Communication of prognosis in head and neck cancer patients; a descriptive qualitative analysis.
In shared decision making it is important to adequately, timely and actively involve patients in treatment decisions. Sharing prognostic information can be of key importance. This study describes whether and how prognostic information on life expectancy is included during communication on diagnosis and treatment plans between physicians and head and neck (H&N) oncologic patients in different phases of disease. A descriptive, qualitative study was performed of n = 23 audiotaped physician-patient conversations in which both palliative and curative treatment options were discussed and questions on prognosis were expected. Verbatim transcribed consultations were systematically analyzed. A distinction was made between prognostic information that was provided (a) quantitatively: by giving numerical probability estimates, such as percentages or years or (b) qualitatively: through the use of words such as 'most likely' or 'highly improbable'. In all consultations, H&N surgeons provided some prognostic information. In 5.9% of the provided prognostic information, a quantitative method was used. In 94.1% prognostic information was provided qualitatively, using six identified approaches. H&N surgeons possibly affect patients' perception of prognostic content with two identified communication styles: directive (more physician-centered) and affective (more patient-centered). This study is first in providing examples of how H&N surgeons communicate with their patients regarding prognosis in all stages of disease. They often exclude specific prognostic information. The study outcomes can be used as a first step in developing a guideline for sharing prognostic information in H&N oncologic patients, in order enable the process of shared decision making.


Atrial fibrillation: stroke prevention in focus.
Atrial fibrillation (AF) is a common arrhythmia and a risk factor for stroke and other, adverse events. Internationally there have been recent advancements in the therapies available for, stroke prevention in AF. Nurses will care for individuals with AF across a variety of primary and acute, care settings and should be familiar with evidence based therapies. This paper provides a review of the epidemiology of AF and stroke, stroke and bleeding risk, assessment tools and evidence based treatments for the prevention of stroke in AF including the use of, novel anti-thrombin agents. A review of key databases was conducted from 2002 to 2012 using the key search terms 'atrial, fibrillation' 'anticoagulation' 'risk assessment' and 'clinical management'. The following electronic, databases were searched: CINAHL, Medline, Scopus, the Cochrane Library and Google Scholar., Reference lists were manually hand searched. Key clinical guidelines from National Institute for, Clinical Excellence (NICE, UK), American Heart Association (AHA, USA), American College of Cardiology, (ACC, USA) and the European Society of Cardiology (ESC) and key government policy documents were, also included. Articles were included in the review if they addressed nursing management with a focus, on Australia. Many treatment options exist for AF. Best practice guidelines make a variety of, recommendations which include cardioversion, ablation, pulmonary vein isolation, pharmacological, agents for rate or rhythm control approaches, and antithrombotic therapy (including anticoagulation, and antiplatelet therapy). Treatment should be patient centred and individualised based upon, persistency of the rhythm, causal nature, risk and co-morbid conditions. AF is a common and burdensome condition where treatment is complex and not without, risk. Nurses will encounter individuals with AF across a variety of primary and acute care areas, understanding the risk of AF and appropriate therapies is important across all care settings. Treatment, must be individually tailored to the needs of the patient and balanced with the best available evidence.


Deep genomic-scale analyses of the metazoa reject Coelomata: evidence from single- and multigene families analyzed under a supertree and supermatrix paradigm.
Solving the phylogeny of the animals with bilateral symmetry has proven difficult. Morphological studies have suggested a variety of alternative hypotheses, of which, Hyman's Coelomata hypothesis has become the most established. Studies based on 18S rRNA have failed to endorse Coelomata, supporting instead the rearrangement of the protostomes into two new clades: the Lophotrochozoa (including, e.g., the molluscs and the annelids) and the Ecdysozoa (including the Panarthropoda and most pseudocoelomates, such as the nematodes and priapulids). Support for this new animal phylogeny has been attained from expressed sequence tag studies, although these generally have a limited gene sampling. In contrast, deep genomic-scale analyses have often supported Coelomata. However, these studies are problematic due to their limited taxonomic sampling, which could exacerbate tree reconstruction artifacts. Here, we address both of these sampling limitations; we study the effect of long-branch attraction (LBA) in deep genomic-scale analyses and provide convincing evidence, using both single- and multigene families, that Coelomata is an artifact. We show that optimal outgroup selection is key in avoiding LBA and identify the use of inadequate outgroups as the reason previous deep genomic-scale analyses found strong support for Coelomata.


Specification and regulation of vascular tissue identity in the Arabidopsis embryo.
Development of plant vascular tissues involves tissue identity specification, growth, pattern formation and cell-type differentiation. Although later developmental steps are understood in some detail, it is still largely unknown how the tissue is initially specified. We used the early Arabidopsis embryo as a simple model to study this process. Using a large collection of marker genes, we found that vascular identity was specified in the 16-cell embryo. After a transient precursor state, however, there was no persistent uniform tissue identity. Auxin is intimately connected to vascular tissue development. We found that, although an AUXIN RESPONSE FACTOR5/MONOPTEROS (ARF5/MP)-dependent auxin response was required, it was not sufficient for tissue specification. We therefore used a large-scale enhanced yeast one-hybrid assay to identify potential regulators of vascular identity. Network and functional analysis of candidate regulators suggest that vascular identity is under robust, complex control. We found that one candidate regulator, the G-class bZIP transcription factor GBF2, can modulate vascular gene expression by tuning MP output through direct interaction. Our work uncovers components of a gene regulatory network that controls the initial specification of vascular tissue identity.


Impaired Cytokine Responses to Epstein-Barr Virus Antigens in Systemic Lupus Erythematosus Patients.
We analyzed cytokine responses against latent and lytic Epstein-Barr virus (EBV) antigens in systemic lupus erythematosus (SLE) patients and healthy controls (HCs) to obtain an overview of the distinctive immune regulatory response in SLE patients and to expand the previously determined impaired EBV-directed T-cell response. The concentrations of 14 cytokines (IL2, IL4, IL5, IL6, IL10, IL12, IL17, IL18, IL1β, IFNγ, TNFα, TNFβ, TGFβ, and GM-CSF) were quantified upon stimulation of whole blood with latent state antigen EBNA1, lytic cycle antigen EBV-EA/D, and the superantigen SEB. To avoid results affected by lack of lymphocytes, we focused on SLE patients with normal levels. Decreased induction of IL12, IFNγ, IL17, and IL6 upon EBNA1 stimulation and that of IFNγ, IL6, TNFβ, IL1β, and GM-CSF upon EBV-EA/D stimulation were detected in SLE patients compared to HCs. IFNγ responses, especially, were shown to be reduced. Induction of several cytokines was furthermore impaired in SLE patients upon SEB stimulation, but no difference was observed in basic levels. Results substantiate the previously proposed impaired regulation of the immune response against latent and lytic cycle EBV infection in SLE patients without lymphopenia. Furthermore, results indicate general dysfunction of leukocytes and their cytokine regulations in SLE patients.


Atorvastatin induces T cell proliferation by a telomerase reverse transcriptase (TERT) mediated mechanism.
Statins are one of the most potent drugs in delaying age-related inflammatory changes in the arterial vessel wall, slowing down the progression of atherosclerosis. Statins have also been shown to abrogate telomere-attributed cardiovascular risk. The goal of our study was to explore a potential effect of atorvastatin on telomerase activity in peripheral blood mononuclear cells (PBMCs) and T-lymphocytes (T cells). Treatment with pharmacologically relevant concentrations (0.1-0.3 μM) of atorvastatin resulted in a 6-fold increase of telomerase activity (TA) (p < 0.0001) in human and mouse PBMCs and CD4 T cells, translating into moderate proliferation of T lymphocytes. In contrast, high doses of atorvastatin (2-5 μM) or the addition of LDL cholesterol completely inhibited proliferation, thereby abrogating telomerase activity. The proliferative effect of atorvastatin was ablated by the absense of the catalytic subunit of telomerase, telomerase reverse transcriptase (TERT). Using transgenic GFP-mTert reporter mice, we observed a decrease in telomerase-positive lymphocytes from 30% to 15% during the first 5 months of age (p < 0.01). This suggests that the decrease in immune cell turnover during normal development and maturation is mirrored by a reduction in telomerase activity in lymphocytes in-vivo. Atorvastatin and cholesterol have opposing effects on telomerase in mononuclear cells and T-lymphocytes. Our study suggests a link between cholesterol metabolism and telomere-related cardiovascular risk.


Acromioclavicular and coracoclavicular cerclage reconstruction for acute acromioclavicular joint dislocations.
Little information is available on the results of the different stabilization techniques described for treatment of acute acromioclavicular (AC) joint injuries. Additionally, no studies have analyzed isometric performance of the shoulder after AC stabilization. The objective of our study was to present functional outcome including isokinetic testing and radiographic evaluation of patients treated with stabilization of AC joint dislocations. Thirty-seven patients with acute type III to V AC joint disruption underwent open coracoclavicular (CC) and AC stabilization with nonabsorbable sutures. The mean follow-up was 4.5 ± 2.5 years (range, 2-10.5). The mean Constant score (CS) was 96. There were 34 (91.9%) excellent results, 1 good (2.7%), 1 satisfactory (2.7%), and 1 fair (2.7%). The disabilities of the arm, shoulder, and hand (DASH) questionnaire revealed good overall subjective evaluation with a mean of 7 points. The mean visual analog scale (VAS) pain score was 0.8. Patients with a CC distance <5 mm, or an anterosuperior AC reduction less than 50%, showed significantly better results in CS and DASH score in comparison to patients with a subluxated AC joint (P < .005). Twenty-two patients agreed to undergo isokinetic evaluation. We were unable to demonstrate any clinically significant difference between the involved and the uninvolved side. The described technique of cerclage augmentation offers an attractive alternative in AC joint stabilization, with good to excellent results. In comparison to other techniques, there were no complications related to any implants, no graft donor site morbidity, or need for implant removal.


Sensory-processing sensitivity moderates the association between childhood experiences and adult life satisfaction.
There are few studies testing the differential susceptibility hypothesis (DSH: hypothesizing that some individuals are more responsive to both positive and negative experiences) with adult personality traits. The current study examined the DSH by investigating the moderating effect of sensory-processing sensitivity (SPS) on childhood experiences and life satisfaction. A total of 185 adults completed measures of SPS, positive/negative childhood experiences and life satisfaction. SPS did moderate the association between childhood experiences and life satisfaction. Simple slopes analysis compared those reporting high and low SPS (+/-1 SD) and revealed that the difference was observed only for those who reported negative childhood experiences; with the high SPS group reporting lower life satisfaction. There was no difference observed in those reporting positive childhood experiences, which supported a diathesis-stress model rather than the DSH.


Renal bicarbonate reabsorption in the rat. III. Distal tubule perfusion study of load dependence and bicarbonate permeability.
Using continuous microperfusion techniques, we studied the load dependence of bicarbonate reabsorption along cortical distal tubules of the rat kidney and their bicarbonate permeability. Net bicarbonate transport was evaluated from changes in tracer inulin concentrations and total CO2 measurements by microcalorimetry. Bicarbonate permeability was estimated from the flux of total CO2 along known electrochemical gradients into bicarbonate-and chloride-free perfusion solution containing 10(-4) M acetazolamide. Transepithelial potential differences were measured with conventional glass microelectrodes. Significant net bicarbonate reabsorption occurred at luminal bicarbonate levels from 5 to 25 mM, and at perfusion rates from 5 to 30 nl/min. Bicarbonate reabsorption increased in a load-dependent manner, both during increments in luminal bicarbonate concentration or perfusion rate, reaching saturation at a load of 250 pmol/min with a maximal reabsorption rate of approximately 75 pmol/min.mm. Rate of bicarbonate reabsorption was flow dependent at luminal concentrations of 10 but not at 25 mM. During chronic metabolic alkalosis, maximal rates of reabsorption were significantly reduced to 33 pmol/min.mm. The bicarbonate permeability was 2.32 +/- 0.13 x 10(-5) cm/s in control rats, and 2.65 +/- 0.26 x 10(-5) cm/s in volume-expanded rats. Our data indicate that at physiological bicarbonate concentrations in the distal tubule passive bicarbonate fluxes account for only 16-21% of net fluxes. At high luminal bicarbonate concentrations, passive bicarbonate reabsorption contributes moderately to net reabsorption of this anion.


Constrained control landscape for population transfer in a two-level system.
The growing success of controlling the dynamics of quantum systems has been ascribed to the favorable topology of the quantum control landscape, which represents the physical observable as a function of the control field. The landscape contains no suboptimal trapping extrema when reasonable physical assumptions are satisfied, including that no significant constraints are placed on the control resources. A topic of prime interest is understanding the effects of control field constraints on the apparent landscape topology, as constraints on control resources are inevitable in the laboratory. This work particularly explores the effects of constraining the control field fluence on the topology and features of the control landscape for pure-state population transfer in a two-level system through numerical simulations, where unit probability population transfer in the system is only accessible in the strong coupling regime within the model explored here. With the fluence and three phase variables used for optimization, no local optima are found on the landscape, although saddle features are widespread at low fluence values. Global landscape optima are found to exist at two disconnected regions of the fluence that possess distinct topologies and structures. Broad scale connected optimal level sets are found when the fluence is sufficiently large, while the connectivity is reduced as the fluence becomes more constrained. These results suggest that seeking optimal fields with constrained fluence or other resources may encounter complex landscape features, calling for sophisticated algorithms that can efficiently find optimal controls.


Periprocedural Antithrombotic Treatment During Acute Mechanical Thrombectomy for Ischemic Stroke: A Systematic Review.
More than one-third of the patients with ischemic stroke caused by an intracranial large vessel occlusion do not recover to functional independence despite fast and successful recanalization by acute mechanical thrombectomy (MT). This may partially be explained by incomplete microvascular reperfusion. Some antithrombotics, e.g., antiplatelet agents and heparin, may be able to restore microvascular reperfusion. However, antithrombotics may also increase the risk of symptomatic intracranial hemorrhage (sICH). The aim of this review was to assess the potential safety and functional outcome of periprocedural antiplatelet or heparin use during acute MT for ischemic stroke. We systematically searched PubMed, Embase, Medline, Web of Science, and Cochrane for studies investigating the safety and functional outcome of periprocedural antiplatelet or heparin treatment during acute MT for ischemic stroke. The primary outcome was the risk for sICH. Secondary outcomes were functional independence after 3-6 months (modified Rankin Scale 0-2) and mortality within 6 months. 837 studies were identified through the search, of which 19 studies were included. The sICH risks of the periprocedural use of antiplatelets ranged from 6 to 17%, and for heparin from 5 to 12%. Two of four studies reporting relative effects of the use of antithrombotics are pointing toward an increased risk of sICH. Among patients treated with antiplatelet agents, functional independence varied from 23 to 60% and mortality from 18 to 33%. For heparin, this was, respectively, 19-54% and 19-33%. The three studies presenting relative effects of antiplatelets on functional independence showed neutral effects. Both studies reporting relative effects of heparin on functional independence found it to increase this chance. Randomized controlled trials investigating the effect of periprocedural antithrombotic treatment in MT are lacking. Some observational studies report a slight increase in sICH risk, which may be acceptable because they also suggest a beneficial effect on functional outcome. Therefore, randomized controlled trials are warranted to address the question whether the potentially higher risk of sICH could be outweighed by improved functional outcome.


Severely suppressed bone turnover and atypical skeletal fragility.
Since their introduction into clinical medicine, bisphosphonates have revolutionized clinical osteoporosis care. Ironically, in rare circumstances, long-term, combined anti-remodeling therapy may be associated with skeletal harm. We report atypical skeletal fragility in three subjects after long-term, combined anti-remodeling therapy. Three subjects experienced spontaneous or minimal-trauma chalk-stick type metadiaphyseal femoral fractures while on long-term bisphosphonate therapy. The fracture location, type, bilaterality, prodromal pain, and delayed healing were atypical for uncomplicated postmenopausal osteoporosis. All three subjects had concomitant circumstances (endogenous estrogen) or medications (glucocorticoids, hormone replacement therapy, and raloxifene) that likely suppressed bone remodeling beyond the effect of the bisphosphonate alone. Biochemical markers of bone turnover were very low or in the low premenopausal range. Double tetracycline-labeled bone biopsy showed very low activation frequency in one subject and limited single tetracycline label in a second consistent with severely suppressed bone turnover (SSBT). These three cases resemble previous descriptions of SSBT. Atypical skeletal fragility may signify SSBT in the setting of long-term, combined anti-remodeling therapy. We speculate that osteoclast tolerance for pharmacological suppression may vary among individual patients and that in some cases combined anti-remodeling therapy may result in skeletal harm.


Endogenous interleukin 6 levels in patients with metastatic malignant melanoma: correlation with tumor burden.
The involvement of interleukin (IL-) 6 in malignant disease has been investigated in a variety of different malignancies. To evaluate whether serum IL-6 is a useful disease marker in metastatic malignant melanoma (MMM), we studied the time course of endogenous IL-6 secretion in 41 patients treated with cisplatinum, IL-2, and IFN-alpha. Furthermore, the relationship of endogenous IL-6 concentrations to the tumor burden and/or the clinical response was also evaluated. The baseline serum IL-6 levels were significantly higher in patients with MMM than in the control group (P = 0.002). When tumor burden was taken into consideration, we found that IL-6 levels were higher in patients with high tumor burden than in patients with low tumor burden. During treatment in the whole patient population, a higher serum IL-6 level was observed in nonresponding as compared to responding patients at days 7 (P = 0.0005), 21 (P = 0.002), and 35 (P = 0.009). The follow-up of serum IL-6 in patients with MMM according to the tumor burden and clinical response demonstrated that: (a) IL-6 levels were significantly higher at days 7 and 21 in patients with high tumor burden as compared to those with low tumor burden; and (b) IL-6 levels remain significantly higher in nonresponding patients as compared to responding patients regardless of the tumor burden. From these results, we can conclude that endogenous IL-6 may play a role in the failure of IL-2 therapy in such patients, since the very early IL-6 increase is correlated with the tumor mass and nonresponse to biochemotherapy. Therefore, it seems that the early detection of endogenous IL-6 may represent valuable information for monitoring the response to biochemotherapy in patients with MMM.


Kinetic Ionic Permeation and Interfacial Doping of Supported Graphene.
Due to its outstanding electrical properties and chemical stability, graphene finds widespread use in various electrochemical applications. Although the presence of electrolytes strongly affects its electrical conductivity, the underlying mechanism has remained elusive. Here, we employ terahertz spectroscopy as a contact-free means to investigate the impact of ubiquitous cations (Li+, Na+, K+, and Ca2+) in aqueous solution on the electronic properties of SiO2-supported graphene. We find that, without applying any external potential, cations can shift the Fermi energy of initially hole-doped graphene by ∼200 meV up to the Dirac point, thus counteracting the initial substrate-induced hole doping. Remarkably, the cation concentration and cation hydration complex size determine the kinetics and magnitude of this shift in the Fermi level. Combined with theoretical calculations, we show that the ion-induced Fermi level shift of graphene involves cationic permeation through graphene. The interfacial cations located between graphene and SiO2 electrostatically counteract the substrate-induced hole doping effect in graphene. These insights are crucial for graphene device processing and further developing graphene as an ion-sensing material.


The antimicrobial lysine-peptoid hybrid LP5 inhibits DNA replication and induces the SOS response in Staphylococcus aureus.
The increase in antibiotic resistant bacteria has led to renewed interest in development of alternative antimicrobial compounds such as antimicrobial peptides (AMPs), either naturally-occurring or synthetically-derived. Knowledge of the mode of action (MOA) of synthetic compounds mimicking the function of AMPs is highly valuable both when developing new types of antimicrobials and when predicting resistance development. Despite many functional studies of AMPs, only a few of the synthetic peptides have been studied in detail. We investigated the MOA of the lysine-peptoid hybrid, LP5, which previously has been shown to display antimicrobial activity against Staphylococcus aureus. At concentrations of LP5 above the minimal inhibitory concentration (MIC), the peptoid caused ATP leakage from bacterial cells. However, at concentrations close to the MIC, LP5 inhibited the growth of S. aureus without ATP leakage. Instead, LP5 bound DNA and inhibited macromolecular synthesis. The binding to DNA also led to inhibition of DNA gyrase and topoisomerase IV and caused induction of the SOS response. Our data demonstrate that LP5 may have a dual mode of action against S. aureus. At MIC concentrations, LP5 binds DNA and inhibits macromolecular synthesis and growth, whereas at concentrations above the MIC, LP5 targets the bacterial membrane leading to disruption of the membrane. These results add new information about the MOA of a new synthetic AMP and aid in the future design of synthetic peptides with increased therapeutic potential.


The nucleosome acidic patch and H2A ubiquitination underlie mSWI/SNF recruitment in synovial sarcoma.
Interactions between chromatin-associated proteins and the histone landscape play major roles in dictating genome topology and gene expression. Cancer-specific fusion oncoproteins, which display unique chromatin localization patterns, often lack classical DNA-binding domains, presenting challenges in identifying mechanisms governing their site-specific chromatin targeting and function. Here we identify a minimal region of the human SS18-SSX fusion oncoprotein (the hallmark driver of synovial sarcoma) that mediates a direct interaction between the mSWI/SNF complex and the nucleosome acidic patch. This binding results in altered mSWI/SNF composition and nucleosome engagement, driving cancer-specific mSWI/SNF complex targeting and gene expression. Furthermore, the C-terminal region of SSX confers preferential affinity to repressed, H2AK119Ub-marked nucleosomes, underlying the selective targeting to polycomb-marked genomic regions and synovial sarcoma-specific dependency on PRC1 function. Together, our results describe a functional interplay between a key nucleosome binding hub and a histone modification that underlies the disease-specific recruitment of a major chromatin remodeling complex.


Identifying actionable targets through integrative analyses of GEM model and human prostate cancer genomic profiling.
Copy-number alterations (CNA) are among the most common molecular events in human prostate cancer genomes and are associated with worse prognosis. Identification of the oncogenic drivers within these CNAs is challenging due to the broad nature of these genomic gains or losses which can include large numbers of genes within a given region. Here, we profiled the genomes of four genetically engineered mouse prostate cancer models that reflect oncogenic events common in human prostate tumors, with the goal of integrating these data with human prostate cancer datasets to identify shared molecular events. Met was amplified in 67% of prostate tumors from Pten p53 prostate conditional null mice and in approximately 30% of metastatic human prostate cancer specimens, often in association with loss of PTEN and TP53. In murine tumors with Met amplification, Met copy-number gain and expression was present in some cells but not others, revealing intratumoral heterogeneity. Forced MET overexpression in non-MET-amplified prostate tumor cells activated PI3K and MAPK signaling and promoted cell proliferation and tumor growth, whereas MET kinase inhibition selectively impaired the growth of tumors with Met amplification. However, the impact of MET inhibitor therapy was compromised by the persistent growth of non-Met-amplified cells within Met-amplified tumors. These findings establish the importance of MET in prostate cancer progression but reveal potential limitations in the clinical use of MET inhibitors in late-stage prostate cancer.


Examining the levels of psychological support available to patients with haematological cancer in England: a mixed methods study.
The psychological impact of a haematological malignancy is well documented. However, few studies have assessed the provision of psychological support to people with these diagnoses. This study explores the extent and nature of psychological support for people diagnosed with haematological cancer to inform future service provision. This study consisted of an online survey with healthcare professionals (phase 1) and qualitative interviews with patients (phase 2) and key health professionals (phase 3). A descriptive analysis of survey data and thematic analysis of interviews were conducted. Two hundred health professionals practising in England completed the survey. Twenty-five interviews were conducted with people diagnosed with haematological cancer in the past 3 years, and 10 with key health professionals, including haematologists, cancer nurse specialists and psychologists were conducted. Level of psychological assessment undertaken with people with haematological cancer, and level and nature of psychological support provided. Less than half (47.3%) of survey respondents strongly agreed/agreed that their patients were well supported in terms of their psychological well-being and approximately half (49.4%) reported providing routine assessment of psychological needs of patients, most commonly at the time of diagnosis or relapse. Patients described their need for psychological support, their experiences of support from health professionals and their experiences of support from psychological therapy services. There was considerable variation in the support patients described receiving. Barriers to providing psychological support reported by health professionals included time, skills, resources and patient barriers. Most doctors (85%) and 40% of nurse respondents reported receiving no training for assessing and managing psychological needs. Psychological well-being should be routinely assessed, and person-centred support should be offered regularly throughout the haematological cancer journey. Greater provision of healthcare professional training in this area and better integration of psychological support services into the patient care pathway are required.


Optimal pandemic influenza vaccine allocation strategies for the canadian population.
The world is currently confronting the first influenza pandemic of the 21st century. Influenza vaccination is an effective preventive measure, but the unique epidemiological features of swine-origin influenza A (H1N1) (pH1N1) introduce uncertainty as to the best strategy for prioritization of vaccine allocation. We sought to determine optimal prioritization of vaccine distribution among different age and risk groups within the Canadian population, to minimize influenza-attributable morbidity and mortality. We developed a deterministic, age-structured compartmental model of influenza transmission, with key parameter values estimated from data collected during the initial phase of the epidemic in Ontario, Canada. We examined the effect of different vaccination strategies on attack rates, hospitalizations, intensive care unit admissions, and mortality. In all scenarios, prioritization of high-risk groups (individuals with underlying chronic conditions and pregnant women) markedly decreased the frequency of severe outcomes. Preferential vaccination of age groups at increased risk of severe outcomes following infection resulted in decreased mortality compared to targeting vaccine to age groups with higher transmission, at a cost of higher population-level attack rates. All simulations were sensitive to the timing of the epidemic peak in relation to vaccine availability, with vaccination having the greatest impact when it was implemented well in advance of the epidemic peak. Our model simulations suggest that vaccine should be allocated to high-risk groups, regardless of age, followed by age groups at increased risk of severe outcomes. Vaccination may significantly reduce influenza-attributable morbidity and mortality, but the benefits are dependent on epidemic dynamics, time for program roll-out, and vaccine uptake.


Risk of exposure to house dust pyroglyphid mites in Poland.
During the period of 1989-2000, 335 house dust samples were collected from dwellings at 27 different localities in Poland. Mite allergen exposure was measured in house dust samples collected by performing of mite taxa determination and measuring of the mite allergen levels by a semiquantitative guanine method (Acarex(R) test). Mites were found in 158 of the samples examined (47.2%). A total 3,714 mites were isolated and 15 species identified, including four species from the family Pyroglyphidae (house dust mites). Among them, Dermatophagoides farinae (DF) was predominant (approximately 67% of the total count), followed by D. pteronyssinus (DP) (17.6%) and Euroglyphus maynei (EM) (1.6%). Hirstia chelidonis (HCh) was found for the first time in house dust samples in Poland. DF was predominant in Iwonicz-Zdroj (96.6%), Katowice (91.8%), Sosnowiec (89.4%), Chorzow (94.8%), Bytom (50.9%), Swiêtochlowice (96.7%) and generally in Upper Silesia (88.2%), whereas DP dominated in Lod (92.9%), Wodzislaw (80.9%), Krakow (45.6%) and Bielsko-Biala (24.8%). Only 14.3% of the mites collected were alive. Total mean number of domestic mites per gram of dust (in all samples examined) was 204.1 +/- 1079.8. The greatest number of mites per 1 gram of dust was 14,971.4. Mite densities and levels of mite allergens (expressed as Acarex test steps) in samples from beds, floors and upholstery furnitures at particular localities in Poland, and in dwellings of atopic versus non-atopic subjects were compared. Highest mite concentrations were usually found in dust from beds, carpets and shutters. D. farinae was distinctly more abundant both per 1 gram of dust and per 1 sample than the species D. pteronyssinus. Other pyroglyphid mites, E. maynei and H. chelidonis, occurred in very small numbers. No significant differences were found between the counts of mites (total and live) in the dwellings of atopic and non-atopic persons. Approximately 49.5% of samples showed positive levels of the mite allergens (Acarex test steps). An influence of some abiotic indoor factors on the mite prevalence in the examined dwellings was analysed separately in relation to samples of bed dust, floor dust and dust from upholstery furnitures. The density of mites was influenced mainly by the type of heating, temperature, type of sleeping accommodation, type of floor or furniture, sampling method, and type of building, whereas levels of the mite allergens were associated with the mite density, relative humidity, month, sampling method, type of building and type of heating.


Towards conceptualizing a neural systems-based anatomy of attention-deficit/hyperactivity disorder.
Convergent data from neuroimaging, neuropsychological, genetic and neurochemical studies in attention-deficit/hyperactivity disorder (ADHD) have implicated dysfunction of the dorsolateral prefrontal cortex (DLPFC) and dorsal anterior cingulate cortex (dACC), which form the cortical arm of the frontostriatal network supporting executive functions. Furthermore, besides the DLPFC and dACC, structural and functional imaging studies have shown abnormalities in key brain regions within distributed cortical networks supporting attention. The conceptualization of neural systems biology in ADHD aims at the understanding of what organizing principles have been altered during development within the brain of a person with ADHD.Characterizing these neural systems using neuroimaging could be critical for the description of structural endophenotypes, and may provide the capability of in vivo categorization and correlation with behavior and genes.


Interobserver and intraobserver variation among experts in the diagnosis of thyroid follicular lesions with borderline nuclear features of papillary carcinoma.
Distinguishing follicular variant of papillary carcinoma (FVPC) from follicular adenoma and follicular carcinoma can be difficult if nuclear features of papillary carcinoma are not well developed or only focally present. We assessed interobserver and intraobserver agreement among 6 thyroid experts by using 15 cases in which original pathologists suspected FVPC. There was unanimous expert agreement in diagnosing FVPC in only 2 cases (13%) and majority agreement in 6 cases (40%). Unanimous agreement on benign and malignant diagnoses was seen in 4 cases (27%) and majority agreement on malignancy in 8 cases (53%). Intraobserver agreement ranged from 17% to 100%. Histologic features considered most helpful in diagnosing FVPC were nuclear clearing, nuclear grooves, nuclear overlapping and crowding, nuclear membrane irregularity, and nuclear enlargement. This considerable interobserver and intraobserver variability in the diagnosis of FVPC seems to result from lack of agreement on the minimal criteria needed to diagnose FVPC, even among experts.


Review of the national external quality assessment (EQA) scheme for breast pathology in the UK.
The National Health Service Breast Screening Programme (NHSBSP; pathology) external quality assurance (EQA) scheme aims to provide a mechanism for examination and monitoring of concordance of pathology reporting within the UK. This study aims to review the breast EQA scheme performance data collected over a 24-year period following its introduction. Data on circulations, number of cases and diagnosis were collected. Detailed analyses with and without combinations of certain diagnostic entities, and over different time periods were performed. Overall, of 576 cases (172 benign, 11 atypical hyperplasia, 98 ductal carcinoma in situ/microinvasive and 295 invasive disease), consistency of assessment of diagnostic parameters was very high (overall k=0.80; k for benign diagnosis=0.79; k for invasive disease=0.91). For distinguishing benign versus malignant lesions, no further improvement is considered possible in view of the limitations of the scheme methodology. Although diagnostic consistency of atypical hyperplasia remains at a low level, combining it with the benign category results in a high level of agreement (k=0.93). The level of consistency of reporting prognostic information is variable and some items such as lymphovascular invasion and tumour size measurement may need further intervention to improve their reporting consistency. Although the level of consistency of reporting of histological grade remained at a moderate level overall (k=0.48), it was variable among cases and appears to have levelled off; no further significant improvement is expected and no significant impact of the previous publication of guidelines is observed. These results provide further evidence to indicate the value of the breast EQA scheme in monitoring performance and the identification of specific areas where improvement or new approaches are required. For most parameters, the concordance of reporting reached a plateaux a few years after the introduction of the EQA scheme. It is important to maintain this high level and also to tackle specific low-performance areas innovatively.


A comparison of direct versus indirect laryngoscopic visualization during endotracheal intubation of lightly embalmed cadavers utilizing the GlideScope®, Storz Medi Pack Mobile Imaging System™ and the New Storz CMAC™ videolaryngoscope.
Studies indicate that the skills needed to use video laryngoscope systems are easily learned by healthcare providers. This study compared several video laryngoscopic (VL) systems and a direct laryngoscope (DL) view when used by medical residents practicing intubation on cadavers. The video devices used included the Storz Medi Pack Mobile Imaging System™, the Storz CMAC® VL System and the GlideScope®. After Institutional Review Board (IRB) approval, University of Nebraska Medical Center, Department of Emergency Medicine (UNMC EM) residents were recruited and given a brief pre-study informational period. The cadavers were lightly embalmed. The study subjects were asked to perform intubations on two cadavers using both DL and VL while using the three different VL systems. Procedural data was recorded for each attempt and pre and post experience perceptions were collected. N=14. All subjects reported their varied previous intubation experience. The average airway score using DL: for the Storz VL was 1.54 (SD = 0.576) and for the C-MAC was 1.46 (SD = 0.637). Success in intubation of the standard airway using DL was 93% versus a 100% success rate when intubating with indirect VL visualization. Based on our data, we believe that the incorporation of VL into cadaver airway management training provided an improved learning environment for the study residents. In our study, the resident subjects were 93% successful with DL intubation even though 50% had less than 30 intubations. As well, there was a 100% success rate when intubating with indirect VL visualization. In conclusion, the researchers believe this cadaver model incorporated with VL is a powerful tool which may help improve the overall learning curve for orotracheal intubation.


The ED-SED Study: A Multicenter, Prospective Cohort Study of Practice Patterns and Clinical Outcomes Associated With Emergency Department SEDation for Mechanically Ventilated Patients.
To characterize emergency department sedation practices in mechanically ventilated patients, and test the hypothesis that deep sedation in the emergency department is associated with worse outcomes. Multicenter, prospective cohort study. The emergency department and ICUs of 15 medical centers. Mechanically ventilated adult emergency department patients. None. All data involving sedation (medications, monitoring) were recorded. Deep sedation was defined as Richmond Agitation-Sedation Scale of -3 to -5 or Sedation-Agitation Scale of 2 or 1. A total of 324 patients were studied. Emergency department deep sedation was observed in 171 patients (52.8%), and was associated with a higher frequency of deep sedation in the ICU on day 1 (53.8% vs 20.3%; p < 0.001) and day 2 (33.3% vs 16.9%; p = 0.001), when compared to light sedation. Mean (SD) ventilator-free days were 18.1 (10.8) in the emergency department deep sedation group compared to 20.0 (9.8) in the light sedation group (mean difference, 1.9; 95% CI, -0.40 to 4.13). Similar results according to emergency department sedation depth existed for ICU-free days (mean difference, 1.6; 95% CI, -0.54 to 3.83) and hospital-free days (mean difference, 2.3; 95% CI, 0.26-4.32). Mortality was 21.1% in the deep sedation group and 17.0% in the light sedation group (between-group difference, 4.1%; odds ratio, 1.30; 0.74-2.28). The occurrence rate of acute brain dysfunction (delirium and coma) was 68.4% in the deep sedation group and 55.6% in the light sedation group (between-group difference, 12.8%; odds ratio, 1.73; 1.10-2.73). Early deep sedation in the emergency department is common, carries over into the ICU, and may be associated with worse outcomes. Sedation practice in the emergency department and its association with clinical outcomes is in need of further investigation.


Social anxiety, fear of negative evaluation and the detection of negative emotion in others.
The present study sought to investigate whether social anxiety is associated with enhanced ability to detect negative emotion in others. Subjects scoring high and low on Fear of Negative Evaluation (FNE) performed two tasks before and after a social threat induction. The first task involved identifying the affect (negative vs neutral) in briefly presented (60 msec) slides of faces. The second involved rating the overall emotion conveyed in brief video clips of an actor and detecting discrepancies in the affect conveyed by the visual and auditory channels of the video. Overall the results suggest that high social anxiety subjects have a bias towards identifying others' emotional expressions as negative in the absence of an enhanced ability to discriminate between different emotional states in others. Implications and limitations of the results are discussed.


Characterization of a mouse model of plague after aerosolization of Yersinia pestis CO92.
Yersinia pestis is a Gram-negative bacterium, and the causative agent of bubonic plague and pneumonic plague. Because of its potential use as a biological warfare weapon, the plague bacterium has been placed on the list of category A select agents. The dynamics of pneumonic infection following aerosolization of the highly virulent Y. pestis CO92 strain have been poorly studied; therefore, the purpose of this study was to determine the LD(50) dose, bacterial dissemination, cytokine/chemokine production and tissue damage in Swiss-Webster mice over a 72 h course of infection. We exposed mice in a whole-body Madison chamber to various doses of Y. pestis CO92 aerosolized by a Collison nebulizer, and determined that the LD(50) presented dose (Dp) of the bacterium in the lungs was 2.1 x 10(3) c.f.u. In a subsequent study, we infected mice at a Dp of 1.3 x 10(4) c.f.u., and harvested organs and blood at 1, 24, 48 and 72 h post-infection. Histopathological examination, in addition to measurement of bacterial dissemination and cytokine/chemokine analysis, indicated progressive tissue injury, and an increased number of animals succumbing to infection over the course of the experiment. Using these data, we were able to characterize the mouse plague model following aerosolization of Y. pestis CO92.


Pro Free Will Priming Enhances "Risk-Taking" Behavior in the Iowa Gambling Task, but Not in the Balloon Analogue Risk Task: Two Independent Priming Studies.
Studies indicated that people behave less responsibly after exposure to information containing deterministic statements as compared to free will statements or neutral statements. Thus, deterministic primes should lead to enhanced risk-taking behavior. We tested this prediction in two studies with healthy participants. In experiment 1, we tested 144 students (24 men) in the laboratory using the Iowa Gambling Task. In experiment 2, we tested 274 participants (104 men) online using the Balloon Analogue Risk Task. In the Iowa Gambling Task, the free will priming condition resulted in more risky decisions than both the deterministic and neutral priming conditions. We observed no priming effects on risk-taking behavior in the Balloon Analogue Risk Task. To explain these unpredicted findings, we consider the somatic marker hypothesis, a gain frequency approach as well as attention to gains and / or inattention to losses. In addition, we highlight the necessity to consider both pro free will and deterministic priming conditions in future studies. Importantly, our and previous results indicate that the effects of pro free will and deterministic priming do not oppose each other on a frequently assumed continuum.


Malignant pleural effusion in the presence of trapped lung. Five-year experience of PleurX tunnelled catheters.
Malignant pleural effusions in the presence of trapped lung remain notoriously difficult to treat. Various methods exist ranging from minimally invasive procedures including repeated needle thoracocentesis to the need for a formal surgical procedure such as placement of a pleuroperitoneal shunt and even thoracotomy and decortication. Controversy exists as to what is the optimum treatment for this condition. Any planned treatment should balance the therapeutic benefit provided against convalesce for a disease with a limited life expectancy. Patients should not spend a significant proportion of their remaining life span recovering from palliative procedures. In a series of patients with malignant pleural effusion the medial survival time was 20 weeks, with 30 days and 1 year mortality rates of 12.8% and 83.6%, respectively. We describe our five-year experience with the use of indwelling PleurX catheters in patients with malignant pleural effusions in the presence of confirmed trapped lung on radiological or VATS investigation. Patient health related quality of life was investigated by telephone questionnaire. The parameters analysed were symptomatic relief, mobility and ease of management following insertion. One hundred and sixteen patients underwent PleurX catheter insertion by a single operator, 48 questionnaires were completed. Of the 48 cases analysed, improvement in all three quality of life indices was recorded following catheter insertion. Ease of mobility was recorded as moderately satisfied and very satisfied in 50% and 15% of patients, respectively. Symptomatic improvement was found to have been increased with 42% and 6% of patients responding to moderately satisfied and very satisfied, respectively. Ease of management was recorded as 'slightly satisfied' and moderately satisfied in 50% and 33% of patients, respectively, demonstrating a high satisfaction index in patients with chronic progressively debilitating malignancies. Complications were either transient or readily correctable. Pain was the predominant complication occurring in 35% of patients lasting <3 days. No patient required catheter removal for resolution of discomfort. Our findings support the use of PleurX catheters for palliative patients with malignant pleural effusions in the presence of trapped lung. The catheters are not only easy to insert and discrete but they can be managed effectively by patients and community nurse practitioners and prevent repeated admissions to hospital in palliative patients with compromised life expectancy.


High Throughput Sediment DNA Sequencing Reveals Azo Dye Degrading Bacteria Inhabit Nearshore Sediments.
Estuaries and coastal environments are often regarded as a critical resource for the bioremediation of organic pollutants such as azo dyes due to their high abundance and diversity of extremophiles. Bioremediation through the activities of azoreductase, laccase, and other associated enzymes plays a critical role in the removal of azo dyes in built and natural environments. However, little is known about the biodegradation genes and azo dye degradation genes residing in sediments from coastal and estuarine environments. In this study, high-throughput sequencing (16S rRNA) of sediment DNA was used to explore the distribution of azo-dye degrading bacteria and their functional genes in estuaries and coastal environments. Unlike laccase genes, azoreductase (azoR), and naphthalene degrading genes were ubiquitous in the coastal and estuarine environments. The relative abundances of most functional genes were higher in the summer compared to winter at locations proximal to the mouths of the Hanjiang River and its distributaries. These results suggested inland river discharges influenced the occurrence and abundance of azo dye degrading genes in the nearshore environments. Furthermore, the azoR genes had a significant negative relationship with total organic carbon, Hg, and Cr (p < 0.05). This study provides critical insights into the biodegradation potential of indigenous microbial communities in nearshore environments and the influence of environmental factors on microbial structure, composition, and function which is essential for the development of technologies for bioremediation in azo dye contaminated sites.


Cardiovascular Regenerative Technologies: Update and Future Outlook.
In the effort of improving treatment for cardiovascular disease (CVD), scientists struggle with the lack of the regenerative capacities of finally differentiated cardiovascular tissues. In this context, the advancements in regenerative medicine contributed to the development of cell-based therapies as well as macro- and micro-scale tissue-engineering technologies. The current experimental approaches focus on different regenerative strategies including a broad spectrum of techniques such as paracrine-based stimulation of autologous cardiac stem cells, mesenchymal cell injections, 3D microtissue culture techniques and vascular tissue-engineering methods. These potential next-generation strategies are leading the way to a revolution in addressing CVD, and numerous studies are now undertaken to assess their therapeutic value. With this review, we provide an update on the current research directions, on their major challenges, limitations, and achievements.


Imaging Submillisecond Membrane Potential Changes from Individual Regions of Single Axons, Dendrites and Spines.
A central question in neuronal network analysis is how the interaction between individual neurons produces behavior and behavioral modifications. This task depends critically on how exactly signals are integrated by individual nerve cells functioning as complex operational units. Regional electrical properties of branching neuronal processes which determine the input-output function of any neuron are extraordinarily complex, dynamic, and, in the general case, impossible to predict in the absence of detailed measurements. To obtain such a measurement one would, ideally, like to be able to monitor, at multiple sites, subthreshold events as they travel from the sites of origin (synaptic contacts on distal dendrites) and summate at particular locations to influence action potential initiation. It became possible recently to carry out this type of measurement using high-resolution multisite recording of membrane potential changes with intracellular voltage-sensitive dyes. This chapter reviews the development and foundation of the method of voltage-sensitive dye recording from individual neurons. Presently, this approach allows monitoring membrane potential transients from all parts of the dendritic tree as well as from axon collaterals and individual dendritic spines.


The perspectives of spouses of stroke survivors on self-management - a focus group study.
This qualitative study explored how stroke survivors' spouses described their own self-management, their partner's self-management post-stroke and how they had been supported in developing self-management. Focus group interviews were conducted with 33 spouses of stroke survivors 34-79 years of age. A constant comparative framework was used for the analysis. Stroke also affected the spouses, gave changes in their relationships and challenged in being a caregiver beside being partner. They felt burdened, lonely, sad, and guilty. To manage themselves, many participants created time for themselves. For most spouses, self-management was connoted with co-management because they perceived their partners were not able to manage themselves completely post-stroke. They often felt lost after their partners came home and reported that they learned how to coach their partners post-stroke by trial and error, without much professional support. Moreover, many spouses experienced informal peer support as helpful. Spouses of stroke survivors should be involved as soon as possible in stroke-rehabilitation and continue at home post-discharge. In addition to enhancing the spouses' skills in caregiving and supporting self-management, stroke survivors' spouses also need support in their own emotional and role management. Moreover, peers can play a role in rehabilitation post-stroke. Implications for Rehabilitation Spouses of stroke survivors should be considered as full participants of stroke-self-management programs to enhance their skills in caregiving and supporting self-management. Stroke survivors' spouses need support in their own emotional and role management. Peer support can play a role in rehabilitation post-stroke for stroke survivors as well as their spouses.


Comparative Accuracy of Facial Models Fabricated Using Traditional and 3D Imaging Techniques.
The purpose of this investigation was to compare the accuracy of facial models fabricated using facial moulage impression methods to the three-dimensional printed (3DP) fabrication methods using soft tissue images obtained from cone beam computed tomography (CBCT) and 3D stereophotogrammetry (3D-SPG) scans. A reference phantom model was fabricated using a 3D-SPG image of a human control form with ten fiducial markers placed on common anthropometric landmarks. This image was converted into the investigation control phantom model (CPM) using 3DP methods. The CPM was attached to a camera tripod for ease of image capture. Three CBCT and three 3D-SPG images of the CPM were captured. The DICOM and STL files from the three 3dMD and three CBCT were imported to the 3DP, and six testing models were made. Reversible hydrocolloid and dental stone were used to make three facial moulages of the CPM, and the impressions/casts were poured in type IV gypsum dental stone. A coordinate measuring machine (CMM) was used to measure the distances between each of the ten fiducial markers. Each measurement was made using one point as a static reference to the other nine points. The same measuring procedures were accomplished on all specimens. All measurements were compared between specimens and the control. The data were analyzed using ANOVA and Tukey pairwise comparison of the raters, methods, and fiducial markers. The ANOVA multiple comparisons showed significant difference among the three methods (p < 0.05). Further, the interaction of methods versus fiducial markers also showed significant difference (p < 0.05). The CBCT and facial moulage method showed the greatest accuracy. 3DP models fabricated using 3D-SPG showed statistical difference in comparison to the models fabricated using the traditional method of facial moulage and 3DP models fabricated from CBCT imaging. 3DP models fabricated using 3D-SPG were less accurate than the CPM and models fabricated using facial moulage and CBCT imaging techniques.


Effects of Obesity and Insulin on Tissue-Specific Recycling Between Cortisol and Cortisone in Men.
11β-Hydroxysteroid dehydrogenase 1 (11βHSD1) reduces inert cortisone into active cortisol but also catalyzes reverse dehydrogenase activity. Drivers of cortisol/cortisone equilibrium are unclear. With obesity, 11βHSD1 transcripts are more abundant in adipose, but the consequences for oxidation vs reduction remain unknown. This work aimed to determine whether 11βHSD1 equilibrium in metabolic tissues is regulated by insulin and obesity. A 2-phase, randomized, crossover, single-blinded study in a clinical research facility was conducted of 10 lean and obese healthy men. 11β-Reductase and 11β-dehydrogenase activities were measured during infusion of 9,11,12,12-[2H]4-cortisol and 1,2-[2H]2-cortisone, respectively, on 2 occasions: once during saline infusion and once during a hyperinsulinemic-euglycemic clamp. Arterialized and venous samples were obtained across forearm skeletal muscle and abdominal subcutaneous adipose. Steroids were quantified by liquid chromatography-tandem mass spectrometry and adipose tissue transcripts by quantitative polymerase chain reaction. Neither whole-body nor tissue-specific rates of production of cortisol or cortisone differed between lean and obese men, however insulin attenuated the diurnal decrease. Whole-body 11β-HSD1 reductase activity tended to be higher in obesity (~ 10%) and was further increased by insulin. Across adipose tissue, 11β-reductase activity was detected in obese individuals only and increased in the presence of insulin (18.99 ± 9.62 vs placebo 11.68 ± 3.63 pmol/100 g/minute; P < .05). Across skeletal muscle, 11β-dehydrogenase activity was reduced by insulin in lean men only (2.55 ± 0.90 vs 4.50 ± 1.42 pmol/100 g/minute, P < .05). Regeneration of cortisol is upregulated by insulin in adipose tissue but not skeletal muscle. In obesity, the equilibrium between 11β-reductase and 11β-dehydrogenase activities likely promotes cortisol accumulation in adipose, which may lead to adverse metabolic consequences.


Validation of the "smart" minimum FFR Algorithm in an unselected all comer population of patients with intermediate coronary stenoses.
Using data from a commercial pressure wire system (St. Jude Medical) we previously developed an automated "smart" algorithm to determine a reproducible value for minimum FFR (smFFR) and confirmed that it correlated very closely with measurements made off-line by experienced coronary physiology core laboratories. In this study we used the same "smart" minimum algorithm to analyze data derived from a different, commercial pressure wire system (Philips Volcano) and compared the values obtained to both operator-defined steady state FFR and the online automated minimum FFR reported by the pressure wire analyser. For this analysis, we used the data collected during the VERIFY 2 study (Hennigan et al. in Circ Cardiovasc Interv, doi: 10.1161/CIRCINTERVENTIONS.116.004016 ) in which we measured FFR in 257 intermediate coronary stenoses (mean DS 48%) in 197 patients. Maximal hyperaemia was induced using intravenous adenosine (140 mcg/kg/min). We recorded both the online minimum FFR generated by the analyser and the operator-reported steady state FFR. Subsequently, the raw pressure tracings were coded, anonymised and 256/257 were subjected to further off-line analysis using the smart minimum FFR (smFFR) algorithm. The operator-defined steady state FFR correlated well with smFFR: r = 0.988 (p < 0.001), average bias 0.008 (SD 0.014), 95% limits of agreement -0.020 to 0.036. The online automated minimum FFR also correlated well with the smFFR: r = 0.998 (p < 0.001), average bias 0.004 (SD 0.006), 95% limits of agreement -0.016 to 0.008. Finally, the online automated minimum FFR correlated well the operator-reported steady state FFR: r = 0.988 (p < 0.001), average bias 0.012 (SD 0.014), 95% limits of agreement -0.039 to 0.015. In 95% of lesions studied (244/256), the operator reported steady-state FFR, smFFR, and online automated minimum FFR agreed with each other to within 0.04, which is within the previously reported test/retest limits of agreement of FFR reported by an experienced core lab. Disagreements >0.05 among methods were rare but in these cases the two automated algorithms almost always agreed with each other rather than with the operator-reported value. Within the VERIFY 2 dataset, experienced operators reported a similar FFR value to both an online automated minimum (Philips Volcano) and off-line "smart" minimum computer algorithm. Thus, treatment decisions and clinical studies using either method will produce nearly identical results.


Invasive non-typhoidal salmonella disease: an emerging and neglected tropical disease in Africa.
Invasive strains of non-typhoidal salmonellae have emerged as a prominent cause of bloodstream infection in African adults and children, with an associated case fatality of 20-25%. The clinical presentation of invasive non-typhoidal salmonella disease in Africa is diverse: fever, hepatosplenomegaly, and respiratory symptoms are common, and features of enterocolitis are often absent. The most important risk factors are HIV infection in adults, and malaria, HIV, and malnutrition in children. A distinct genotype of Salmonella enterica var Typhimurium, ST313, has emerged as a new pathogenic clade in sub-Saharan Africa, and might have adapted to cause invasive disease in human beings. Multidrug-resistant ST313 has caused epidemics in several African countries, and has driven the use of expensive antimicrobial drugs in the poorest health services in the world. Studies of systemic cellular and humoral immune responses in adults infected with HIV have revealed key host immune defects contributing to invasive non-typhoidal salmonella disease. This emerging pathogen might therefore have adapted to occupy an ecological and immunological niche provided by HIV, malaria, and malnutrition in Africa. A good understanding of the epidemiology of this neglected disease will open new avenues for development and implementation of vaccine and public health strategies to prevent infections and interrupt transmission.


Youth: a health plan-based lifestyle intervention increases bone mineral density in adolescent girls.
To test the efficacy of a health plan-based lifestyle intervention to increase bone mineral density in adolescent girls. Two-year randomized, controlled trial. Large health maintenance organization. Girls 14 to 16 years old with body mass index below the national median. Intervention Behavioral intervention (bimonthly group meetings, quarterly coaching telephone calls, and weekly self-monitoring) designed to improve diet and increase physical activity. Total bone mineral density was measured by dual-energy x-ray absorptiometry. Behavioral outcomes included intake of calcium, vitamin D, soda, and fruits and vegetables; high-impact and strength-training physical activity; measures of strength and fitness; and biomarkers (osteocalcin and naltrexone). Compared with control subjects, girls in the intervention group had significantly higher bone mineral density in the spine and trochanter regions during the first study year, which was maintained during the second study year. The naltrexone biomarker demonstrated a greater relative decrease in the intervention group compared with the control group, with nonsignificant changes in osteocalcin consistent with more bone building in the intervention group. Participants in the intervention group reported significantly greater consumption of calcium in both study years, vitamin D in the first year, and fruits and vegetables in both years. We found no effect on soda consumption or target exercise rates. A comprehensive health care-based lifestyle intervention can effectively improve dietary intake and increase bone mineral gains in adolescent girls. To our knowledge, this study is the first to significantly improve bone mass in adolescent girls in a non-school-based intervention. Trial Registration ClinicalTrials.gov Identifier: NCT00067600.


Prevalence of latent tuberculosis infection in Sudan: a case-control study comparing interferon-γ release assay and tuberculin skin test.
Most people exposed to M. tuberculosis show no evidence of clinical disease. Five to 10% of individuals with latent infection progress to develop overt disease during their life time. Identification of people with latent TB infection will increase case detection rates and may dictate new treatment policies to control tuberculosis. This study aimed to determine LTBI point prevalence in a population from Sudan using two different diagnostic methods: the tuberculin skin test (TST) and the IFN-γ release assay (IGRA). This was a prospective, community-based and case-controlled study. Following informed consent, household contacts (HHCs; n = 98) of smear-positive index cases and Community controls (CCs; 186), were enrolled. Tuberculin skin test (TST), whole blood stimulation with ESAT-6/CFP-10 ± TB7.7 antigens or purified protein derivative (PPD) and IFN-γ levels determination with ELISA were performed. The levels of IFN-γ and TST induration between the CCs and the HHCs were compared using student t-test, Chi-square and Kappa coefficient. Pearson correlation test was used to compare TST and IFN-γ. P levels of <0.05 were considered significant. TST induration of ≥ 10 mm gave an LTBI point prevalence of 327 cases/1000 individuals among HHCs compared to 126 cases/1000 individuals among CCs (p = 0.000). PPD-induced IFN-γ release assay gave an LTBI point prevalence of 418 cases/1000 individuals among HHCs compared to 301 cases/1000 individuals among CCs (p =0.06). On the other hand ESAT-6/CFP-10 ± TB7.7-induced IFN-γ gave an LTBI point prevalence of 429 cases/1000 individuals among HHCs compared to 268 cases/1000 individuals among CCs (p = 0.01). IFN-γ productions levels induced by ESAT-6/CPF-10 ± TB7.7 antigens in HHCS and CCs were not significantly different from those induced by PPD (p = 0.7). IFN-γ release assay (IGRA) gave higher LTBI point prevalence compared to TST in HHCs and CCs. PPD gave comparable results to ESAT-6/CFP-10 ± TB7.7 antigens in whole blood IFN-γ release, making it a cheap alternative to the recombinant antigens.


The future of clinical research in oncology: where are we heading to?
Despite considerable investment in oncological research, the rate of improvement in cancer treatments remains frustratingly slow and the attrition rate in anticancer drug development has reached exasperatingly high levels. New skills are required to expand upon platforms to integrate clinical, biological and imaging data in the decision making process so that we can control the attrition rate of new drugs and/or determine tumor molecular sub-entities which will ultimately benefit new therapeutic strategies. Furthermore, modern clinical trials will be unable to generate reliable and robust evidence if they are not quality assured. Decreasing the number of poorly designed clinical trials through stronger collaboration between industry and academia is a win-win situation and will reduce the current high attrition rate and minimize exposure of patients to ineffective investigational therapies.


Inception of a false memory by optogenetic manipulation of a hippocampal memory engram.
Memories can be easily distorted, and a lack of relevant animal models has largely hindered our understanding of false-memory formation. Here, we first identified a population of cells in the dentate gyrus (DG) of the hippocampus that bear the engrams for a specific context; these cells were naturally activated during the encoding phase of fear conditioning and their artificial reactivation using optogenetics in an unrelated context was sufficient for inducing the fear memory specific to the conditioned context. In a further study, DG or CA1 neurons activated by exposure to a particular context were labelled with channelrhodopsin-2 (ChR2). These neurons were later optically reactivated during fear conditioning in a different context. The DG experimental group showed increased freezing in the original context in which a foot shock was never delivered. The recall of this false memory was context specific, activated similar downstream regions engaged during natural fear-memory recall, and was also capable of driving an active fear response. Together, our data demonstrate that by substituting a natural conditioned stimulus with optogenetically reactivated DG cells that bear contextual memory engrams, it is possible to incept an internally and behaviourally represented false fear memory.


Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer's disease.
To examine the relationship between stereologic estimates of AD-related pathology and severity of cognitive deficits in brain aging. Previous studies reported substantial contributions of neurofibrillary tangles (NFT), amyloid deposits, and neuronal loss to the development of dementia. However, the prediction of cognitive status based on nonstereologic quantification of these measures has led to conflicting results. Such studies have measured densities, rather than absolute numbers, and most do not take into account the potential interaction between the above pathologic hallmarks in a global multivariate analysis. Clinicopathologic study in 22 elderly cases. Cognitive status assessed prospectively using the Mini-Mental State Examination (MMSE); stereologic assessment of NFT, unaffected neurons, and total amyloid volume in the CA1 field of the hippocampus, entorhinal cortex, and area 9. Statistical analysis was performed using both univariate and multivariate linear regression models. High total NFT counts but not amyloid volume were strongly associated with a lower number of unaffected neurons in all areas studied. A high proportion of variability in MMSE scores was explained by NFT and neuronal counts in the CA1 field (83% and 85.4%), entorhinal cortex (87.8% and 83.7%), and area 9 (87% and 79%); amyloid volume in the entorhinal cortex, but not in the CA1 field and area 9, accounted for 58.5% of MMSE variability. Multivariate analyses showed that total NFT counts in the entorhinal cortex and area 9 as well as neuron numbers in the CA1 field were the best predictors of MMSE score. These new stereologic data indicate that neuronal pathology in hippocampal formation and frontal cortex closely reflects the progression of cognitive deficits in brain aging and AD. They also demonstrate that amyloid volume has no additional predictive value, in terms of clinicopathologic correlations, beyond its interaction with NFT.


Windswept hip deformity in children with cerebral palsy: a population-based prospective follow-up.
To analyze the development of windswept hip deformity (WS) in a total population of children with cerebral palsy (CP) up to 20 years of age, the association between WS and hip dislocation, and femoral varus osteotomy and scoliosis, and the impact of a hip surveillance program on the subsequent incidence of WS. This is a prospective study on children with CP in southern Sweden included in the Swedish follow-up programme and registry for CP (CPUP). All children born between 1990 and 1995 with CP were included; those born between 1990 and 1991 did not partake in the hip surveillance program until they were older (3-5 years of age) and served as a historic control group. Children born between 1992 and 1995 were included in the hip surveillance program from about 2 years of age and constituted the study group. In the control group, 12 of 68 children (18 %) developed WS. In the study group of 139 children, 13 (9 %) developed WS (p = 0.071). Of all 25 children with WS, 21 also developed scoliosis and 5 developed a hip dislocation. The number of children with WS starting in the lower extremities was significantly lower in the study group (p = 0.028). No difference between the two groups was seen regarding WS that started in combination with scoliosis. With early inclusion in a hip surveillance program and early treatment of contractures, it appears possible to reduce the frequency of WS starting in the lower extremities.


Identification and Characterization of Preferred DNA-Binding Sites for the Thermus thermophilus HB8 Transcriptional Regulator TTHA0973.
Advances in genomic sequencing have allowed the identification of a multitude of genes encoding putative transcriptional regulatory proteins. Lacking, often, is a fuller understanding of the biological roles played by these proteins, the genes they regulate or regulon. Conventionally this is achieved through a genetic approach involving putative transcription factor gene manipulation and observations of changes in an organism's transcriptome. However, such an approach is not always feasible or can yield misleading findings. Here, we describe a biochemistry-centric approach, involving identification of preferred DNA-binding sequences for the Thermus thermophilus HB8 transcriptional repressor TTHA0973 using the selection method Restriction Endonuclease Protection, Selection and Amplification (REPSA), massively parallel sequencing, and bioinformatic analyses. We identified a consensus TTHA0973 recognition sequence of 5'-AACnAACGTTnGTT-3' that exhibited nanomolar binding affinity. This sequence was mapped to several sites within the T. thermophilus HB8 genome, a subset of which corresponded to promoter regions regulating genes involved in phenylacetic acid degradation. These studies further demonstrate the utility of a biochemistry-centric approach for the facile identification of potential biological functions for orphan transcription factors in a variety of organisms.


Re-ordering connections: UK healthcare workers' experiences of emotion management during the COVID-19 pandemic.
This paper examines the impact of disruptions to the organisation and delivery of healthcare services and efforts to re-order care through emotion management during the COVID-19 pandemic in the UK. Framing care as an affective practice, studying healthcare workers' (HCWs) experiences enables better understanding of how interactions between staff, patients and families changed as a result of the pandemic. Using a rapid qualitative research methodology, we conducted interviews with frontline HCWs in two London hospitals during the peak of the first wave of the pandemic and sourced public accounts of HCWs' experiences of the pandemic from social media (YouTube and Twitter). We conducted framework analysis to identify key factors disrupting caring interactions. Fear of infection and the barriers of physical distancing acted to separate staff from patients and families, requiring new affective practices to repair connections. Witnessing suffering was distressing for staff, and providing a 'good death' for patients and communicating care to families was harder. In addition to caring for patients and families, HCWs cared for each other. Infection control measures were important for limiting the spread of COVID-19 but disrupted connections that were integral to care, generating new work to re-order interactions.


Methods for visualization of enzymes in polyacrylamide gels.
White bands resulting from precipitation of dodecan-1-ol liberated by hydrolysis of sodium dodecyl sulfate and decan-5-ol released by hydrolysis of decan-5-yl sulfate produced zymograms of the primary and secondary alkylsulfatases from Pseudomonas C(12)B. Gas-liquid chromatographic analyses of ether extracts of the precipitate-containing segments of the zymograms confirmed the identity of the alcohols which were not discerned in extracts of segments of the gels other than those containing precipitates. beta-Galactosidase from Escherichia coli was marked on zymograms by the liberation of o-nitrophenol from o-nitrophenyl-beta-D-galactoside, and arylsulfatase from Pseudomonas C(12)B was marked in gels by liberation of p-nitrophenol from p-nitrophenyl sulfate. Membrane-associated dissimilatory nitrate reductases from a nitrate respirer (Enterobacter aerogenes) and a denitrifier (Pseudomonas perfectomarinus) did not penetrate either 6.8 or 3% polyacrylamide gel but were demonstrable at the top of the gels. In the membrane-bound state, formate served as electron donor for nitrate reductase from E. aerogenes, and reduced nicotinamide adenine dinucleotide (NADH) served as donor for nitrate reductase from P. perfectomarinus. Both enzymes reduced nitrate at the expense of reduced benzyl viologen as well. Assimilatory nitrate reductase from E. aerogenes moved easily into the 6.8% gels (R(f) = 0.43 under the conditions of these experiments). The reduced dye served as electron donor for the assimilatory reductase, but formate and NADH did not. Incubation of the membrane-associated nitrate reductases with 2% Triton X-100 solubilized the enzymes and removed the capacity of formate and NADH to serve as electron donors. Both retained the ability to reduce nitrate at the expense of reduced benzyl viologen. The solubilized dissimilatory reductase from E. aerogenes moved further in the gels (R(f) = 0.49) than the soluble assimilatory reductase; the solubilized dissimilatory reductase from the denitrifier, P. perfectomarinus, moved further in the gels (R(f) = 0.64) than either of the enzymes from E. aerogenes.


SOCS3 deletion promotes optic nerve regeneration in vivo.
Axon regeneration failure accounts for permanent functional deficits following CNS injury in adult mammals. However, the underlying mechanisms remain elusive. In analyzing axon regeneration in different mutant mouse lines, we discovered that deletion of suppressor of cytokine signaling 3 (SOCS3) in adult retinal ganglion cells (RGCs) promotes robust regeneration of injured optic nerve axons. This regeneration-promoting effect is efficiently blocked in SOCS3-gp130 double-knockout mice, suggesting that SOCS3 deletion promotes axon regeneration via a gp130-dependent pathway. Consistently, a transient upregulation of ciliary neurotrophic factor (CNTF) was observed within the retina following optic nerve injury. Intravitreal application of CNTF further enhances axon regeneration from SOCS3-deleted RGCs. Together, our results suggest that compromised responsiveness to injury-induced growth factors in mature neurons contributes significantly to regeneration failure. Thus, developing strategies to modulate negative signaling regulators may be an efficient strategy of promoting axon regeneration after CNS injury.


Helminths in common eiders (Somateria mollissima): Sex, age, and migration have differential effects on parasite loads.
In birds, parasites cause detrimental effects to the individual host, including reduced survival and reproductive output. The level of parasitic infection can vary with a range of factors, including migratory status, body size, sex, and age of hosts, or season. Understanding this baseline variation is important in order to identify the effects of external changes such as climate change on the parasitic load and potential impacts to individuals and populations. In this study, we compared the infection level (prevalence, intensity, and abundance) of gastrointestinal parasites in a total of 457 common eiders (Somateria mollissima) from four different sampling locations (Belcher Islands, Cape Dorset, West Greenland and Newfoundland), and explored the effects of migration, sex and age on levels of parasitism. Across all samples, eiders were infected with one nematode genus, two acanthocephalan genera, three genera of cestodes, and three trematode genera. Migratory phase and status alone did not explain the observed variation in infection levels; the expectation that post-migratory eiders would be more parasitized than pre-migratory eiders, due to the energetic cost of migration, did not fit our results. No effect of age was detected, whereas effects of sex and body size were only detected for certain parasitic taxa and was inconsistent with location. Since gastrointestinal helminths are trophically-transmitted, future studies of the regional and temporal variation in the diet of eiders and the associated variation and infestation level of intermediate hosts might further explain the observed variation of the parasitic load in eiders in different regions.


Strong and Ductile Non-equiatomic High-Entropy Alloys: Design, Processing, Microstructure, and Mechanical Properties.
We present a brief overview on recent developments in the field of strong and ductile non-equiatomic high-entropy alloys (HEAs). The materials reviewed are mainly based on massive transition-metal solute solutions and exhibit a broad spectrum of microstructures and mechanical properties. Three relevant aspects of such non-equiatomic HEAs with excellent strength-ductility combination are addressed in detail, namely phase stability-guided design, controlled and inexpensive bulk metallurgical processing routes for appropriate microstructure and compositional homogeneity, and the resultant microstructure-property relations. In addition to the multiple principal substitutional elements used in these alloys, minor interstitial alloying elements are also considered. We show that various groups of strong and ductile HEAs can be obtained by shifting the alloy design strategy from single-phase equiatomic to dual- or multiphase non-equiatomic compositional configurations with carefully designed phase instability. This design direction provides ample possibilities for joint activation of a number of strengthening and toughening mechanisms. Some potential research efforts which can be conducted in the future are also proposed.


Sensory neuronal STAT3 is critical for IL-31 receptor expression and inflammatory itch.
IL-31 receptor blockade suppresses pruritus of atopic dermatitis. However, cell-type-specific contributions of IL-31 receptor to itch, its expression mechanism, and the downstream signaling pathway to induce itch remain unknown. Here, using conditional knockout mice, we demonstrate that IL-31-induced itch requires sensory neuronal IL-31 receptor and STAT3. We find that IL-31 receptor expression is dependent on STAT3 in sensory neurons. In addition, pharmacological experiments suggest that STAT3 activation is important for the itch-inducing signaling downstream of the IL-31 receptor. A cutaneous IL-31 injection induces the nuclear accumulation of activated STAT3 first in sensory neurons that abundantly express IL-31 receptor and then in other itch-transmitting neurons. IL-31 enhances itch induced by various pruritogens including even chloroquine. Finally, pruritus associated with dermatitis is partially dependent on sensory neuronal IL-31 receptor and strongly on sensory neuronal STAT3. Thus, sensory neuronal STAT3 is essential for IL-31-induced itch and further contributes to IL-31-independent inflammatory itch.


MMV in partnership: the Eurartesim® experience.
This case study describes how a public-private partnership between Medicines for Malaria Venture (MMV) and Sigma-Tau Industrie Farmaceutiche Riunite SpA achieved international regulatory approval for use of the fixed-dose artemisinin-based combination therapy dihydroartemisinin-piperaquine (Eurartesim®) for the treatment of malaria, enabling more widespread access to the medicine in malaria-endemic countries. The combination of dihydroartemisinin and piperaquine demonstrated success in clinical trials for the treatment of malaria in Asia and Africa in the 2000s. However, as it had not been developed to international regulatory standards it was out of the reach of the majority of patients in disease-endemic countries, particularly those reliant on public healthcare systems supported by international donor funding. To overcome this, as of 2004 MMV worked in partnership with Sigma-Tau, Holleykin, Oxford University, the Institute of Tropical Medicine Antwerp, and the National Institute of Malaria Research India to develop the dihydroartemisinin-piperaquine combination to international standards. In 2011, the European Commission granted full marketing authorization to Sigma-Tau for Eurartesim. The partnership between MMV, Sigma-Tau, and numerous other academic and industrial partners across the world, led to the successful development to EMA regulatory standards of a high-quality and highly efficacious anti-malarial treatment that otherwise would not have been possible. The dossier has also been submitted to the WHO for prequalification, and a safety statement to guide correct use of Eurartesim has been produced. In July 2012, the first delivery to a disease-endemic country was made to Cambodia, where the medicine is being used to treat patients and help counter the emergence of artemisinin resistance in the area. A paediatric dispersible formulation of Eurartesim is being developed, with the objective to submit the dossier to the EMA by the end of 2014. The development of Eurartesim to international regulatory standards exemplifies the strengths of the product development partnership model in utilising the individual skills and expertise of partners with differing objectives to achieve a common goal. Successful uptake of Eurartesim by public health systems in malaria-endemic countries poses new challenges, which may require additional partnerships as we move forward.


Sulfatides are required for renal adaptation to chronic metabolic acidosis.
Urinary ammonium excretion by the kidney is essential for renal excretion of sufficient amounts of protons and to maintain stable blood pH. Ammonium secretion by the collecting duct epithelia accounts for the majority of urinary ammonium; it is driven by an interstitium-to-lumen NH3 gradient due to the accumulation of ammonium in the medullary and papillary interstitium. Here, we demonstrate that sulfatides, highly charged anionic glycosphingolipids, are important for maintaining high papillary ammonium concentration and increased urinary acid elimination during metabolic acidosis. We disrupted sulfatide synthesis by a genetic approach along the entire renal tubule. Renal sulfatide-deficient mice had lower urinary pH accompanied by lower ammonium excretion. Upon acid diet, they showed impaired ammonuria, decreased ammonium accumulation in the papilla, and chronic hyperchloremic metabolic acidosis. Expression levels of ammoniagenic enzymes and Na(+)-K(+)/NH4(+)-2Cl(-) cotransporter 2 were higher, and transepithelial NH3 transport, examined by in vitro microperfusion of cortical and outer medullary collecting ducts, was unaffected in mutant mice. We therefore suggest that sulfatides act as counterions for interstitial ammonium facilitating its retention in the papilla. This study points to a seminal role of sulfatides in renal ammonium handling, urinary acidification, and acid-base homeostasis.


Globally minimal surfaces by continuous maximal flows.
In this paper, we address the computation of globally minimal curves and surfaces for image segmentation and stereo reconstruction. We present a solution, simulating a continuous maximal flow by a novel system of partial differential equations. Existing methods are either grid-biased (graph-based methods) or suboptimal (active contours and surfaces). The solution simulates the flow of an ideal fluid with isotropic velocity constraints. Velocity constraints are defined by a metric derived from image data. An auxiliary potential function is introduced to create a system of partial differential equations. It is proven that the algorithm produces a globally maximal continuous flow at convergence, and that the globally minimal surface may be obtained trivially from the auxiliary potential. The bias of minimal surface methods toward small objects is also addressed. An efficient implementation is given for the flow simulation. The globally minimal surface algorithm is applied to segmentation in 2D and 3D as well as to stereo matching. Results in 2D agree with an existing minimal contour algorithm for planar images. Results in 3D segmentation and stereo matching demonstrate that the new algorithm is robust and free from grid bias.


Combinatorial synthesis of genetic networks.
A central problem in biology is determining how genes interact as parts of functional networks. Creation and analysis of synthetic networks, composed of well-characterized genetic elements, provide a framework for theoretical modeling. Here, with the use of a combinatorial method, a library of networks with varying connectivity was generated in Escherichia coli. These networks were composed of genes encoding the transcriptional regulators LacI, TetR, and lambda CI, as well as the corresponding promoters. They displayed phenotypic behaviors resembling binary logical circuits, with two chemical "inputs" and a fluorescent protein "output." Within this simple system, diverse computational functions arose through changes in network connectivity. Combinatorial synthesis provides an alternative approach for studying biological networks, as well as an efficient method for producing diverse phenotypes in vivo.


The role of the Director Zmago Slokan in the development of Maribor General Hospital in the first period after the Second World War (1953-1970).
The author explores and explains the role of the director of Maribor General Hospital in the first period after Second World War. The period was problematic on account of the difficult economic situation and changes in the political system. On one hand the hospital suffered relatively large damage due to bombing attacks during the war and on the other it had to face numerous staffing problems, especially with a lack of physicians and trained nursing staff (from 1948 an executive order entered into force forbidding the nursing nuns from performing nursing care in hospitals). The change in the political system required the management of the hospital to be taken over by an individual who enjoyed the political, professional and economic trust of the then authorities. Based on his engagement during the Second World War, the director, Zmago Slokan, represented a form of guarantee for the political system of that time, which nevertheless wanted the quality-based, professional and economic progress of the hospital. Using his personal characteristics, professional medical and economic knowledge as well as political experience, he was able to manage different tendencies to continue the quality-based progress of the institution. Thus, he set a proper foundation for its development in the periods that followed, in the Socialist Federative Republic of Yugoslavia as well as in the independent Republic of Slovenia (after 1991). The author discusses the role of the director in the hospital's progress chronologically.


Self-assembly of stimuli-responsive coiled-coil fibrous hydrogels.
Owing to their tunable properties, hydrogels comprised of stimuli-sensitive polymers are one of the most appealing scaffolds with applications in tissue engineering, drug delivery and other biomedical fields. We previously reported a thermoresponsive hydrogel formed using a coiled-coil protein, Q. Here, we expand our studies to identify the gelation of Q protein at distinct pH conditions, creating a protein hydrogel system that is sensitive to temperature and pH. Through secondary structure analysis, transmission electron microscopy, and rheology, we observed that Q self-assembles and forms fiber-based hydrogels exhibiting upper critical solution temperature behavior with increased elastic properties at pH 7.4 and pH 10. At pH 6, however, Q forms polydisperse nanoparticles, which do not further self-assemble and undergo gelation. The high net positive charge of Q at pH 6 creates significant electrostatic repulsion, preventing its gelation. This study will potentially guide the development of novel scaffolds and functional biomaterials that are sensitive towards biologically relevant stimuli.


Multicompartment micelles with adjustable poly(ethylene glycol) shell for efficient in vivo photodynamic therapy.
We describe the preparation of well-defined multicompartment micelles from polybutadiene-block-poly(1-methyl-2-vinyl pyridinium methyl sulfate)-block-poly(methacrylic acid) (BVqMAA) triblock terpolymers and their use as advanced drug delivery systems for photodynamic therapy (PDT). A porphyrazine derivative was incorporated into the hydrophobic core during self-assembly and served as a model drug and fluorescent probe at the same time. The initial micellar corona is formed by negatively charged PMAA and could be gradually changed to poly(ethylene glycol) (PEG) in a controlled fashion through interpolyelectrolyte complex formation of PMAA with positively charged poly(ethylene glycol)-block-poly(L-lysine) (PLL-b-PEG) diblock copolymers. At high degrees of PEGylation, a compartmentalized micellar corona was observed, with a stable bottlebrush-on-sphere morphology as demonstrated by cryo-TEM measurements. By in vitro cellular experiments, we confirmed that the porphyrazine-loaded micelles were PDT-active against A549 cells. The corona composition strongly influenced their in vitro PDT activity, which decreased with increasing PEGylation, correlating with the cellular uptake of the micelles. Also, a PEGylation-dependent influence on the in vivo blood circulation and tumor accumulation was found. Fully PEGylated micelles were detected for up to 24 h in the bloodstream and accumulated in solid subcutaneous A549 tumors, while non- or only partially PEGylated micelles were rapidly cleared and did not accumulate in tumor tissue. Efficient tumor growth suppression was shown for fully PEGylated micelles up to 20 days, demonstrating PDT efficacy in vivo.


Association of Material Deprivation Status, Access to Health Care Services, and Lifestyle With Screening and Prevention of Disease, Montreal, Canada, 2012.
The objective of this study was to provide information on the effect of disparities in material deprivation, access to health care services, and lifestyle on the likelihood of undergoing screening for disease prevention. We used data from a probability sample (N = 10,726) of the Montreal population aged 15 years or older and assessed 6 dependent variables (screening for breast cancer, cervical cancer, colon cancer, blood glucose, and high blood pressure and receipt of the seasonal influenza vaccination), and 3 independent variables (disparities in material deprivation, access to health care services, and personal lifestyle habits). We used logistic regression to analyze data and determine associations. Use of preventive health services increased as material deprivation declined, access to health care improved, and lifestyle habits became healthier. The combined effect of household income, an individual measure, and the material deprivation index (consisting of quintiles representing a range from the most privileged [quintile 1: best education, employment, and income] to the most deprived [quintile 5: least education, employment, and income) an ecological measure, showed that having a Papanicolaou test was significantly associated with high annual household income (≥$40,000) even if the woman resided in a deprived neighborhood (quintiles 4 and 5 of the material deprivation index) (odds ratio [OR], 1.38; 95% confidence interval (95% [CI], 1.04-1.84), whereas odds of having a mammogram or influenza vaccination were significantly associated with living in a privileged neighborhood (quintiles 1, 2, and 3 of the material deprivation index) even among people with a low annual household income (<$40,000) (mammogram: OR, 1.54; 95% CI, 1.00-2.38; influenza vaccination: OR, 1.31; 95% CI, 1.04-1.66). In addition to influencing lifestyle habits and access to health care services, disparities in material deprivation influence whether a person uses preventive health services. Public health professionals need to establish screening outreach programs in socioeconomically disadvantaged neighborhoods to enhance public participation in disease prevention programs and reduce disparities in health.