome 1B.
Zhou 8425B, possessing the leaf rust resistance gene LrZH84, is an elite wheat (Triticum aestivum) parental line in the Yellow-Huai Valley region of China. In the present study, 2,086 F(2) plants derived from Zhou 8425B/Chinese Spring were used for fine mapping of LrZH84 with expressed sequence tag (EST) and sequence-tagged site (STS) markers. Seventy inter-simple sequence repeat EST and STS markers on 1BL were used to screen the two parents and resistant and susceptible bulks; those polymorphic were used to analyze the entire F(2) population. Three EST markers (BF474863, BE497107, and CD373538) were closely linked to LrZH84, with genetic distances of 0.7, 0.7, and 1.7 cM, respectively. STS marker Hbsf-1 was developed from the sequences of polymerase chain reaction fragments amplified from EST marker BF474863. LrZH84 was 8.19 cM proximal to Lr44, but may be allelic to LrXi and LrG98 although they showed different reactions with some Puccinia triticina pathotypes.


Cellular adaptation of the trapezius muscle in strength-trained athletes.
The aim of this study was to elucidate the cellular events that occur in the trapezius muscle following several years of strength training. In muscle biopsies from ten elite power lifters (PL) and six control subjects (C), several parameters were studied: cross-sectional area of muscle fibres, myosin heavy chain composition (MHC) and capillary supply [capillaries around fibres (CAF) and CAF/fibre area]. A method was also developed for counting the number of myonuclei and satellite cell nuclei. The proportion of fibres expressing MHC IIA, the cross-sectional area of each fibre type and the number of myonuclei, satellite cells and fibres expressing markers for early myogenesis were significantly higher in PL than in C (P<0.05). A significant correlation between the myonuclear number and the cross-sectional area was observed. Since myonuclei in mature muscle fibres are not able to divide, we suggest that the incorporation of satellite cell nuclei into muscle fibres resulted in the maintenance of a constant nuclear to cytoplasmic ratio. The presence of small diameter fibres expressing markers for early myogenesis indicates the formation of new muscle fibres.


The effects of the potent glucocorticoid budesonide on adhesion of eosinophils to human vascular endothelial cells and on endothelial expression of adhesion molecules.
An important early event in the formation of the allergic late-phase cellular infiltrate is the adhesion of eosinophils to vascular endothelium. Because glucocorticoids are potent inhibitors of this late-phase inflammatory reaction, we examined the effect of the glucocorticoid budesonide on in vitro adhesion of human eosinophils to cultured human umbilical vein endothelial cells (HUVEC). Pretreatment of eosinophils, HUVEC or both with budesonide (10(-7) M) did not inhibit either baseline adhesion or that stimulated by interleukin-1 beta (50 U/ml, 4 hr) or interleukin-4 (100 U/ml, 21-23 hr) or the leukocyte activators N-formyl-methionyl-leucyl-phenylalanine (10(-6) M, 10 min) or platelet-activating factor (10(-6) M, 10 min). Pretreatment of HUVEC with budesonide also failed to affect expression of the adhesion molecules E-selectin, intercellular adhesion molecule-1, or vascular cell adhesion molecule-1 on resting HUVEC or after stimulation with interleukin-1 beta (10 U/ml, 4 hr), tumor necrosis factor (6 U/ml, 4 hr) or interleukin-4 (50 U/ml, 24 hr). Because budesonide failed to inhibit stimulus-induced eosinophil adhesion responses or endothelial adhesion molecule expression, we speculate that glucocorticoids inhibit the formation of eosinophil-enriched tissue infiltrates by inhibiting the production rather than the activity of eosinophil- or endothelial-activating factors or by altering the survival of eosinophils in tissues.


Identification of Key Root Volatiles Signaling Preference of Tomato over Spinach by the Root Knot Nematode Meloidogyne incognita.
The root knot nematode, Meloidogyne incognita (Kofoid and White) Chitwood, is a serious pest of tomato ( Solanum lycopersicum) and spinach ( Spinacea oleracea) in sub-Saharan Africa. In East Africa these two crops are economically important and are commonly intercropped by smallholder farmers. The role of host plant volatiles in M. incognita interactions with these two commodities is currently unknown. Here, we investigate the olfactory basis of attraction of tomato and spinach roots by the infective second stage juveniles (J2s) of M. incognita. In olfactometer assays, J2s were attracted to root volatiles from both crops over moist sand (control), but in choice tests using the two host plants, volatiles of tomato roots were more attractive than those released by spinach. Root volatiles sampled by solid phase microextraction (SPME) fiber and analyzed by gas chromatography/mass spectrometry (GC/MS) identified a total of eight components, of which five (2-isopropyl-3-methoxypyrazine, 2-(methoxy)-3-(1-methylpropyl)pyrazine, tridecane, and α- and β-cedrene) occurred in the root-emitted volatiles of both plants, with three (δ-3-carene, sabinene, and methyl salicylate) being specific to tomato root volatiles. In a series of bioassays, methyl salicylate contributed strongly to the attractiveness of tomato, whereas 2-isopropyl-3-methoxypyrazine and tridecane contributed to the attractiveness of spinach. M. incognita J2s were also more attracted to natural spinach root volatiles when methyl salicylate was combined than to spinach volatiles alone, indicating that the presence of methyl salicylate in tomato volatiles strongly contributes to its preference over spinach. Our results indicate that since both tomato and spinach roots are attractive to M. incognita, identifying cultivars of these two plant species that are chemically less attractive can be helpful in the management of root knot nematodes.


Astrophysicists' conversational connections on Twitter.
Because Twitter and other social media are increasingly used for analyses based on altmetrics, this research sought to understand what contexts, affordance use, and social activities influence the tweeting behavior of astrophysicists. Thus, the presented study has been guided by three research questions that consider the influence of astrophysicists' activities (i.e., publishing and tweeting frequency) and of their tweet construction and affordance use (i.e. use of hashtags, language, and emotions) on the conversational connections they have on Twitter. We found that astrophysicists communicate with a variety of user types (e.g. colleagues, science communicators, other researchers, and educators) and that in the ego networks of the astrophysicists clear groups consisting of users with different professional roles can be distinguished. Interestingly, the analysis of noun phrases and hashtags showed that when the astrophysicists address the different groups of very different professional composition they use very similar terminology, but that they do not talk to each other (i.e. mentioning other user names in tweets). The results also showed that in those areas of the ego networks that tweeted more the sentiment of the tweets tended to be closer to neutral, connecting frequent tweeting with information sharing activities rather than conversations or expressing opinions.


Hepatitis B virus X protein-induced aberrant epigenetic modifications contributing to human hepatocellular carcinoma pathogenesis.
Hepatocellular carcinoma (HCC) remains one of the most prevalent malignant diseases worldwide, and the majority of cases are related to hepatitis B virus (HBV) infection. Interactions between the HBV-encoded X (HBx) protein and host factors are known to play major roles in the onset and progression of HBV-related HCC. These dynamic molecular mechanisms are extremely complex and lead to prominent changes in the host genetic and epigenetic architecture. This review summarizes the current knowledge about HBx-induced epigenetic changes, including aberrations in DNA methylation, histone modifications, and microRNA expression, and their roles in HBV-infected liver cells and HBV-related HCC. Moreover, the HBx-mediated epigenetic control of HBV covalently closed circular DNA (cccDNA) is also discussed. Although this field of study is relatively new, the accumulated evidence has indicated that the epigenetic events induced by HBx play important roles in the development of HBV-related HCC. Ongoing research will help to identify practical applications of the HBV-related epigenetic signatures as biomarkers for early HCC detection or as potential targets to prevent and treat HBV-related HCC.


Mindful Self-Care and Resiliency (MSCR): protocol for a pilot trial of a brief mindfulness intervention to promote occupational resilience in rural general practitioners.
The Mindful Self-Care and Resiliency (MSCR) programme is a brief psychosocial intervention designed to promote resilience among various occupational groups. The intervention is based on the principles of mindfulness and also incorporates an educational self-care component. The current paper presents the protocol for a pilot study that will evaluate the effectiveness of this programme among general practitioners working in rural Queensland, Australia. We will measure the impact of the MSCR programme on levels of employee resilience (Connor-Davidson Resilience Scale; State-Trait Assessment of Resilience STARS), compassion satisfaction and compassion fatigue (Professional Quality of Life Scale), self-compassion (Self-Compassion Scale) and mood (Positive and Negative Affect Scale). We will also assess the impact of the programme on job satisfaction (The Abridged Job in General Scale), absenteeism/presenteeism (The WHO Health and Work Performance Questionnaire) and general well-being (WHO Five Well-being Index). Repeated measures analysis of variance will be used to analyse the impact of the intervention on the outcome measures taken at pre, post, 1-month, 3-month and 6-month follow-ups. We will conduct individual interviews with participants to gather data on the feasibility and acceptability of the programme. Finally, we will conduct an initial cost-effectiveness analysis of the programme. Approval for this study was obtained from the Curtin University Human Research ethics committee and the study has been registered with the Australian Clinical Trials Registry. Results will be published and presented at national and international congresses. ACTRN12617001479392p; Pre-results.


Culturally relevant model program to prevent and reduce agricultural injuries.
Limited research has explored pesticide injury prevention among American Indian farmers. In a five-year agricultural intervention, a university-community partnership, including the University of New Mexico School of Medicine, New Mexico State University, Shiprock Area Cooperative Extension Service, and Navajo Nation communities, used a culturally relevant model to introduce and maintain safe use of integrated pest management techniques. We applied the Diffusion of Innovations theory and community-based approaches to tailor health promotion strategies for our intervention. In a longitudinal study with repeated measures, we trained six "model farmers" to be crop management experts in pesticide safety, application, and control. Subsequently, these model farmers worked with 120 farm families randomized into two groups: intervention (Group 1) and delayed intervention (Group 2). Measurements included a walk-through analysis, test of knowledge and attitudes, and yield analysis. Both groups demonstrated improvements in pesticide storage behaviors after training. Test scores regarding safety practices improved significantly: from 57.3 to 72.4 for Group 1 and from 52.6 to 76.3 for Group 2. Group 1 maintained their knowledge and safety practices after the intervention. Attitudes about pesticides and communication of viewpoints changed across the study years. With pesticides and fertilizer, the number of corn ears increased by 56.3% and yield (kg m(-2)) of alfalfa increased by 41.2%. The study combined traditional farming practices with culturally relevant approaches and behavior change theory to affect knowledge, safety practices, attitudes, communication channels, and crop yield. Storage behaviors, use of pesticides and safety and application equipment, and safety practice knowledge changed significantly, as did attitudes about social networking, social support, and the compatibility and relative advantage of pesticides for farms.


Mammalian peptidylglycine alpha-amidating monooxygenase mRNA expression can be modulated by the La autoantigen.
Peptidylglycine alpha-amidating monooxygenase (PAM; EC 18.104.22.168) catalyzes the COOH-terminal alpha-amidation of peptidylglycine substrates, yielding amidated products. We have previously reported a putative regulatory RNA binding protein (PAM mRNA-BP) that binds specifically to the 3' untranslated region (UTR) of PAM-mRNA. Here, the PAM mRNA-BP was isolated and revealed to be La protein using affinity purification onto a 3' UTR PAM RNA, followed by tandem mass spectrometry identification. We determined that the core binding sequence is approximately 15-nucleotides (nt) long and is located 471 nt downstream of the stop codon. Moreover, we identified the La autoantigen as a protein that specifically binds the 3' UTR of PAM mRNA in vivo and in vitro. Furthermore, La protein overexpression caused a nuclear retention of PAM mRNAs and resulted in the down-regulation of endogenous PAM activity. Most interestingly, the nuclear retention of PAM mRNA is lost upon expressing the La proteins that lack a conserved nuclear retention element, suggesting a direct association between PAM mRNA and La protein in vivo. Reporter assays using a chimeric mRNA that combined luciferase and the 3' UTR of PAM mRNA demonstrated a decrease of the reporter activity due to an increase in the nuclear localization of reporter mRNAs, while the deletion of the 15-nt La binding site led to their clear-cut cytoplasmic relocalization. The results suggest an important role for the La protein in the modulation of PAM expression, possibly by mechanisms that involve a nuclear retention and perhaps a processing of pre-PAM mRNA molecules.


Estimation of the basic reproduction number of BSE: the intensity of transmission in British cattle.
The basic reproduction number, R0, of an infectious agent is a key factor determining the rate of spread and the proportion of the host population affected. We formulate a general mathematical framework to describe the transmission dynamics of long incubation period diseases with complex pathogenesis. This is used to derive expressions for R0 of bovine spongiform encephalopathy (BSE) in British cattle, and back-calculation methods are used to estimate R0 throughout the time-course of the BSE epidemic. We show that the 1988 meat and bonemeal ban was effective in rapidly reducing R0 below 1, and demonstrate that this indicates that BSE will be unable to become endemic in the UK cattle population even when case clustering is taken into account. The analysis provides some insight into absolute infectiousness for bovine-to-bovine transmission, indicating maximally infectious animals may have infected up to 400 animals each. The relationship between R0 and the early stages of the BSE epidemic and the requirements for additional research are also discussed.


A common class of transcripts with 5'-intron depletion, distinct early coding sequence features, and N1-methyladenosine modification.
Introns are found in 5' untranslated regions (5'UTRs) for 35% of all human transcripts. These 5'UTR introns are not randomly distributed: Genes that encode secreted, membrane-bound and mitochondrial proteins are less likely to have them. Curiously, transcripts lacking 5'UTR introns tend to harbor specific RNA sequence elements in their early coding regions. To model and understand the connection between coding-region sequence and 5'UTR intron status, we developed a classifier that can predict 5'UTR intron status with >80% accuracy using only sequence features in the early coding region. Thus, the classifier identifies transcripts with 5' proximal-intron-minus-like-coding regions ("5IM" transcripts). Unexpectedly, we found that the early coding sequence features defining 5IM transcripts are widespread, appearing in 21% of all human RefSeq transcripts. The 5IM class of transcripts is enriched for non-AUG start codons, more extensive secondary structure both preceding the start codon and near the 5' cap, greater dependence on eIF4E for translation, and association with ER-proximal ribosomes. 5IM transcripts are bound by the exon junction complex (EJC) at noncanonical 5' proximal positions. Finally, N1-methyladenosines are specifically enriched in the early coding regions of 5IM transcripts. Taken together, our analyses point to the existence of a distinct 5IM class comprising ∼20% of human transcripts. This class is defined by depletion of 5' proximal introns, presence of specific RNA sequence features associated with low translation efficiency, N1-methyladenosines in the early coding region, and enrichment for noncanonical binding by the EJC.


Association of ACE inhibitors and angiotensin receptor blockers with keratinocyte cancer prevention in the randomized VATTC trial.
The observation that angiotensin II is a potent angiogenic and growth factor raises the possibility that blocking its effects could reduce the incidence of cancer. We evaluated associations between use of angiotensin-converting enzyme (ACE) inhibitors and of angiotensin receptor blockers (ARBs) and keratinocyte cancer incidence in a population at high risk of the disease. A cohort study design was conducted using data on 1051 participants in the randomized Department of Veterans Affairs Topical Tretinoin Chemoprevention (VATTC) Trial, all of whom were at increased risk of basal cell carcinoma (BCC) or squamous cell carcinoma (SCC). We followed participants from enrollment (November 1998 through January 2003) until first BCC or SCC. Study participants were examined every 6 months by a study dermatologist; biopsies were taken on all suspicious lesions and centrally reviewed. Use of ACE inhibitors and ARBs was ascertained from VA pharmacy records. Cox proportional hazards models were used to estimate adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) of BCC and SCC with use of ACE inhibitors or ARBs. During a median follow-up of 3.4 years, 472 incident BCCs, 309 SCCs, and 200 deaths from any cause were observed. Compared with nonusers, users of ACE inhibitors or ARBs had statistically significantly reduced risks of BCC (IRR(BCC) = 0.61, 95% CI = 0.50 to 0.76) and SCC (IRR(SCC) = 0.67, 95% CI = 0.52 to 0.87). The combined absolute incidence rates of BCC and SCC were 237 per 1000 person-years among users of ACE inhibitors or ARBs and 374 per 1000 person-years among nonusers. The greatest reduction in keratinocyte cancer was seen among people who initiated use of ACE inhibitors or ARBs during the study period (IRR(BCC) = 0.45 [95% CI = 0.34 to 0.59]; IRR(SCC) = 0.48 [95% CI = 0.35 to 0.67]). Among a high-risk group of veterans, users of ACE inhibitors or ARBs had a lower incidence of keratinocyte cancers than nonusers. The more pronounced reduction among those who initiated use during the study may indicate an immediate effect.


Current strategies of secondary prevention after a cerebrovascular event: the Vienna stroke registry.
Oral anticoagulation (OAC) and antiplatelet drugs are effective in the secondary prevention of ischemic cerebrovascular events. Only few data exist about the factors influencing the choice of a specific therapy for secondary prevention in patients with a recent stroke or transient ischemic attack (TIA). Within a cross-sectional study, nested in a cohort we identified 931 patients with a recent ischemic stroke or TIA who were discharged with OAC or with one of the antiplatelet medications aspirin, clopidogrel, or the combination of aspirin and extended-release dipyridamole. By means of multivariate logistic regression analysis, we determined the influence of several clinical variables on the decision between OAC and overall antiplatelet therapy as well as on the decision between different antiplatelet therapies. A cardioembolic etiology of the index event and atrial fibrillation were independently associated with the use of OAC. Age was inversely associated with the use of OAC. Different estimations of contraindications to OAC were the main reason for the considerable variability among the participating centers. The most important factor promoting the use of clopidogrel was therapy with aspirin before the index event. Patients with large- or small-vessel disease received clopidogrel more often than those with an event of undetermined etiology. We found an extremely high interhospital variability for the use of the combination of aspirin with extended-release dipyridamole. Current recommendations are applied in clinical practice, but great variability between different centers remains. More clearly defined guidelines for indications for, as well as contraindications against, a specific therapy are necessary.


Nuclear and nucleoid localization are independently conserved functions in bacteriophage terminal proteins.
Bacteriophage terminal proteins (TPs) prime DNA replication and become covalently linked to the DNA 5'-ends. In addition, they are DNA-binding proteins that direct early organization of phage DNA replication at the bacterial nucleoid and, unexpectedly, contain nuclear localization signals (NLSs), which localize them to the nucleus when expressed in mammalian cells. In spite of the lack of sequence homology among the phage TPs, these three properties share some common features, suggesting a possible evolutionary common origin of TPs. We show here that NLSs of three different phage TPs, Φ29, PRD1 and Cp-1, are mapped within the protein region required for nucleoid targeting in bacteria, in agreement with a previously proposed common origin of DNA-binding domains and NLSs. Furthermore, previously reported point mutants of Φ29 TP with no nuclear localization still can target the bacterial nucleoid, and Cp-1 TP contains two independent NLSs, only one of them required for nucleoid localization. Altogether, our results show that nucleoid and nucleus localization sequence requirements partially overlap, but they can be uncoupled, suggesting that conservation of both features could have a common origin but, at the same time, they have been independently conserved during evolution.


The impact of adult major trauma centre status on paediatric trauma activity.
The London Trauma Network was launched in April 2010 in order to centralise trauma care in the capital city. The consultation and resourcing of the four new major trauma centres (MTC) was adult focused. The objective of this study was to assess the impact that adult MTC status has on paediatric trauma workload. A retrospective review of paediatric major trauma calls was performed between 1 April 2009 to 31 January 2010, before MTC status, and the same time period in 2010/11 when St George's Healthcare Trust was a designated adult MTC. The following variables were assessed; number of trauma calls, admissions to hospital, radiological services usage, inpatient stay, mechanism of injury and injury severity score (ISS)--calculated from abbreviated injury score. There was a 200% increase in trauma calls between the two time periods and a 191% increase in admission to hospital. The usage of radiology increased 221% for CT and 161% for plain radiology. Mean inpatient stay decreased by 0.2 days. Mechanisms of injury were similar. Despite becoming a MTC the relative volume of major injuries (ISS>15) decreased between the two time periods by 1% with a relative increase in minor trauma (ISS<5) from 63% to 72%. These results may suggest at present paediatric trauma patients are being over triaged. Major adult trauma centre status has a significant effect on paediatric trauma workload and hence resources. When reconfiguration of trauma services are being considered it is essential to take into account the impact on paediatric services alongside those of the adult population.


Investigation of a staphylococcal food poisoning outbreak combining case-control, traditional typing and whole genome sequencing methods, Luxembourg, June 2014.
In June 2014, a staphylococcal food poisoning outbreak occurred at an international equine sports event in Luxembourg requiring the hospitalisation of 31 persons. We conducted a microbiological investigation of patients and buffet items, a case-control study and a carriage study of catering staff. Isolates of Staphylococcus aureus from patients, food and catering staff were characterised and compared using traditional typing methods and whole genome sequencing. Genotypically identical strains (sequence type ST8, spa-type t024, MLVA-type 4698, enterotoxin A FRI100) were isolated in 10 patients, shiitake mushrooms, cured ham, and in three members of staff. The case-control study strongly suggested pasta salad with pesto as the vehicle of infection (p<0.001), but this food item could not be tested, because there were no leftovers. Additional enterotoxigenic strains genetically unrelated to the outbreak strain were found in four members of staff. Non-enterotoxigenic strains with livestock-associated sequence type ST398 were isolated from three food items and two members of staff. The main cause of the outbreak is likely to have been not maintaining the cold chain after food preparation. Whole genome sequencing resulted in phylogenetic clustering which concurred with traditional typing while simultaneously characterising virulence and resistance traits.


Circulating adiponectin is inversely associated with risk of thyroid cancer: in vivo and in vitro studies.
Circulating adiponectin has been inversely associated with risk for several malignancies. Its association with thyroid cancer has not yet been evaluated. We measured circulating adiponectin levels in 175 thyroid carcinoma patients and 107 controls. We also examined the expression of adiponectin receptors (AdipoR1 and AdipoR2) using immunohistochemistry in 82 thyroid carcinoma tissues and using RT-qPCR in 40 human thyroid carcinoma tissues (32 papillary, six follicular/Hurthle, one anaplastic, one medullary), four normal human thyroid tissue specimens, and the BHP7 and SW579 thyroid cancer cell lines. We then utilized these thyroid cancer cell lines to investigate whether adiponectin could directly regulate cell cycle or apoptosis. Thyroid cancer patients had lower circulating adiponectin levels than controls (17.00 ± 6.32 vs. 19.26 ± 6.28 μg/ml; P < 0.001). Subjects in the highest tertile of circulating adiponectin concentrations had significantly lower odds of developing any type of thyroid carcinoma (odds ratio = 0.29; 95% confidence interval, 0.16-0.55), or papillary thyroid carcinoma (odds ratio = 0.27; 95% confidence interval, 0.14-0.55), before and after adjustment for potential confounders. Both thyroid carcinoma cell lines and tissues expressed AdipoR1 and AdipoR2. Recombinant adiponectin did not exert a clinically significant direct effect on cell cycle, proliferation, or apoptosis in thyroid cancer cell lines in vitro. Circulating adiponectin is independently and inversely associated with the risk of thyroid cancer. Human thyroid carcinomas and cell lines express adiponectin receptors. However, in the absence of a major direct effect of adiponectin on thyroid cancer cell lines in vitro, the negative association observed herein may be attributed to the metabolic effects of adiponectin.


Severe group a streptococcal soft-tissue infections in Ontario: 1992-1996.
A prospective, population-based, surveillance study of invasive soft-tissue infections due to group A streptococci was conducted in Ontario, Canada, from 1992 through 1996. Demographic and clinical information was obtained by patient interview and chart review. Isolates were characterized by M protein and T agglutination typing. The incidence of necrotizing fasciitis (NF) increased from 0.08 cases per 100,000 population in 1992 to 0.49 cases per 100,000 population in 1995. The case-fatality rate was 13% (68 of 520 patients died). Hypotension and multiorgan dysfunction complicated 64 cases (12%), and NF complicated 119 cases (23%). Underlying diabetes, alcohol abuse, cancer, and cardiac and pulmonary disease increased the risk of disease. Prior use of nonsteroidal anti-inflammatory agents did not influence disease severity. All 197 patients without NF, underlying illness, and hypotension at presentation survived, as did 95 (99%) of 96 normotensive patients who were <65 years old but who had underlying chronic illness. Previously healthy patients without hypotension or NF may be considered for outpatient treatment.


Nurse educators and the demands of research.
The purpose of this research was to study perceptions of baccalaureate nursing faculty regarding the pressures to publish and conduct research. The research was a nonexperimental, correlational, retrospective study. One hundred baccalaureate nurse educators completed a questionnaire that assessed their beliefs regarding the pressure to publish and their preferences between teaching and research. The majority of participants reported the perception of high to intense pressure to publish, the belief that they could remain current in nursing without a major focus on research, and the belief that the increased emphasis on research diminishes the quality of classroom instruction. The majority of participants would select a teaching-only career track if they could still be promoted and achieve tenure. Recommendations included broadening the definition of research to include the teaching and application of research, and the implementation of two career tracks with promotion and tenure opportunities.


An endothelin-1 induced model of optic nerve ischemia in the rabbit.
To evaluate blood flow reduction and topographic optic nerve changes after the local administration of endothelin-1 in vivo, delivered to the perineural region of the anterior optic nerve in the rabbit. Endothelin-1 (five rabbits) in a dosage of 0.1 microgram/day or balanced salt solution (two rabbits) was delivered to the perineural region of the anterior optic nerve with osmotically driven minipumps. Optic nerve blood flow was determined by the colored microspheres technique after 14 days of local endothelin-1 or balanced salt solution administration to the microvasculature of the optic nerve. In addition, optic nerve blood flow was determined in two rabbits that had no minipump implants. The morphologic changes induced by reduction of blood flow were assessed in five additional rabbits implanted with osmotically driven minipumps containing endothelin-1 (0.1 microgram/day). These rabbits were observed for 8 weeks, and the morphologic optic nerve changes were monitored with a confocal scanning laser ophthalmoscope. Independent of intraocular pressure, endothelin-1 induced a decrease in blood flow of approximately 38% in the experimental eye, compared to the decrease induced by balanced salt solution or to the decrease in rabbits without minipumps (analysis of covariance, P = 0.0092). Multivariate statistical analysis showed a significant change in topometric parameters (cup area, cup depth, rim volume) obtained with a confocal scanning laser ophthalmoscope, indicating an increase in optic nerve cupping and a decrease of the perineural rim volume in the experimental eyes (P = 0.017). The current results suggest that morphologic optic nerve alterations can be induced experimentally in the rabbit model after ischemia produced by the local administration of endothelin-1 to the perineural region of the anterior optic nerve.


Resolving Conflicts: Modeling Genetic Control of Plant Morphogenesis.
Computational modeling of tissue morphogenesis reveals how spatiotemporal patterns of gene activity control tissue shape by introducing several types of tissue conflict. These conflicts reflect genetic modulation of processes that influence the cellular mechanical properties and may underlie the enormous diversity of forms that have evolved in plants and animals.


Interactions of human mismatch repair proteins MutSalpha and MutLalpha with proteins of the ATR-Chk1 pathway.
At clinically relevant doses, chemotherapeutic S(N)1 DNA methylating agents induce an ATR-mediated checkpoint response in human cells that is dependent on functional MutSalpha and MutLalpha. Deficiency of either mismatch repair activity renders cells highly resistant to this class of drug, but the mechanisms linking mismatch repair to checkpoint activation have remained elusive. In this study we have systematically examined the interactions of human MutSalpha and MutLalpha with proteins of the ATR-Chk1 pathway using both nuclear extracts and purified proteins. Using nuclear co-immunoprecipitation, we have detected interaction of MutSalpha with ATR, TopBP1, Claspin, and Chk1 and interaction of MutLalpha with TopBP1 and Claspin. We were unable to detect interaction of MutSalpha or MutLalpha with Rad17, Rad9, or replication protein A in the extract system. Use of purified proteins confirmed direct interaction of MutSalpha with ATR, TopBP1, and Chk1 and of MutLalpha with TopBP1. MutSalpha-Claspin and MutLalpha-Claspin interactions were not demonstrable with purified proteins, suggesting that extract interactions are indirect or depend on post-translational modification. Use of a modified chromatin immunoprecipitation assay showed that proliferating cell nuclear antigen, ATR, TopBP1, and Chk1 are recruited to chromatin in a MutLalpha- and MutSalpha-dependent fashion after N-methyl-N'-nitro-N-nitrosoguanidine treatment. However, chromatin enrichment of replication protein A, Claspin, Rad17-RFC, and Rad9-Rad1-Hus1 was not detected in these experiments. Although our failure to observe enrichment of the latter activities could be due to sensitivity limitations, these observations may indicate a novel mechanism for ATR activation.


Chromosome translocation can occur on either side of the c-myc oncogene in Burkitt lymphoma cells.
In Burkitt lymphoma cells reciprocal chromosomal translocations are observed between the long arm of chromosome 8 (8q24) and either the long arm of chromosome 14 (14q32), the short arm of chromosome 2 (2p12) or the long arm of chromosome 22 (22q11). Gene mapping studies have shown that c-myc, the cellular homologue of the viral myc oncogene, is localized at 8q24 (ref 3-5) and that the three immunoglobulin gene loci map at the breakpoints involved in the translocation: immunoglobulin heavy-chain genes are located at 14q32 (refs 6, 7), kappa light chains at 2p12 (ref. 8) and delta light chains at, or close to, 22q11 (ref 9, 10). This correlation suggests an association of immunoglobulin gene rearrangements with the occurrence of these specific translocations. By using in situ hybridization we have examined the translocation point with respect to c-myc in two cell lines containing 2;8 translocation, and report here that the c-myc gene remains on the chromosome 8 involved in the reciprocal exchange with chromosome 2. We have also confirmed that the c-myc gene moves from the translocated chromosome 8 in a cell line having a 8;14 translocation. These results show that chromosomal breakage can occur on either side of the c-myc gene in Burkitt lymphoma cells.


Dynamics of Lgr6⁺ Progenitor Cells in the Hair Follicle, Sebaceous Gland, and Interfollicular Epidermis.
The dynamics and interactions between stem cell pools in the hair follicle (HF), sebaceous gland (SG), and interfollicular epidermis (IFE) of murine skin are still poorly understood. In this study, we used multicolor lineage tracing to mark Lgr6⁺ -expressing basal cells in the HF isthmus, SG, and IFE.We show that these Lgr6⁺ cells constitute long-term self-renewing populations within each compartment in adult skin. Quantitative analysis of clonal dynamics revealed that the Lgr6⁺ progenitor cells compete neutrally in the IFE, isthmus, and SG, indicating population asymmetry as the underlying mode of tissue renewal. Transcriptional profiling of Lgr6⁺ and Lgr6⁺ cells did not reveal a distinct Lgr6⁺ -associated gene expression signature, raising the question of whether Lgr6⁺ expression requires extrinsic niche signals. Our results elucidate the interrelation and behavior of Lgr6⁺ populations in the IFE, HF, and SG and suggest population asymmetry as a common mechanism for homeostasis in several epithelial skin compartments.


Individual Organ Failure and Concomitant Risk of Mortality Differs According to the Type of Admission to ICU - A Retrospective Study of SOFA Score of 23,795 Patients.
Organ dysfunction or failure after the first days of ICU treatment and subsequent mortality with respect to the type of intensive care unit (ICU) admission is poorly elucidated. Therefore we analyzed the association of ICU mortality and admission for medical (M), scheduled surgery (ScS) or unscheduled surgery (US) patients mirrored by the occurrence of organ dysfunction/failure (OD/OF) after the first 72h of ICU stay. For this retrospective cohort study (23,795 patients; DIVI registry; German Interdisciplinary Association for Intensive Care Medicine (DIVI)) organ dysfunction or failure were derived from the Sequential Organ Failure Assessment (SOFA) score (excluding the Glasgow Coma Scale). SOFA scores were collected on admission to ICU and 72h later. For patients with a length of stay of at least five days, a multivariate analysis was performed for individual OD/OF on day three. M patients had the lowest prevalence of cardiovascular failure (M 31%; ScS 35%; US 38%), and the highest prevalence of respiratory (M 24%; ScS 13%; US 17%) and renal failure (M 10%; ScS 6%; US 7%). Risk of death was highest for M- and ScS-patients in those with respiratory failure (OR; M 2.4; ScS 2.4; US 1.4) and for surgical patients with renal failure (OR; M 1.7; ScS 2.7; US 2.4). The dynamic evolution of OD/OF within 72h after ICU admission and mortality differed between patients depending on their types of admission. This has to be considered to exclude a systematic bias during multi-center trials.


Parent versus teacher ratings on the BRIEF-preschool version in children with and without ADHD.
Caregiver rating scales represent an important component of comprehensive child neuropsychological assessments for conditions such as Attention-deficit/Hyperactivity Disorder (ADHD); however, low inter-rater reliability (parent vs. teacher) often complicates interpretation. It has been challenging to identify the factors contributing to inter-rater variability, particularly when parents and teachers complete slightly different versions of the same rating scale. The present study examined the associations between parent- and teacher-reported executive functions in 84 children, ages 4-5 years, with and without symptoms of ADHD, using the Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P). Use of the BRIEF-P allows for direct comparison of symptom ratings because parents and teachers complete the exact same measure. Significant associations between raters were observed on 4 of 5 BRIEF-P subscales when rating children with ADHD, but on only 1 subscale when rating typically developing (TD) children. The Shift scale in particular displayed low, non-significant inter-rater association in both groups. Significant group-by-rater interactions were observed for Working Memory and Plan/Organize scales, and driven by larger inter-rater T-score discrepancies in the TD group, such that teachers rated children as having more symptoms than parents. Conversely, examination of raw scores reflected no significant rater differences in the TD group, but significant or nearly significant differences on multiple scales in the ADHD group, such that parents rated more symptoms than teachers. Inter-rater associations for the BRIEF-P appear to vary based on who is being rated (i.e., children with or without ADHD), the specific subscales, and whether standardized or raw scores are analyzed.


Effect of chronic treatment with the glucocorticoid antagonist RU 486 in man: toxicity, immunological, and hormonal aspects.
Suppression of immune function was traditionally thought to occur only with pharmacological levels of glucocorticoids. However, recent studies in rodents have suggested that glucocorticoids exert tonic antiinflammatory/immunosuppressive effects even at basal nonstress concentrations. To examine whether basal glucocorticoid secretion modulates immune function in man we employed the specific glucocorticoid receptor antagonist RU 486. If a tonic level of inhibition of the immune system by basal glucocorticoid levels was present, then a potentiation or enhancement of immune function might evolve in the absence of glucocorticoid action. To examine this hypothesis, we studied 11 healthy male normal volunteers who received RU 486 (10 mg/kg.day) or placebo vehicle, divided into 2 daily oral doses, for 7-14 days. Blood samples were collected every 2 days for measurement of plasma ACTH and cortisol concentrations along with 24-h urine samples for measurement of 17-hydroxysteroid and free cortisol excretion. Complete and differential blood counts, erythrocyte sedimentation rates, C-reactive protein, antinuclear antibodies, rheumatoid factor, and quantitative immunoglobulins were also determined at 2-day intervals. Leukocytes were obtained by leukopheresis for phenotypic characterization and functional analysis before and 7 days after the initiation of RU 486 or placebo therapy. Blockade of cortisol receptors with RU 486 was associated with marked compensatory elevations of plasma ACTH and cortisol and increases in 24-h urinary excretion of 17-hydroxysteroids and free cortisol. Unexpectedly, 8 of the 11 subjects developed generalized exanthem after 9 days of RU 486 treatment. One subject developed symptoms and signs consistent with the diagnosis of adrenal insufficiency. Total white blood cell counts, absolute lymphocyte, neutrophil and eosinophil counts, erythrocyte sedimentation rate, and quantitative immunoglobulins did not change with RU 486 therapy. Similarly, T-, B-, and natural killer cell subsets did not change during RU 486 treatment. Furthermore, functional evaluation of lymphocyte cytotoxicity and proliferation revealed no changes. We conclude that administration of high doses of RU 486 to normal volunteers does not result in measurable enhancement of immune function. This suggests that in man, glucocorticoids may not exert a tonic inhibitory effect on the immune system as they appear to do in rodents. Alternatively, the compensatory increase in endogenous cortisol may obviate any effect of the glucocorticoid antagonist on the immune system.(ABSTRACT TRUNCATED AT 400 WORDS)


hMLH1 and hMSH2 mutations in families with familial clustering of gastric cancer and hereditary non-polyposis colorectal cancer.
The pattern of hMLHI and hMSH2 mutations was assessed to identify the genetic correlation between hereditary gastric and colorectal cancers. Four disease groups and their healthy family members were assembled according to the presentation of gastric cancer: FG, familial clustering of gastric cancer (n = 32); CG, family with one or more colorectal and gastric cancers in first-degree relatives (n = 22); HS, seven HNPCC families corresponding to the Amsterdam criteria (AMS+) and 12 suspected HNPCC families which did not satisfy one of the criteria (AMS-), but no gastric cancer among first- and second-degree relatives (n = 19); and SG, sporadic gastric cancer (n = 33). In the CG group, three were included in AMS + and six in AMS- criteria. Peripheral blood was obtained from them to detect hMLHI and hMLH2 mutations using PCR-SSCP analysis and direct sequencing. The incidence of mutations was 9.4% in the FG group, 54.5% in the CG group, 31.6% in the HS group, and none in the SG group. The incidence, type, and number of the mutation were not different between the CG and HS groups. Thirty-four different mutations included 19 in hMLH1 and 15 in hMSH2. Gastric cancer was the most common extracolonic malignancy in HNPCC and suspected HNPCC families (9/28, 32.1%). The hMLH1 or hMSH2 mutation occurred in seven of 10 families with AMS+, whereas it occurred in four of 18 with AMS- (70% vs. 22.2%, P = .013). Five mutations in the hMLH1 and six mutations in the hMSH2 were exclusively found in families with gastric cancer. All three mutations in the FG group were in hMLHI and there was no mutation in their healthy family members. This study demonstrates that some familial clustering type of gastric cancer appears to be associated with hMLHI mutations thereby indicating a difference from the hereditary gastric cancer studies previously reported. In addition, hMLHI and hMSH2 mutations may impact the gastric cancer carcinogenesis in HNPCC or suspected HNPCC.


Virtual Reality: Beyond Visualization.
Virtual reality (VR) has recently become an affordable technology. A wide range of options are available to access this unique visualization medium, from simple cardboard inserts for smartphones to truly advanced headsets tracked by external sensors. While it is now possible for any research team to gain access to VR, we can still question what it brings to scientific research. Visualization and the ability to navigate complex three-dimensional data are undoubtedly a gateway to many scientific applications; however, we are convinced that data treatment and numerical simulations, especially those mixing interactions with data, human cognition, and automated algorithms will be the future of VR in scientific research. Moreover, VR might soon merit the same level of attention to imaging data as machine learning currently has. In this short perspective, we discuss approaches that employ VR in scientific research based on some concrete examples.


Central pattern generation involved in oral and respiratory control for feeding in the term infant.
Drinking and eating are essential skills for survival and benefit from the coordination of several pattern generating networks and their musculoskeletal effectors to achieve safe swallows. Oralpharyngoesophageal motility develops during infancy and early childhood, and is influenced by various factors, including neuromuscular maturation, dietary and postural habits, arousal state, ongoing illnesses, congenital anomalies, and the effects of medical or surgical interventions. Gastroesophageal reflux is frequent in neonates and infants, and its role in neonatal morbidity including dysphagia, chronic lung disease, or apparent life-threatening events is not well understood. This review highlights recent studies aimed at understanding the development of oral feeding skills, and cross-system interactions among the brainstem, spinal, and cerebral networks involved in feeding. Functional linkages between suck-swallow and swallow-respiration manifest transitional forms during late gestation through the first year of life, which can be delayed or modified by sensory experience or disease processes, or both. Relevant central pattern generator (CPG) networks and their neuromuscular targets attain functional status at different rates, which ultimately influences cross-system CPG interactions. Entrainment of trigeminal primary afferents accelerates pattern genesis for the suck CPG and transition-to-oral feed in the RDS preterm infant. The genesis of within-system CPG control for rate and amplitude scaling matures differentially for suck, mastication, swallow, and respiration. Cross-system interactions among these CPGs represent targets of opportunity for new interventions, which optimize experience-dependent mechanisms to promote safe swallows among newborn and pediatric patients.


Parents' reactions to participating in interviews about end-of-life decision making.
Although in-depth interviewing is well suited to studying the sensitive topic of end-of-life decision making, no reports have been published assessing the effects on parents of participating in interviews regarding end-of-life decision making for critically ill children. To examine the reactions of pediatric intensive care unit (PICU) patients' parents to interviews on end-of-life decision making for their child. We conducted semistructured interviews on end-of-life decision making with PICU patients' parents from two tertiary care PICUs. We approached 117 parents of 102 patients. Seventy-four parents (63%) of 69 patients participated. Forty-three parents (61%) described the interview as "a good experience," 20 (29%) as "a neutral experience," and 1 (1%) as "a bad experience." The parent who judged the interview negatively stated that, "It bothers me a little bit because my son is [out] there having difficulties and I'm in here and not out there." Fifty-four of 59 parents (92%) said they would participate in another similar interview. Most parents (92%) felt the medical community should continue research on end-of-life decision making. Themes identified from the responses included: emotional reaction to the interviews; exposure to end-of-life decision-making issues; impact on parents' views; and impact on future end-of-life decision making. Parents' comments suggested that many perceived the interviews as beneficial. This study demonstrates the willingness of many parents of critically ill children to participate in study interviews regarding end-of-life decision making, a topic that most parents felt was important and warranted more research.


Developing a dashboard to help measure and achieve the triple aim: a population-based cohort study.
Health system planners aim to pursue the three goals of Triple Aim: 1) reduce health care costs; 2) improve population health; and 3) improve the care experience. Moreover, they also need measures that can reliably predict future health care needs in order to manage effectively the health system performance. Yet few measures exist to assess Triple Aim and predict future needs at a health system level. The purpose of this study is to explore the novel application of a case-mix adjustment method in order to measure and help improve the Triple Aim of health system performance. We applied a case-mix adjustment method to a population-based analysis to assess its usefulness as a measure of health system performance and Triple Aim. The study design was a retrospective, cohort study of adults from Ontario, Canada using administrative databases: individuals were assigned a predicted illness burden score using a case-mix adjustment system from diagnoses and health utilization data in 2008, and then followed forward to assess the actual health care utilization and costs in the following year (2009). We applied the Johns Hopkins Adjusted Clinical Group (ACG) Case-Mix System to categorize individuals into 60 levels of healthcare need, called ACGs. The outcomes were: 1) Number of individuals per ACG; 2) Total system costs per ACG; and 3) Mean cost per person per ACG, which together formed a health system "dashboard". We identified 11.4 million adults. 16.1% were aged 65 or older, 3.2 million (28%) did not use health care services that year, and 45,000 (0.4%) were in the highest acuity ACG category using 12 times more than an average adult. The sickest 1%, 5% and 15% of the population use about 10%, 30% and 50% of total health system costs respectively. The dashboard measures 2 dimensions of Triple Aim: 1) reduced costs: when total system costs per ACG or when average costs per person is reduced; and 2) improved population health: when more people move into healthier rather than sicker ACGs. It can help to achieve the third aim, improved care experience, when ACG utilization predictions are reported to providers to proactively develop care plans. The dashboard, developed via case-mix methods, measures 2 of the Triple Aim goals and can help health system planners better manage their health delivery systems.


Role of stem cells during diabetic liver injury.
Diabetes mellitus is one of the most severe endocrine metabolic disorders in the world that has serious medical consequences with substantial impacts on the quality of life. Type 2 diabetes is one of the main causes of diabetic liver diseases with the most common being non-alcoholic fatty liver disease. Several factors that may explain the mechanisms related to pathological and functional changes of diabetic liver injury include: insulin resistance, oxidative stress and endoplasmic reticulum stress. The realization that these factors are important in hepatocyte damage and lack of donor livers has led to studies concentrating on the role of stem cells (SCs) in the prevention and treatment of liver injury. Possible avenues that the application of SCs may improve liver injury include but are not limited to: the ability to differentiate into pancreatic β-cells (insulin producing cells), the contribution for hepatocyte regeneration, regulation of lipogenesis, glucogenesis and anti-inflammatory actions. Once further studies are performed to explore the underlying protective mechanisms of SCs and the advantages and disadvantages of its application, there will be a greater understand of the mechanism and therapeutic potential. In this review, we summarize the findings regarding the role of SCs in diabetic liver diseases.


Treatment of mild hypertension in elderly males.
1. Males, born between 1900 and 1925, with mild hypertension have been treated for periods varying from 300 to 2000 days. 2. The life and death status of all patients (except two) was known on 1st November 1978. 3. A group of patients with mild hypertension receiving treatment based on a thiazide diuretic had a greater mortality than the other drug-treated group. 4. The increased mortality was caused by an increased number of myocardial infarcts. 5. Elderly male patients with mild hypertension probably have preexisting vascular disease and therapy should not automatically be started. If therapy is started, beta-adrenoreceptor-blocking drugs may be a preferred therapy.


Odontoid fractures: update on management.
Recognition of the incidence of odontoid fractures as well as the associated morbidity and unexpectedly high mortality rates has prompted significant changes in the management of these fractures in the past decade. Nonsurgical management of type II odontoid fracture has historically been associated with a high nonunion rate. Thus, new classification systems have been devised to identify patients who might benefit from early surgical treatment. The decision-making process is particularly difficult when treating elderly patients. Increased familiarity with anterior and posterior surgical techniques has led to more aggressive treatment of odontoid fracture, with the intent of hastening functional rehabilitation. However, these clinical decisions have been associated with a significant rate of complications. The treatment algorithm for odontoid fractures continues to evolve based on the improved understanding of, and evidence-based literature on, anterior screw fixation, posterior spinal fusion, and halo-vest immobilization.