Squamous cell carcinoma-associated antigens used in novel strategies for the detection and treatment of minimal residual head and neck cancer.
The improvement of detection and eradication of minimal residual disease, to reduce local and distant relapse after primary therapy, is one of the major challenges in the management of squamous cell carcinoma of the head and neck (HNSCC). This paper describes perspectives arising from the use of monoclonal antibodies (MAbs) E48 and U36 directed against HNSCC-associated antigens, and the molecular characterization of these antigens. Novel strategies for the detection of minimal residual disease are outlined and comprise the use of immunocytochemistry in combination with automated image analysis, and the use of an E48-specific reverse transcriptase-polymerase chain reaction (RT-PCR) method. These methods have potential for the detection of single HNSCC cells in lymph nodes, bone marrow and peripheral blood, and may contribute to the better staging of head and neck cancer in the near future. Besides this, preclinical and clinical data on HNSCC targeting with radiolabelled MAbs E48 and U36 are summarized, illustrating the perspectives of systemic adjuvant radioimmunotherapy with these MAbs.


Biodistribution and clearance of intra-articular liposomes in a large animal model using a radiographic marker.
The intra-articular (IA) route of administration in treating arthritis has potential for targeting drug delivery to affected tissues, thereby minimising the attendant side-effects of systemically administered drugs. The ultra-structure of the synovium however facilitates rapid drug efflux from the joint; effectively the IA route is equivalent to other non-IV parenteral routes with regards absorption and redistribution into the systemic circulation. The aim of this study was to extend the drug residence time within the knee joint by using a liposome formulation. DPPC-based liposomes were prepared with the radio contrast agent iohexol as a drug marker. 8 sheep had their right knees injected IA with iohexol liposomes and the contralateral joints with either free iohexol or empty liposomes. Joints were radiographed at multiple time points up to 16 days post-injection. Iohexol-mediated radiopacity was quantified by densitometer. Sheep were sacrificed at the end of the study for microscopy of synovial tissues. Good visualization of iohexol-mediated radiopacity with fine anatomical definition was possible throughout the experiment. Also evident on the films was extra-articular radiopacity with liposomes tracking along muscle facial planes. Cellular and tissue localization with light microscopy was possible through use of frozen sections and because of the large liposome size. Residence of encapsulated iohexol within the knee joint was greatly prolonged. Liposomal iohexol declined bi-exponentially with a terminal elimination half-life of 134 hours. In contrast, free iohexol was undetectable at 3 hours post-injection.


Effects of exogenous melatonin and circadian synchronization on tumor progression in melanoma-bearing C57BL6 mice.
Circadian rhythmicity impairment reportedly becomes significant as a tumor progresses, while the incidence of cancer can be affected by disruption of the circadian system. Melatonin has oncostatic effects on several types of cancer (breast, prostate, and colorectal cancers), while it can be self-defeating in others, such as lymphoma. Melanoma is one of the most aggressive cancers in humans; however, it seems to respond positively to melatonin in vitro. The present work tested whether body temperature (BT) rhythms are impaired by tumor progression, and whether exogenous melatonin restricts tumor growth and restores circadian rhythmicity; therefore, enhancing survival. To this end, C57 mice were intraperitoneal implanted with a temperature data logger and subcutaneously inoculated with melanoma cells. Animals were then submitted to light-dark (LD) 12:12 cycles or continuous light (LL), with or without melatonin administration. Under LD light conditions, the BT rhythm exhibited a marked reduction in the first circadian harmonic amplitude, and increased phase instability (Rayleigh vector) as the tumor progressed. Melatonin administration (2 mg/kg BW/day), on the other hand, increased the BT rhythm amplitude and phase stability, reduced tumor weight and prevented intraperitoneal dissemination. Exposure to LL induced a free-running rhythm (1500 min), significantly increasing tumor malignity, and therefore reducing survival. Surprisingly, the highest tumor weights and morbidity by metastasis were seen in the LL group treated with melatonin probably because this indoleamine was being administered at different subjective hours to free-running animals. Circadian rhythmicity can thus be used as a marker rhythm for tumor progression, as rhythm impairment increases along with tumor malignancy. While melatonin administration improves rhythmicity and enhances survival under LD conditions, the results are self-defeating when they coexist with circadian disruption as it occurs under LL. This emphasizes the importance of taking into account endogenous rhythmicity and limiting melatonin administration to the subjective night in order to restrict melanoma progression.


Effects of health policy reforms on nursing resources and patient outcomes in New Zealand.
Health policy reforms in New Zealand during the 1990s impacted on hospital operations, on the nursing workforce, and on patients. This study analyses changes in rates of 20 adverse patient outcomes that are potentially sensitive to nursing (OPSNs) before (1989-1993), during (1993-2000), and after (2000-2006) the policy reforms, using all New Zealand public hospital inpatient discharge data for this period. Comparisons of changes in mean annual rates across periods revealed the expected trajectory of acceleration during the reform period relative to the prereform period, and a subsequent deceleration in the postreform period. This S-shaped pattern was clearly evident in 16 of the 20 OPSNs, and partially evident in the remaining 4. These results are interpreted as evidence that the 1990s policy reforms inspired by managerialism had deleterious effects on patient outcomes, and that these effects coincided with changes in nursing resources and the work environment.


Effect of high-intensity versus low-intensity praziquantel treatment on HIV disease progression in HIV and Schistosoma mansoni co-infected patients: a randomised controlled trial.
Background: It has been hypothesised that Schistosoma co-infection exacerbates HIV progression, and hence anthelminthic intervention in co-infected individuals will delay it. We evaluated effects of high-intensity versus low-intensity praziquantel treatment of schistosomiasis on HIV disease progression among co-infected patients from fishing populations around Lake Victoria, Uganda. Methods: Between August 2012 and September 2015, we conducted an open-label randomised, controlled trial. Adults, antiretroviral therapy-naïve, CD4 counts ≥350 cells/μl, HIV and S. mansoni co-infected, were randomised 1:1 to praziquantel (40mg/kg) given quarterly (starting at enrolment) or annually (starting 12 weeks after enrolment; such that low-intensity participants were still untreated when sampled at 12 weeks). A non-randomised HIV-positive S. mansoni-negative comparison group was recruited. The primary outcome was mean change in plasma viral load at 12 and 60 weeks. Results: In total 363 participants (high-intensity 113, low-intensity 113, comparison group 137) were recruited; 96 (85.0%), 97 (85.8%) and 107 (78.1%) completed 60 weeks of follow up, respectively. Adjusting for baseline age and viral load, the geometric mean ratio (aGMR [95%CI]) viral load for high-intensity vs low-intensity groups at 12 weeks was 0.90 [0.65, 1.25] p=0.55 and at 60 weeks 1.88 [0.78, 4.53] p=0.16. Results in the comparison group were similar to trial arms. High-intensity, compared to low-intensity, treatment resulted in substantially lower S. mansoni prevalence at all follow up visits (p<0.05). Conclusions: In communities with a high burden of both S. mansoni and HIV infection, high-intensity treatment of S. mansoni does not delay HIV progression despite relevant benefit for parasite clearance. Trial registration: ISRCTN15371662 (17/11/2016).


Specific recognition of human leukemic cells by allogeneic T cells: II. Evidence for HLA-D restricted determinants on leukemic cells that are crossreactive with determinants present on unrelated nonleukemic cells.
Transplantation of immunocompetent cells present within allogeneic bone marrow has been associated with the elimination of residual host leukemia, both in animal tumor models and in patients receiving marrow transplants for leukemia. This observation has been called the "graft-versus-leukemia effect." We have attempted to study this phenomenon in vitro by characterizing the cytolytic response of T cells from normal donors after in vitro activation with allogeneic leukemic cells. As expected, most T cells that react against an allogeneic patient's leukemic cells recognize their foreign HLA antigens and lyse the patient's nonleukemic remission lymphoid cells. In addition, we have shown that a small fraction of the T cells recognize and lyse foreign leukemic targets without lysis of nonmalignant remission targets from the same leukemic patient. These T cells have been isolated and characterized as CD3+, CD4+ cells expressing the alpha/beta T cell receptor (TCR). Their lysis appears to reflect specific antigen recognition mediated via the CD3-TCR complex and interactions involving the CD4 receptor. Some of these "leukemic specific" T cell lines, which are restricted by HLA class II molecules, can also lyse occasional nonleukemic cells from certain unrelated donors. This recognition appears to involve crossreactive determinants shared by the leukemic cells and the unrelated allogeneic nonleukemic cells. These specific interactions may represent an in vitro model of the graft-versus-leukemia effect.


Embedded System for Prosthetic Control Using Implanted Neuromuscular Interfaces Accessed Via an Osseointegrated Implant.
Despite the technological progress in robotics achieved in the last decades, prosthetic limbs still lack functionality, reliability, and comfort. Recently, an implanted neuromusculoskeletal interface built upon osseointegration was developed and tested in humans, namely the Osseointegrated Human-Machine Gateway. Here, we present an embedded system to exploit the advantages of this technology. Our artificial limb controller allows for bioelectric signals acquisition, processing, decoding of motor intent, prosthetic control, and sensory feedback. It includes a neurostimulator to provide direct neural feedback based on sensory information. The system was validated using real-time tasks characterization, power consumption evaluation, and myoelectric pattern recognition performance. Functionality was proven in a first pilot patient from whom results of daily usage were obtained. The system was designed to be reliably used in activities of daily living, as well as a research platform to monitor prosthesis usage and training, machine-learning-based control algorithms, and neural stimulation paradigms.


Presynaptic terminals independently regulate synaptic clustering and autophagy of GABAA receptors in Caenorhabditis elegans.
Synaptic clustering of GABAA receptors is important for the function of inhibitory synapses, influencing synapse strength and, consequently, the balance of excitation and inhibition in the brain. Presynaptic terminals are known to induce GABAA receptor clustering during synaptogenesis, but the mechanisms of cluster formation and maintenance are not known. To study how presynaptic neurons direct the formation of GABAA receptor clusters, we have investigated GABAA receptor localization in postsynaptic cells that fail to receive presynaptic contacts in Caenorhabditis elegans. Postsynaptic muscles in C. elegans receive acetylcholine and GABA motor innervation, and GABAA receptors cluster opposite GABA terminals. Selective loss of GABA inputs caused GABAA receptors to be diffusely distributed at or near the muscle cell surface, confirming that GABA presynaptic terminals induce GABAA receptor clustering. In contrast, selective loss of acetylcholine innervation had no effect on GABAA receptor localization. However, loss of both GABA and acetylcholine inputs together caused GABAA receptors to traffic to intracellular autophagosomes. Autophagosomes normally transport bulk cytoplasm to the lysosome for degradation. However, we show that GABAA receptors traffic to autophagosomes after endocytic removal from the cell surface and that acetylcholine receptors in the same cells do not traffic to autophagosomes. Thus, autophagy can degrade cell-surface receptors and can do so selectively. Our results show that presynaptic terminals induce GABAA receptor clustering by independently controlling synaptic localization and surface stability of GABAA receptors. They also demonstrate a novel function for autophagy in GABAA receptor degradative trafficking.


Artificial neural networks using complex numbers and phase encoded weights.
The model of a simple perceptron using phase-encoded inputs and complex-valued weights is proposed. The aggregation function, activation function, and learning rule for the proposed neuron are derived and applied to Boolean logic functions and simple computer vision tasks. The complex-valued neuron (CVN) is shown to be superior to traditional perceptrons. An improvement of 135% over the theoretical maximum of 104 linearly separable problems (of three variables) solvable by conventional perceptrons is achieved without additional logic, neuron stages, or higher order terms such as those required in polynomial logic gates. The application of CVN in distortion invariant character recognition and image segmentation is demonstrated. Implementation details are discussed, and the CVN is shown to be very attractive for optical implementation since optical computations are naturally complex. The cost of the CVN is less in all cases than the traditional neuron when implemented optically. Therefore, all the benefits of the CVN can be obtained without additional cost. However, on those implementations dependent on standard serial computers, CVN will be more cost effective only in those applications where its increased power can offset the requirement for additional neurons.


Astrocytes refine cortical connectivity at dendritic spines.
During cortical synaptic development, thalamic axons must establish synaptic connections despite the presence of the more abundant intracortical projections. How thalamocortical synapses are formed and maintained in this competitive environment is unknown. Here, we show that astrocyte-secreted protein hevin is required for normal thalamocortical synaptic connectivity in the mouse cortex. Absence of hevin results in a profound, long-lasting reduction in thalamocortical synapses accompanied by a transient increase in intracortical excitatory connections. Three-dimensional reconstructions of cortical neurons from serial section electron microscopy (ssEM) revealed that, during early postnatal development, dendritic spines often receive multiple excitatory inputs. Immuno-EM and confocal analyses revealed that majority of the spines with multiple excitatory contacts (SMECs) receive simultaneous thalamic and cortical inputs. Proportion of SMECs diminishes as the brain develops, but SMECs remain abundant in Hevin-null mice. These findings reveal that, through secretion of hevin, astrocytes control an important developmental synaptic refinement process at dendritic spines.


Inclusion of emergency department patients in early stages of sepsis in a quality improvement programme has the potential to improve survival: a prospective dual-centre study.
Sepsis quality improvement programmes typically focus on severe sepsis (ie, with acute organ failure). However, quality of ED care might be improved if these programmes included patients whose progression to severe sepsis could still be prevented (ie, infection without acute organ failure). We compared the impact on mortality of implementing a quality improvement programme among ED patients with a suspected infection with or without acute organ failure. This prospective observational study among ED patients hospitalised with suspected infection was conducted in two hospitals in the Netherlands. After stratification by sepsis category (with or without organ failure), in-hospital mortality was compared between a full compliance (all quality performance measures achieved) and an incomplete compliance group. Multivariable logistic regression analysis was used to quantify the impact of full compliance on in-hospital mortality, adjusting for disease severity, disposition and hospital. There were 1732 ED patients and 130 deaths. Full compliance was independently associated with approximately two-thirds reduction in the odds of hospital mortality (adjusted OR of 0.30 (95% CI 0.19 to 0.47), which was similar in patients with and without organ failure. Among the 1379 patients with suspected infection without acute organ failure, there were 64 deaths, 15 (1.1%) in the full compliance group and 49 (3.6%) in the incomplete compliance group (mortality difference 2.5% (95% CI 1.6% to 3.3%)). Among 353 patients with organ failure, there were 66 deaths, 12 (3.4%) in the full compliance compared with 54 (15.3%) in the incomplete compliance group (mortality difference 11.9% (95% CI 8.5% to 15.3%)). Thus, there was a difference of 76 deaths between full and incomplete compliance groups, and 34 (45%) who benefited were those without acute organ failure. Sepsis quality improvement programmes should incorporate ED patients in earlier stages of sepsis given the potential to reduce in-hospital mortality among this population.


Caveolin proteins in signaling, oncogenic transformation and muscular dystrophy.
In adult animals and humans, signal transduction maintains homeostasis. When homeostatic mechanisms are interrupted, an illness or disease may ensue. Caveolae are plasma membrane specializations that contain the structural proteins caveolins, and appear to be important for normal signal transduction. The caveolin scaffolding domain interacts with several signaling molecules, sequestering them in the absence of activating signals, and thereby reducing the signal-to-noise ratio. Deletion and mutation of genes that encode caveolins is implicated in the pathogenesis of several human diseases. Down-regulation of caveolin-1 protein expression leads to deregulated signaling and consequently tumorigenesis, whereas naturally occurring dominant-negative caveolin-3 mutations cause muscular dystrophy.


Being an agent or an observer: different spectral dynamics revealed by MEG.
Several neuroimaging studies reported that a common set of regions is recruited during action observation and execution and it has been proposed that the modulation of the μ rhythm, in terms of oscillations in the alpha and beta bands might represent the electrophysiological correlate of the underlying brain mechanisms. However, the specific functional role of these bands within the μ rhythm is still unclear. Here, we used magnetoencephalography (MEG) to analyze the spectral and temporal properties of the alpha and beta bands in healthy subjects during an action observation and execution task. We associated the modulation of the alpha and beta power to a broad action observation network comprising several parieto-frontal areas previously detected in fMRI studies. Of note, we observed a dissociation between alpha and beta bands with a slow-down of beta oscillations compared to alpha during action observation. We hypothesize that this segregation is linked to a different sequence of information processing and we interpret these modulations in terms of internal models (forward and inverse). In fact, these processes showed opposite temporal sequences of occurrence: anterior-posterior during action (both in alpha and beta bands) and roughly posterior-anterior during observation (in the alpha band). The observed differentiation between alpha and beta suggests that these two bands might pursue different functions in the action observation and execution processes.


Well-being in Hispanic and non-Hispanic white survivors of breast cancer.
To test a well-being model on Hispanic and non-Hispanic white survivors of breast cancer by comparing responses about variables hypothesized to predict well-being. Healthcare orientation, uncertainty, social support, resourcefulness, self-esteem, and well-being. Descriptive and comparative. 50 Hispanic and 50 non-Hispanic white women who completed treatment for breast cancer and were disease-free. Regional cancer center in southwestern United States. Subjects completed the Psychosocial Adjustment to Illness Scale-Health Care Orientation Subscale, Mishel Uncertainty Illness Scale, Personal Resource Questionnaire, Self-Control Schedule, Self-Esteem Inventory, and Index of Well-Being. Both groups of women reported high well-being. Sample characteristics were not related significantly to well-being in either group. No statistically significant differences were found between Hispanic and non-Hispanic white women on any variables. Comparison of well-being models revealed similarities between the two groups, including variables entering each regression equation, and explained variance. Further research is needed to explore whether commonalities in women's responses to breast cancer exist independent of ethnicity. Nurses should continue encouraging both Hispanic and non-Hispanic white women to share concerns and seek information from healthcare providers while strengthening feelings of self-worth because these factors directly affect well-being.


Support for and aspects of use of educational games in family medicine and internal medicine residency programs in the US: a survey.
The evidence supporting the effectiveness of educational games in graduate medical education is limited. Anecdotal reports suggest their popularity in that setting. The objective of this study was to explore the support for and the different aspects of use of educational games in family medicine and internal medicine residency programs in the United States. We conducted a survey of family medicine and internal medicine residency program directors in the United States. The questionnaire asked the program directors whether they supported the use of educational games, their actual use of games, and the type of games being used and the purpose of that use. Of 434 responding program directors (52% response rate), 92% were in support of the use of games as an educational strategy, and 80% reported already using them in their programs. Jeopardy like games were the most frequently used games (78%). The use of games was equally popular in family medicine and internal medicine residency programs and popularity was inversely associated with more than 75% of residents in the program being International Medical Graduates. The percentage of program directors who reported using educational games as teaching tools, review tools, and evaluation tools were 62%, 47%, and 4% respectively. Given a widespread use of educational games in the training of medical residents, in spite of limited evidence for efficacy, further evaluation of the best approaches to education games should be explored.


What if the number of nanotoxicity data is too small for developing predictive Nano-QSAR models? An alternative read-across based approach for filling data gaps.
Over the past decade, computational nanotoxicology, in particular Quantitative Structure-Activity Relationship models (Nano-QSAR) that help in assessing the biological effects of nanomaterials, have received much attention. In effect, a solid basis for uncovering the relationships between the structure and property/activity of nanoparticles has been created. Nonetheless, six years after the first pioneering computational studies focusing on the investigation of nanotoxicity were commenced, these computational methods still suffer from many limitations. These are mainly related to the paucity of widely available, systematically varied, libraries of experimental data necessary for the development and validation of such models. This results in the still-low acceptance of these methods as valuable research tools for nanosafety and raises the query as to whether these methods could gain wide acceptance of regulatory bodies as alternatives for traditional in vitro methods. This study aimed to give an answer to the following question: How to remedy the paucity of experimental nanotoxicity data and thereby, overcome key roadblock that hinders the development of approaches for data-driven modeling of nanoparticle properties and toxicities? Here, a simple and transparent read-across algorithm for a pre-screening hazard assessment of nanomaterials that provides reasonably accurate results by making the best use of existing limited set of observations will be introduced.


On the measurement of relaxation times of acoustic vibrations in metal nanowires.
The mechanical resonances of metal nanostructures are strongly affected by their environment. In this paper the way the breathing modes of single metal nanowires are damped by liquids with different viscosities was studied by ultrafast pump-probe microscopy experiments. Both nanowires supported on a glass substrate and nanowires suspended over trenches were investigated. The measured quality factors for liquid damping for the suspended nanowires are in good agreement with continuum mechanics calculations for an inviscid fluid that assume continuity in stress and displacement at the nanowire-liquid interface. This shows that liquid damping is controlled by radiation of sound waves into the medium. For the nanowires on the glass surface the quality factors for liquid damping are approximately 60% higher than those for the suspended nanowires. This is attributed to a shadowing effect. The nanowires in our measurements have pentagonal cross-sections. This produces two different breathing modes and also means that one of the faces for the supported nanowires is blocked by the substrate, which reduces the amount of damping from the liquid. Comparing the supported and suspended nanowires also allows us to estimate the effect of the substrate on the acoustic mode damping. We find that the substrate has a weak effect, which is attributed to poor mechanical contact between the nanowires and the substrate.


Factors Associated with a Second Opioid Prescription Fill in Total Knee Arthroplasty.
Total knee arthroplasty (TKA) creates a relatively large degree of nociception, making it a good setting to study variation in pain intensity and pain alleviation. The purpose of this study is to investigate factors associated with a second prescription of opioid medications within 30 days of primary TKA. Using an insurance database, we studied 1372 people over a 6-year period with no mental health comorbidities including substance misuse and no comorbid pain illness at the time of TKA. Factors associated with a second prescription of opioid medication within 30 days of TKA were sought among patient demographics and the overall prescription morphine milligram equivalents. Patient and prescription-related risk factors were evaluated utilizing logistic relative risk regression. We reserved a year of data, 222 people, to evaluate the performance of the derived model. More than half the patients filled a second prescription for opioids within 30 days of TKA. Factors associated with a second prescription of opioid medication within 30 days of TKA included age (P < .01), current smoker (P = .01), and the total morphine milligram equivalents of the initial prescription (P < .01). Applied to the 222 people we reserved for validation, the model was 81% sensitive and 14% specific for a second prescription within 30 days, with a positive predictive value of 74%, and a negative predictive value of 20%. People that are given more opioids tend to request more opioids, but our model had limited diagnostic performance characteristics indicating that we are not accounting for the key factors associated with a second opioid prescription. Future studies might address undiagnosed patient social and mental health opportunities, factors known to associate with pain intensity and satisfaction with pain alleviation. Diagnostic Level III.


Self-Healing Textile: Enzyme Encapsulated Layer-by-Layer Structural Proteins.
Self-healing materials, which enable an autonomous repair response to damage, are highly desirable for the long-term reliability of woven or nonwoven textiles. Polyelectrolyte layer-by-layer (LbL) films are of considerable interest as self-healing coatings due to the mobility of the components comprising the film. In this work mechanically stable self-healing films were fabricated through construction of a polyelectrolyte LbL film containing squid ring teeth (SRT) proteins. SRTs are structural proteins with unique self-healing properties and high elastic modulus in both dry and wet conditions (>2 GPa) due to their semicrystalline architecture. We demonstrate LbL construction of multilayers containing native and recombinant SRT proteins capable of self-healing defects. Additionally, we show these films are capable of utilizing functional biomolecules by incorporating an enzyme into the SRT multilayer. Urease was chosen as a model enzyme of interest to test its activity via fluorescence assay. Successful construction of the SRT films demonstrates the use of mechanically stable self-healing coatings, which can incorporate biomolecules for more complex protective functionalities for advanced functional fabrics.


Knee Joint Distraction Compared to Total Knee Arthroplasty for Treatment of End Stage Osteoarthritis: Simulating Long-Term Outcomes and Cost-Effectiveness.
In end-stage knee osteoarthritis the treatment of choice is total knee arthroplasty (TKA). An alternative treatment is knee joint distraction (KJD), suggested to postpone TKA. Several studies reported significant and prolonged clinical improvement of KJD. To make an appropriate decision regarding the position of this treatment, a cost-effectiveness and cost-utility analysis from healthcare perspective for different age and gender categories was performed. A treatment strategy starting with TKA and a strategy starting with KJD for patients of different age and gender was simulated. To extrapolate outcomes to long-term health and economic outcomes a Markov (Health state) model was used. The number of surgeries, QALYs, and treatment costs per strategy were calculated. Costs-effectiveness is expressed using the cost-effectiveness plane and cost-effectiveness acceptability curves. Starting with KJD the number of knee replacing procedures could be reduced, most clearly in the younger age categories; especially revision surgery. This resulted in the KJD strategy being dominant (more effective with cost-savings) in about 80% of simulations (with only inferiority in about 1%) in these age categories when compared to TKA. At a willingness to pay of 20.000 Euro per QALY gained, the probability of starting with KJD to be cost-effective compared to starting with a TKA was already found to be over 75% for all age categories and over 90-95% for the younger age categories. A treatment strategy starting with knee joint distraction for knee osteoarthritis has a large potential for being a cost-effective intervention, especially for the relatively young patient.


Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease.
The properties and outcome of an immune response are best predicted by the lymphokine phenotype of the responding T cells. Cytokines produced by CD4+ T helper type 1 (Th1) T cells mediate delayed type hypersensitivity (DTH) and inflammatory responses, whereas cytokines produced by Th2 T cells mediate helper T cell functions for antibody production. To determine whether induction of Th2-like cells would modulate an inflammatory response, interleukin 4 (IL-4) was administered to animals with experimental allergic encephalomyelitis (EAE), a prototypic autoimmune disease produced by Th1-like T cells specific for myelin basic protein (MBP). IL-4 treatment resulted in amelioration of clinical disease, the induction of MBP-specific Th2 cells, diminished demyelination, and inhibition of the synthesis of inflammatory cytokines in the central nervous system (CNS). Modulation of an immune response from one dominated by excessive activity of Th1-like T cells to one dominated by the protective cytokines produced by Th2-like T cells may have applicability to the therapy of certain human autoimmune diseases.


Inflammatory mediators, infection, sepsis, and multiple organ failure after severe trauma.
The relation of (multiple) organ failure (OF) to the release of inflammatory mediators and the incidence of infection and sepsis was studied prospectively in 100 patients with multiple trauma (injury severity score = 37). Sixteen patients died of OF, 47 patients survived OF, and 37 patients had no OF. Fifteen (24%) of the patients with OF showed no signs of infection. In patients with early onset of OF (n=45), infection followed with a lag of 2 or more days. In 16 (44%) of these patients, infection led to a deterioration in organ function. With late onset of OF (n=18), infection preceded OF in nine patients. Polymorphonuclear leukocyte-elastase, neopterin, C-reactive protein, lactate, antithrombin III, and phospholipase A discriminated significantly among the three outcome groups. Of all factors, only polymorphonuclear leukocyte-elastase showed a difference between patients with and without infection or sepsis, respectively. These data indicate that infection might not play a crucial role in the pathogenesis of posttraumatic OF in a substantial portion of patients with trauma. Early OF, especially, seems to be mainly influenced by the direct sequelae of tissue damage and shock (eg, the release of inflammatory mediators). Since infection and sepsis did not lead to an augmented release of mediators in patients with trauma, the role of both entities remains unclear.


Atypical oscillatory dynamics during emotional face processing in paediatric obsessive-compulsive disorder with MEG.
Children and youth with obsessive-compulsive disorder (OCD) demonstrate difficulties with social, emotional and cognitive functions in addition to the core diagnosis of obsessions and compulsions. This is the first magnetoencephalography (MEG) study to examine whole-brain neurophysiological functional connectivity of emotional face processing networks in paediatric OCD. Seventy-two participants (OCD: n = 36; age 8-17 yrs; typically developing controls: n = 36, age 8-17 yrs) completed an implicit emotional face processing task in the MEG. Functional connectivity networks in canonical frequency bands were compared between groups, and within OCD and control groups between emotions (angry vs. happy). Between groups, participants with OCD showed increased functional connectivity in the gamma band to angry faces, suggesting atypical perception of angry faces in OCD. Within groups, the OCD group showed greater engagement of the beta band, suggesting the over-use of top-down processing when perceiving happy versus angry emotions, while controls engaged in bottom-up gamma processing, also greater to happy faces. Over-activation of top-down processing has been linked to difficulties modifying one's cognitive set. Findings establish altered patterns of neurophysiological connectivity in children with OCD, and are striking in their oscillatory specificity. Our results contribute to a greater understanding of the neurobiology of the disorder, and are foundational for the possibility of alternative targets for intervention.


First Report of Cobweb Disease Caused by Cladobotryum mycophilum on the Edible Mushroom Pleurotus eryngii in Korea.
Pleurotus eryngii is one of the most commercially important mushrooms in Korea. In May 2009, unusual symptoms were observed in P. eryngii grown in mushroom farms in Changnyeong and Hapcheon, in Gyeong-nam Province, Korea. One of the main symptoms was cobweb-like growth of fungal mycelia over the mushroom surface. Colonies on the surface rapidly overwhelmed the mushrooms, which turned pale brown or yellow. Mushrooms eventually turned dark brown and became rotten. Colonies of the isolates on potato dextrose agar (PDA) were yellowish, and a reddish or orange color was evident in the agar. The colonies grew 20 to 30 mm per day on PDA. Large spores with a single septum were produced on vertically branched conidiophores bearing two to four, mostly three to four, sporogenous cells, ranging from 17.2 to 20.5 μm long and 8.0 to 10.2 μm thick. The shape of the conidia was ellipsoid and obovoid. These morphological characteristics are consistent with descriptions of Cladobotryum mycophilum, a causal agent of cobweb disease in Agaricus bisporus (1,4). To identify the isolated fungal pathogen, the ITS region was amplified with ITS1 and ITS4 primers and sequenced. The sequence data from the isolate was deposited in GenBank (Accession No. JF693809). A BLAST search showed that the isolated strain belonged to a species of Cladobotryum. The highest similarity (99.5%) was to the ITS sequence of C. mycophilum (teleomorph Hypomyces odoratus) (GenBank Accession Nos. JF505112 and Y17096) (3,4). The strain that was tested for pathogenicity was grown on PDA at 25°C for 72 h. The inoculum was prepared by flooding the agar surface with 10 ml of sterilized double distilled water and scraping it with a spatula. The resulting spore suspension was filtered through three layers of cheesecloth. Conidial concentration was adjusted with a hemacytometer to 1 × 106 conidia ml-1. A conidia suspension was inoculated onto each of several stages of mushroom cultivation with a pipette. The control was spotted with double distilled water. In the case of infection during the inoculation and spawn running stages, the fungal mycelia colonized the media and hampered development of the mycelium of P. eryngii. In the regeneration and primordia formation stages of the host, the mycelium of the pathogen covered the surface of the plastic bottle containing the substrates and developed many spores. In the growing and harvesting stages, the surface of mushroom was overwhelmed by the mycelium of the fungal pathogen and turned pale or dark brown, accompanied by cracking of the stipe surface and finally rotting with a foul odor. These symptoms were similar to the observation from natural infection. The symptoms of the cobweb-like disease in A. bisporus (1,2) were observed within 5 to 7 days of inoculation with conidia suspensions of C. mycophilum. Fungi isolated from inoculated mushrooms were shown to be identical, based on phenotypic characteristic, to the inoculated strain used in these pathogenicity tests. No symptoms were observed on controls. To our knowledge, this is the first report on the occurrence of C. mycophilum on the edible mushroom P. eryngii in Korea. Based on the pathogenicity test results, the pathogen could attack P. eryngii in any cultivation stage, making it a potentially serious fungal pathogen in P. eryngii. References: (1) C. G. Back et al. J. Gen. Plant Pathol. 76:232, 2010. (2) R. H. Gaze. Mushroom J. 546:23, 1995. (3) F. J. Gea et al. Plant Dis. 95:1030, 2011. (4) H. M. Grogan and R. H. Gaze. Mycol. Res. 104:357, 2000.


Cost-effectiveness of modern radiotherapy techniques in locally advanced pancreatic cancer.
Radiotherapy may improve the outcome of patients with pancreatic cancer but at an increased cost. In this study, the authors evaluated the cost-effectiveness of modern radiotherapy techniques in the treatment of locally advanced pancreatic cancer. A Markov decision-analytic model was constructed to compare the cost-effectiveness of 4 treatment regimens: gemcitabine alone, gemcitabine plus conventional radiotherapy, gemcitabine plus intensity-modulated radiotherapy (IMRT); and gemcitabine with stereotactic body radiotherapy (SBRT). Patients transitioned between the following 5 health states: stable disease, local progression, distant failure, local and distant failure, and death. Health utility tolls were assessed for radiotherapy and chemotherapy treatments and for radiation toxicity. SBRT increased life expectancy by 0.20 quality-adjusted life years (QALY) at an increased cost of $13,700 compared with gemcitabine alone (incremental cost-effectiveness ratio [ICER] = $69,500 per QALY). SBRT was more effective and less costly than conventional radiotherapy and IMRT. An analysis that excluded SBRT demonstrated that conventional radiotherapy had an ICER of $126,800 per QALY compared with gemcitabine alone, and IMRT had an ICER of $1,584,100 per QALY compared with conventional radiotherapy. A probabilistic sensitivity analysis demonstrated that the probability of cost-effectiveness at a willingness to pay of $50,000 per QALY was 78% for gemcitabine alone, 21% for SBRT, 1.4% for conventional radiotherapy, and 0.01% for IMRT. At a willingness to pay of $200,000 per QALY, the probability of cost-effectiveness was 73% for SBRT, 20% for conventional radiotherapy, 7% for gemcitabine alone, and 0.7% for IMRT. The current results indicated that IMRT in locally advanced pancreatic cancer exceeds what society considers cost-effective. In contrast, combining gemcitabine with SBRT increased clinical effectiveness beyond that of gemcitabine alone at a cost potentially acceptable by today's standards.


Kidney-induced hypertension depends on superoxide signaling in the rostral ventrolateral medulla.
Reactive oxygen species in peripheral cardiovascular tissues are implicated in the pathogenesis of 2 kidney-1 clip hypertension. We recently identified an imbalance between reactive oxygen species generation and oxidant scavenging in the rostral ventrolateral medulla (RVLM) of 2 kidney-1 clip in rats. We tested whether enhanced superoxide signaling in RVLM of 2 kidney-1 clip rats contributes to the chronic hypertension via sympathetic activation in conscious rats. We enhanced superoxide scavenging in RVLM by overexpressing cytoplasmically targeted superoxide dismutase using an adenoviral vector (Ad-CMV-CuZnSOD) in Wistar rats (male, 150 to 180 g) in which the left renal artery was occluded partially 3 weeks earlier. Hypertension was documented using radiotelemetry recording of arterial pressure in conscious rats for 6 weeks. Renovascular hypertension elevated both serine phosphorylation of p47phox subunit of NADPH and superoxide levels in RVLM. The elevated superoxide levels were normalized by expression of CuZnSOD in RVLM. Moreover, the hypertension produced in the 2 kidney-1 clip rats was reversed 1 week after viral-mediated expression of CuZnSOD. This antihypertensive effect was maintained and associated with a decrease in the low-frequency spectra of systolic blood pressure variability, suggesting reduced sympathetic vasomotor tone. The expression of CuZnSOD was localized to RVLM neurons, of which some contained tyrosine hydroxylase. None of the above variables changed in control rats receiving Ad-CMV-eGFP in RVLM. In Goldblatt hypertension, superoxide signaling in the RVLM plays a major role in the generation of sympathetic vasomotor tone and the chronic sustained hypertension in this animal model.


Variation in surgical decision making for degenerative spinal disorders. Part I: lumbar spine.
Survey-based descriptive study. To study relationships between surgeon-specific factors and surgical approach to degenerative diseases of the lumbar spine. Geographic variations in the rates of lumbar spine surgery are significant within the United States. Although surgeon density correlates with the rates of spine surgery, other reasons for variation such as surgeon age and training background are poorly understood. A total of 22 orthopedic surgeons and 8 neurosurgeons of varied ages and geographic regions answered questions regarding the need for surgery, surgical approach, and use of fusion and instrumentation for 5 simulated cases. Cases included: (1) multilevel stenosis without deformity or instability, (2) degenerative spondylolisthesis with stenosis, (3) isthmic (spondylolytic) spondylolisthesis with foraminal stenosis, (4) degenerative scoliosis with stenosis, and (5) recurrent stenosis following prior laminectomy without deformity or instability. The effects of surgeon age and training background on surgical decision making were analyzed using an independent samples t test and Fisher exact test, respectively. Significant variation in treatment approach among surgeons was noted for all cases except the patient with lytic spondylolisthesis, for whom all surgeons recommended fusion. Orthopedists recommended fusion and instrumentation more often than neurosurgeons for all cases, reaching significance for degenerative scoliosis with stenosis (P = 0.02 for both fusion and instrumentation). Younger surgeons were generally more likely to recommend instrumentation than their older peers, reaching significance for multilevel stenosis without deformity or instability and recurrent stenosis following prior laminectomy without deformity or instability (P = 0.05 and 0.01, respectively). Variations in surgical approach to lumbar degenerative diseases may depend on a patient's clinical condition. This study found strong agreement in the approach to lytic spondylolisthesis but significant variation for other degenerative conditions of the lumbar spine. In addition, recommendation for fusion and instrumentation varied with surgeon age and training background. Previously documented geographic variations may result in part from a lack of consensus on appropriate treatment techniques for specific lumbar degenerative conditions, as well as surgeon-specific factors.


Mild musculoskeletal and locomotor alterations in adult rats with white matter injury following prenatal ischemia.
Early brain injury including white matter damage (WMD) appears strongly correlated to perinatal hypoxia-ischemia and adverse neurological outcomes in preterm survivors. Indeed, WMD has been widely associated with subtle to major motor disturbances, sensory, behavioral and cognitive impairments in preterm infants who afterward develop cerebral palsy (CP). Prenatal ischemia (PI) has been shown to reproduce the main features of WMD observed in preterm infants. The present study was aimed at determining in adult rats the impact of PI on brain axons, musculoskeletal histology and locomotor activity. PI was induced by unilateral intrauterine artery ligation at E17 in pregnant rats. We found axonal degeneration and reactive astrogliosis in several white matter regions of adult PI rats. We found mild myopathic and secondary joint changes, including increased variability in myofiber size in several hind limb muscles, decreased myofibers numbers but increased Pax 7 cells and myofiber size in the gastrocnemius, and mild knee and ankle chondromalacia. Although treadmill locomotion appeared normal, several kinematic parameters, such as stride length, amplitude, velocity and leg joint angles were altered in adult PI rats compared to shams. Using intra- and inter-group variability of kinematic parameters, PI seemed to impair the maturation of locomotion on the treadmill. In addition, PI rats exhibited spontaneous hyperactivity in open-field test. Musculoskeletal changes appeared concomitant with mild impairments in gait and posture. Our rodent model of WMD based on PI reproduces the mild motor deficits and musculoskeletal changes observed in many preterm infants with a perinatal history of hypoxia-ischemia, and contributes towards a better understanding of the interplay between brain injury, musculoskeletal histopathology and gait disturbances encountered subsequently.


Audiotactile interactions in near and far space.
In this study we investigated audiotactile spatial interactions in the region behind the head. In experiment 1, participants made unspeeded temporal order judgments (TOJs) regarding pairs of auditory and tactile stimuli presented at varying stimulus onset asynchronies (SOAs) using the method of constant stimuli. Electrocutaneous stimuli were presented to the left or right earlobe while auditory stimuli were presented from just behind the participant's head on either the same or opposite side. Participants responded significantly more accurately when the stimuli were presented from different sides rather than from the same side. In experiment 2, we used a distractor interference task to show that speeded left/right discrimination responses to electrocutaneous targets were also modulated by the spatial congruency of auditory distractors presented behind the head. Performance was worse (i.e. response latencies were slower and error rates higher) when the auditory distractors were presented on the opposite side to the electrocutaneous target than when they were presented on the same side. This crossmodal distractor interference effect was larger when white noise distractors were presented from close to the head (20 cm) than when they were presented far from the head (70 cm). By contrast, pure tone distractors elicited a smaller crossmodal distractor interference effect overall, and showed no modulation as a function of distance. Taken together, these results suggest that the spatial modulation of audiotactile interactions occurs predominantly for complex auditory stimuli (for example, white noise) originating from the region close to the back of the head.


Diffusion-weighted MR imaging for characterizing musculoskeletal lesions.
Diffusion-weighted (DW) imaging is a functional magnetic resonance (MR) imaging technique that can readily be incorporated into a routine non-contrast material-enhanced MR imaging protocol with little additional scanning time. DW imaging is based on changes in the Brownian motion of water molecules caused by tissue microstructure. The apparent diffusion coefficient (ADC) is a quantitative measure of Brownian movement: Low ADC values typically reflect highly cellular microenvironments in which diffusion is restricted by the presence of cell membranes, whereas acellular regions allow free diffusion and result in elevated ADC values. Thus, with ADC mapping, one may derive useful quantitative information regarding the cellularity of a musculoskeletal lesion using a nonenhanced technique. The role of localized DW imaging in differentiating malignant from benign osseous and soft-tissue lesions is still evolving; when carefully applied, however, this modality has proved helpful in a subset of tumor types, such as nonmyxoid soft-tissue tumors. Studies of the use of DW imaging in assessing the treatment response of both osseous and soft-tissue tumors have shown that higher ADC values correlate with better response to cytotoxic therapy. Successful application of DW imaging in the evaluation of musculoskeletal lesions requires familiarity with potential diagnostic pitfalls that stem from technical artifacts and confounding factors unrelated to lesion cellularity. Further investigation is needed to evaluate the impact of DW imaging-ADC mapping on management and outcome in patients with musculoskeletal lesions.


Melatonin-triggered post-transcriptional and post-translational modifications of ADAMTS1 coordinately retard tumorigenesis and metastasis of renal cell carcinoma.
A disintegrin and metalloprotease with thrombospondin motifs (ADAMTS) family are widely implicated in tissue remodeling events manifested in cancer development. ADAMTS1, the most fully characterized ADAMTS, plays conflicting roles in different cancer types; however, the role of ADAMTS1 in renal cell carcinoma (RCC) remains unclear. Herein, we found that ADAMTS1 is highly expressed in RCC tissues compared to normal renal tissues, and its expression was correlated with an advanced stage and a poor prognosis of RCC patients. In vitro, we observed higher expression of ADAMTS1 in metastatic (m)RCC cells compared to primary cells, and manipulation of ADAMTS1 expression affected cell invasion and clonogenicity. Results from protease array showed that ADAMTS1 is modulated by melatonin through mechanisms independent of the MT1 receptor in mRCC cells, and overexpression of ADAMTS1 relieved the invasion/clonogenicity and growth/metastasis inhibition imposed by melatonin treatment in vitro and in an orthotopic xenograft model. The human microRNA (miR) OneArray showed that miR-181d and miR-let-7f were induced by melatonin and, respectively, targeted the 3'-UTR and non-3'-UTR of ADAMTS1 to suppress its expression and mRCC invasive ability. Clinically, RCC patients with high levels of miR-181d or miR-let-7f and a low level of ADAMTS1 had the most favorable prognoses. In addition, ubiquitin/proteasome-mediated degradation of ADAMTS1 can also be triggered by melatonin. Together, our study indicates that ADAMTS1 may be a useful biomarker for predicting RCC progression. The novel convergence between melatonin and ADAMTS1 post-transcriptional and post-translational regulation provides new insights into the role of melatonin-induced molecular regulation in suppressing RCC progression.


Variation in gymnemic acid content and non-destructive harvesting of Gymnema sylvestre (Gudmar).
Madhunashini (Gymnema sylvestre R. Br.) commonly known as 'Gudmar' in Hindi is an important medicinal climber and extensively used in almost all Indian System of Medicine as a remedy for diabetes, rheumatism, cough, ulcer, jaundice, dyspepsia, constipation, eyes pain and also in snakebite. In India, it is found growing in Andhra Pradesh, Bihar, Chhattisgarh, Karnataka, Kerala, Madhya Pradesh, Maharastra, Orissa, Tamil Nadu, Uttar Pradesh and West Bengal. The major phytoconstituents are gymnemic acids, gudmarin and saponins. In the present study, Gymnema germplasm collected from various regions of Madhya Pradesh was evaluated on the basis of their morphological characteristics and gymnemic acid content. Gymnemic acid content in the leaves was estimated by HPLC. We have also standardized the non-destructive harvesting practices of Gudmar. Selective harvesting was done without harming the main plant. Only mature leaves (60%) were hand plucked in the month of October. Second harvest was done in the month of June. Data revealed that gymnemic acid content varied between 0.96% ± 0.03 (Seoni) to 1.58% ±0.03 (Amarkantak). It was also observed that the leaves left at the time of 1(st) harvest during October matured in June at the time of 2(nd) harvest. Non destructive harvesting practice did not have any negative impact on overall development of the plant. It is evident that there is wide variation in the morphological characteristics and gymnemic acid content in G. sylvestre collected from various locations, which can be exploited for further crop improvement programmes.


Forecasting head lice (Pediculidae: Pediculus humanus capitis) infestation incidence hotspots based on spatial correlation analysis in Northwest Iran.
Pediculus humanus capitis has been prevalent throughout the world, especially in developing countries among elementary students and societies with a weak socio-economic status. This study aimed to forecast head lice (Pediculidae: P. capitis) infestation incidence hotspots based on spatial correlation analysis in Ardabil Province, Northwest Iran. In this retrospective analytical study, all cases of head lice infestations who were confirmed by Centers for Disease Control office have been studied from 2016 to 2018. Head lice infestation incidence hotspots in the province should be detected based on general G statistics in ArcMap GIS10.4.1. Furthermore, MaxEnt.3.3.3 model was used for modeling the high-risk areas. The prevalence rate of pediculosis was 14.90/100,000 populations. The general G statistics revealed that the head lice infestation in this study area has a high cluster pattern. The analysis showed that the Parsabad and Germi counties were identified as a head lice infestation incidence hotspots. Statistical and spatial analyses of head lice infestation incidence showed a significant positive correlation with head lice infestation incidence hotspots and the altitudes (15-500 m), annual temperature range (14-16.5°C), and slope and average diurnal temperature (12-18°C). The results of this study showed that the most ecologically suitable areas of head lice occurrence were identified in two hotspots (Parsabad and Germi) in the Northern areas of Ardabil Province (Parsabad and Germi counties); in the borderline of Iran and the Republic of Azerbaijan.


Glucose homeostasis abnormalities associated with use of gatifloxacin.
More than 20 published case reports have described an association between the use of gatifloxacin and hypoglycemia or hyperglycemia. We compare the rates of glucose homeostasis abnormality (GHA) adverse event reports (AERs) associated with the use of gatifloxacin and comparator quinolones. We obtained spontaneous AERs associated with the use of ciprofloxacin, gatifloxacin, levofloxacin, and moxifloxacin from the US Food and Drug Administration that were reported between November 1997 and September 2003. We removed duplicate and foreign cases. We used specific coding terms to identify GHA AERs. We calculated GHA AER rates, using either the total number of AERs or estimated retail prescriptions as denominators. The use of ciprofloxacin, gatifloxacin, levofloxacin, and moxifloxacin was associated with 10,025 unique AERs in the United States, including 568 GHA AERs, 25 of which had fatality. Use of gatifloxacin was associated with 453 GHA AERs (80%) and 17 GHA AERs with fatality (68%). GHA AERs comprised 24% of all AERs associated with gatifloxacin, compared with ciprofloxacin (1.3%), levofloxacin (1.6%), and moxifloxacin (1.3%) (P<.0001 for each comparison). Use of gatifloxacin was associated with 477 GHA AERs per 10(7) retail prescriptions, compared with ciprofloxacin (4 GHA AERs), levofloxacin (11 GHA AERs), and moxifloxacin (39 GHA AERs) (P<.0001 for each comparison). Patients with GHA AERs were older and more likely to be receiving concomitant treatment for diabetes. Limitations of the study include the use of spontaneous adverse event reporting, which is incomplete and potentially biased. This analysis cannot be used alone to demonstrate causality. Use of gatifloxacin is associated with a much higher rate of GHA AERs than are comparator quinolones. This analysis is consistent with the results of in vitro analyses, animal studies, human volunteer studies, case reports, and a large randomized trial. Alternatives to gatifloxacin should be used in patients with diabetes.


A novel liver retractor for reduced or single-port laparoscopic surgery.
Retraction of either lobe of liver is required for surgical access to the respective organ. A novel liver retractor device and technique is described, which applies a vacuum between the liver and diaphragm to lift the liver, and which does not require additional incisions. A novel liver retractor was tested in two anesthetized sheep at incrementally higher levels of suction from -100 to -700 mmHg (-13 to -93 kPa), and any signs of trauma were recorded. The animals recovered for 5 days, then were humanely killed and postmortem examination of the liver and diaphragms performed. Successful liver retraction was achieved from -200 to -600 mmHg (-27 to -80 kPa) suction. An imprint of the retractor was observed on the liver surface, but there was no breach of the liver serosa. Negligible ecchymoses were observed on the corresponding surface of the diaphragms. Both sheep recovered well after surgery. There was no macroscopic evidence of injury to the liver and diaphragm 5 days postoperatively. Histological examination revealed normal liver parenchyma deep to the site where the devices had been placed, and hemorrhagic changes within the serosa only varied between a few microns to a maximum of 1.4-mm depth. The novel liver retractor described achieved an effective liver retraction without trauma. It has potential application in reduced or single-port laparoscopic upper abdominal surgery.


The use of microcalorimetry to compare the biological activity of a CAS and a MBR sludge-application to pharmaceutical active compounds.
Micropollutants removal, such as pharmaceutical substances, during wastewater treatment processes is becoming a greater issue everyday. In order to optimize it, their biodegradation processes have to be better understood. So far, microcalorimetry has been used worldwide to investigate chemical reactions. For few years now it has also been developed to model and control biological processes. In the case of micropollutants, respirometry is, most of the time, not precise enough to determine biodegradation. That is why, microcalorimetric experiments have been set up. For this purpose, a 2 L Bio-RC1 (Mettler-Toledo) has been modified to reach a resolution of 5-10 mW.L(-1).In this study, the biodegradation rate of standard substrates (Ethanol and Ammonia) by an activated sludge from a full-scale CAS and one from a MBR pilot plant operating in parallel have been compared by means of microcalorimetry. Then few trials to determine the biodegradation of selected pharmaceutical substances, as well as the eventual inhibition induced by them have been made. The first results did not exhibit any biological activity. However, they have displayed inhibition for both studied substances.


Early, but not advanced, glomerulopathy is reversed by pancreatic islet transplants in experimental diabetic rats: correlation with glomerular extracellular matrix mRNA levels.
In this study, we investigated 1) whether long-term restoration of euglycemia by means of pancreatic islet transplants is capable of preventing and/or reversing renal functional and structural alterations in an experimental model of insulin-deficient diabetes, and 2) whether changes in extracellular matrix (ECM) and cell turnover at the glomerular level and biochemical abnormalities associated with hyperglycemia correlate with the renal outcome after transplantation. Male Lewis rats, rendered diabetic by intravenous injection of streptozotocin, underwent homologous islet transplantation via the portal vein at 2 weeks (study A), at 4 months (study B), and at 8 months (study C) after the induction of diabetes and killed 12 months after transplantation in study A and 4 months after transplantation in studies B and C. Age-matched nondiabetic and untreated diabetic rats were used as control animals and were studied at 4, 8, and 12 months. In the untreated diabetic animals, metabolic derangement was associated with increased erythrocyte polyol and fructose levels, tail-tendon content of advanced glycation end products (AGEs), total proteinuria, albuminuria, kidney weight, and mean glomerular volume as well as with marked glomerular and extraglomerular lesions. Glomerular gene expression for the ECM components fibronectin and collagen IV and for TGF-beta was also increased, whereas glomerular cell proliferation was unaffected by diabetes. In study A, changes in renal function and structure observed in diabetic rats at 12 months were completely prevented by successful islet transplants. In study B, all functional and structural abnormalities detected in diabetic rats at 4 months of disease duration were virtually reversed by 4 months of euglycemia in transplanted animals, whereas they progressed further in untreated diabetic rats. In study C, the course of functional and structural changes observed in untreated diabetic rats was not reversed by islet transplantation. Likewise, tissue AGE accumulation and particularly upregulation of glomerular ECM and transforming growth factor (TGF)-beta gene expression, which are believed to play a role in the pathogenesis of altered renal function and structure in diabetes, were normalized in transplanted rats from study A and study B, but not in those from study C. These experiments show that restoration of euglycemia by islet transplants is capable of preventing experimental diabetic glomerulopathy and reversing early changes in renal function and structure induced by diabetes. In a later phase of the disease, when glomerular matrix gene expression becomes independent of hyperglycemia, possibly because of the persistent increase in tissue AGE accumulation, metabolic control is not capable of reversing renal abnormalities.


Feedback-driven self-assembly of symmetry-breaking optical metamaterials in solution.
Thermodynamically driven self-assembly offers a direct route to organize individual nanoscopic components into three-dimensional structures over a large scale. The most thermodynamically favourable configurations, however, may not be ideal for some applications. In plasmonics, for instance, nanophotonic constructs with non-trivial broken symmetries can display optical properties of interest, such as Fano resonance, but are usually not thermodynamically favoured. Here, we present a self-assembly route with a feedback mechanism for the bottom-up synthesis of a new class of symmetry-breaking optical metamaterials. We self-assemble plasmonic nanorod dimers with a longitudinal offset that determines the degree of symmetry breaking and its electromagnetic response. The clear difference in plasmonic resonance profiles of nanorod dimers in different configurations enables high spectra selectivity. On the basis of this plasmonic signature, our self-assembly route with feedback mechanism promotes the assembly of desired metamaterial structures through selective excitation and photothermal disassembly of unwanted assemblies in solution. In this fashion, our method can selectively reconfigure and homogenize the properties of the dimer, leading to highly monodispersed aqueous metamaterials with tailored symmetries and electromagnetic responses.


How algorithmic popularity bias hinders or promotes quality.
Algorithms that favor popular items are used to help us select among many choices, from top-ranked search engine results to highly-cited scientific papers. The goal of these algorithms is to identify high-quality items such as reliable news, credible information sources, and important discoveries-in short, high-quality content should rank at the top. Prior work has shown that choosing what is popular may amplify random fluctuations and lead to sub-optimal rankings. Nonetheless, it is often assumed that recommending what is popular will help high-quality content "bubble up" in practice. Here we identify the conditions in which popularity may be a viable proxy for quality content by studying a simple model of a cultural market endowed with an intrinsic notion of quality. A parameter representing the cognitive cost of exploration controls the trade-off between quality and popularity. Below and above a critical exploration cost, popularity bias is more likely to hinder quality. But we find a narrow intermediate regime of user attention where an optimal balance exists: choosing what is popular can help promote high-quality items to the top. These findings clarify the effects of algorithmic popularity bias on quality outcomes, and may inform the design of more principled mechanisms for techno-social cultural markets.


Does magnetic resonance imaging predict future low back pain? A systematic review.
Magnetic resonance imaging (MRI) has the potential to identify pathology responsible for low back pain (LBP). However, the importance of findings on MRI remains controversial. We aimed to systematically review whether MRI findings of the lumbar spine predict future LBP in different samples with and without LBP. MEDLINE, CINAHL and EMBASE databases were searched. Included were prospective cohort studies investigating the relationship between baseline MRI abnormalities of the lumbar spine and clinically important LBP outcome at follow-up. We excluded cohorts with specific diseases as the cause of their LBP. Associations between MRI findings and LBP pain outcomes were extracted from eligible studies. A total of 12 studies met the inclusion criteria. Six studies presented data on participants with current LBP; one included a sample with no current LBP, three included a sample with no history of LBP and two included mixed samples. Due to small sample size, poor overall quality and the heterogeneity between studies in terms of participants, MRI findings and clinical outcomes investigated, it was not possible to pool findings. No consistent associations between MRI findings and outcomes were identified. Single studies reported significant associations for Modic changes type 1 with pain, disc degeneration with disability in samples with current LBP and disc herniation with pain in a mixed sample. The limited number, heterogeneity and overall quality of the studies do not permit definite conclusions on the association of MRI findings of the lumbar spine with future LBP (PROSPERO: CRD42012002342).


Dimerization and N-terminal domain proximity underlie the function of the molecular chaperone heat shock protein 90.
Heat shock protein (hsp)90 functions in a complex chaperoning pathway where its activity is modulated by ATP and by interaction with several co-chaperones. One co-chaperone, p23, binds selectively to the ATP-bound state of hsp90. However, the isolated ATP-binding domain of hsp90 does not bind p23. In an effort to identify the p23-binding domain, we have constructed a series of hsp90 deletion mutants fused with glutathione-S-transferase (GST). Full-length GST-hsp90 is able to bind p23, and also, to chaperone assembly of progesterone receptor complexes. Truncations from the C terminus of GST-hsp90 reveal a C-terminal boundary for the p23-binding domain at approximately residue 490. This fragment contains, in order, the ATP-binding domain, a highly charged region, and 203 residues beyond the charged region. p23 binding is unaffected by deletion of the charged region, indicating that two noncontiguous regions of hsp90 are involved in p23 binding. These regions are only effective when hsp90 is in a dimeric state as shown by loss of p23 binding upon removal of GST or as shown by use of FK506-binding protein12-hsp90 constructs that form dimers and bind p23 only in the presence of a bivalent drug. Thus, p23 binding requires an hsp90 dimer with close proximity between N-terminal regions of hsp90 and a conformation specified by ATP.


Effects of L-Arginine Supplementation on Leukogram, Inflammatory Bowel Infiltrates and Immunoglobulins with 5-FU Use in Rats.
This study evaluated the effects of L-arginine supplementation on blood parameters, kidney and liver function, immunoglobulins and noninflammatory infiltrates in the small intestines of rats subjected to chemotherapy with 5-fluorouracil (5-FU). Thirty-two Wistar rats were randomly distributed into 4 groups (8 rats/group): an untreated control group, and test groups receiving one dose of 5-FU (G5-FU group), one dose of 5-FU and 295 mg L-arginine/day (GArg295 group) or one dose of 5-FU and 458 mg L-arginine/day (GArg458 group). Neutrophil count, platelet count, serum IgA, and fibrinogen levels in GArg295 and GArg458 remained within normal limits after chemotherapy. In addition, in GArg458 the inflammatory bowel infiltrates improved in 57% of the rats, which showed mild inflammation. The results suggest that daily supplementation with 295 or 458 mg L-arginine attenuates the side effects of 5-FU, including thrombocytopenia and neutropenia, and modulates IgA production. Supplementation with 458 mg of L-arginine/day can also reduce mucositis levels in the small intestine after 5-FU chemotherapy.


Randomized controlled trial of cervical cap with intracervical reservoir versus standard intracervical injection to inseminate cryopreserved donor semen.
A prospective controlled study of donor insemination without sperm preparation or ovarian stimulation was performed to compare the use of a cervical cap incorporating an intracervical reservoir with a standard intracervical injection technique to inseminate 0.5 ml cryopreserved semen. Treatments were alternated in successive cycles in each patient after initial randomized selection. A total of 198 patients had 635 treatment cycles (median 3, range 1-7), 309 with reservoir and 326 by standard injection. A total of 56 women became pregnant, 24 (7.8% per cycle) with the reservoir and 32 (9.8% per cycle) by injection. There were no significant differences between the pregnancy rates per cycle overall or cycle-specific cumulative rates calculated using the life-table method. There were no significant differences in age, parity, baseline gonadotrophin measurements, mid-luteal serum progesterone concentrations, frequency of adverse fertility factors in the woman or her partner's cause of infertility between women who conceived and those who failed to conceive. We conclude that use of a cervical reservoir and cap for donor insemination does not offer any advantage over standard intracervical insemination.


Disposition of carbamazepine and its 10,11-epoxide metabolite in the isolated perfused rat liver.
The disposition of carbamazepine and its metabolite, the 10,11-epoxide, was investigated in isolated perfused livers from control and phenobarbital-pretreated rats. The mean hepatic clearance of carbamazepine was 0.28 ml per min per g of liver corresponding to a mean extraction ratio of 0.16 and a mean intrinsic clearance of 0.33 ml per min g of liver. In phenobarbital-pretreated rats, there was an approximately 40% increase in the hepatic clearance due to a concomitant increase in the mean extraction ratio from 0.16 to 0.26. The carbamazepine-10,11-epoxide generated in the liver approached and attained its peak concentration more rapidly in pretreated than in control rat livers. In the latter group there was virtually no disappearance of the epoxide from the perfusate, whereas in the pretreated rat livers the perfusate concentrations declined after 90 min. The extremely low clearance of the epoxide generated by metabolism in control rat liver was confirmed by administration of the epoxide per se to the perfusion system. The mean extraction ratio of the epoxide in this situation was only 0.016 and it was unaffected by prior treatment of the rats with phenobarbital. However, the epoxids exhibited dose-dependent kinetics with a 3-fold increase in the extraction ratio when the administered dose was reduced from 500 to 166 microng. The observed induction of the hepatic clearance of carbamazepine is supportive of the involvement of this mechanism in the interaction of this drug with various other anticonvulsants in both children and adults.


Nanometer precise adjustment of the silver shell thickness during automated Au-Ag core-shell nanoparticle synthesis in micro fluid segment sequences.
In this work, a wet-chemical synthesis method for gold-silver core-shell particles with nanometer precise adjustable silver shell thicknesses is presented. Typically wet-chemical syntheses lead to relatively large diameter size distributions and losses in the yield of the desired particle structure due to thermodynamical effects. With the here explained synthesis method in micro fluidic segment sequences, a combinatorial in situ parameter screening of the reactant concentration ratios by programmed flow rate shifts in conjunction with efficient segment internal mixing conditions is possible. The highly increased mixing rates ensure a homogeneous shell deposition on all presented gold core particles while the amount of available silver ions was adjusted by automated flow rate courses, from which the synthesis conditions for exactly tunable shell thicknesses between 1.1 and 6.1 nm could be derived. The findings according to the homogeneity of size and particle structure were confirmed by differential centrifugal sedimentation (DCS), scanning and transmission electron microscopy (SEM, TEM) and X-ray photoelectron spectroscopy (XPS) measurements. In UV-Vis measurements, a significant contribution of the core metal was found in the shape of the extinction spectra in the case of thin shells. These results were confirmed by theoretical calculations.


Swedish-Registered Nurse Anesthetists' Evaluation of Their Professional Self.
This study aimed to explore how the nurse anesthetist values their professional self, compared with their peers, and also to explore whether professional self is affected by age, work experience, and/or gender. An explorative and prospective cross-sectional design. During April 2011, a total of 108 registered nurse anesthetists from three different hospitals were surveyed using the Professional Self-Description Form with questions covering 21 items. A total of 87 (80%) responded: 21 men and 66 women with a mean age of 45 years (range, 28 to 64 years) and mean professional experience of 12 years (range, 1 to 41 years). Four factors were found: professionalism, trait of character, scientific knowledge, and empathy, with Cronbach alpha of 0.96 overall. Analysis showed that perceived professional self depends on age and amount of work experience, but not on gender. The Professional Self-Description Form exhibits satisfactory internal consistency. Work experience and age influenced the development of professional self of nurse anesthetists.


Kdm6b regulates cartilage development and homeostasis through anabolic metabolism.
Epigenetic mechanisms have been reported to play key roles in chondrogenesis and osteoarthritis (OA) development. Here, we sought to identify specific histone demethylases that are involved and delineate the underlying mechanisms. We screened the expression of 17 distinct histone demethylases by quantitative real time PCR (qRT-PCR) during chondrogenic differentiation of C3H10T1/2 cells. The role of Kdm6b in cartilage development was then analysed with transgenic Col2a1-CreERT2;Kdm6bf/f . RNA-Seq was applied to explore the underlying changes in chondrocytes upon knockdown of Kdm6b. Experimental OA in mice was induced by destabilisation of the medial meniscus in C57BL/6J (wild type, Kdm6bf/f and Col2a1-CreERT2;Kdm6bf/f ) mice, either with intra-articular injection of shKdm6b lentivirus or after tamoxifen treatment. Mouse joints and human cartilage samples were used for histological analysis. Kdm6b expression was significantly increased during cartilage development. Col2a1-CreERT2;Kdm6bf/f mice displayed obvious skeletal abnormalities at E16.5 and E18.5 with intraperitoneal injection of tamoxifen at E12.5. RNA-Seq and qRT-PCR analyses revealed decreased expression of chondrocyte anabolic genes in Col2a1-CreERT2;Kdm6bf/f chondrocytes. The histological OA score was significantly higher in mice injected with Kdm6b short hairpin RNA lentivirus. Col2a1-CreERT2;Kdm6bf/f mice exhibited accelerated OA development at 8 and 12 weeks following surgical induction. The number of Kdm6b-positive chondrocytes was lower in both mice and human OA cartilage samples. These findings indicate that knockdown of Kdm6b in chondrocytes leads to abnormal cartilage development and accelerated OA progression via inhibition of the anabolic metabolism of chondrocytes. Understanding the epigenetic mechanism of joint cartilage development and homeostasis would be useful for development of new therapeutic modalities for OA.


Combinatorial drug conjugation enables nanoparticle dual-drug delivery.
A new approach to loading multiple drugs onto the same drug-delivery nanocarrier in a precisely controllable manner, by covalently preconjugating multiple therapeutic agents through hydrolyzable linkers to form drug conjugates, is reported. In contrast to loading individual types of drugs separately, this drug-conjugates strategy enables the loading of multiple drugs onto the same carrier with a predefined stoichiometric ratio. The cleavable linkers allow the therapeutic activity of the individual drugs to be resumed after the drug conjugates are delivered into the target cells and unloaded from the delivery vehicle. As a proof of concept, the synthesis and characterization of paclitaxel-gemcitabine conjugates are demonstrated. The time-dependent hydrolysis kinetics and cytotoxicity of the combinatorial drug conjugates against human pancreatic cancer cells are examined. It is shown that the synthesized drug conjugates can be readily encapsulated into a lipid-coated polymeric drug-delivery nanoparticle, which significantly improves the cytotoxicity of the drug conjugates as compared to the free drug conjugates.


Photograph use on social network sites among South Korean college students: the role of public and private self-consciousness.
This study challenges theories of computer-mediated communication (CMC) that typically assume a lack of visual cues in CMC and conceptualize them as a situational factor. We examine individual differences in photo use on social network sites and link them to the dispositional tendency of self-consciousness (SC). Included were 231 students from one university in South Korea, who owned and maintained Cyworld profiles (called "mini-homepages"). Findings suggest that public SC, but not private SC, was positively associated with the higher frequency of posting photos, replying to comments on the photos, and scrapping photos on their mini-homepages. The frequency of posting specific content types of photos (concerning social relationships or life events) was also determined by participants' public SC but not by private SC. Implications of the findings for CMC theories are discussed.


Applications of Ultrasound to Stimulate Therapeutic Revascularization.
Many pathological conditions are characterized or caused by the presence of an insufficient or aberrant local vasculature. Thus, therapeutic approaches aimed at modulating the caliber and/or density of the vasculature by controlling angiogenesis and arteriogenesis have been under development for many years. As our understanding of the underlying cellular and molecular mechanisms of these vascular growth processes continues to grow, so too do the available targets for therapeutic intervention. Nonetheless, the tools needed to implement such therapies have often had inherent weaknesses (i.e., invasiveness, expense, poor targeting, and control) that preclude successful outcomes. Approximately 20 years ago, the potential for using ultrasound as a new tool for therapeutically manipulating angiogenesis and arteriogenesis began to emerge. Indeed, the ability of ultrasound, especially when used in combination with contrast agent microbubbles, to mechanically manipulate the microvasculature has opened several doors for exploration. In turn, multiple studies on the influence of ultrasound-mediated bioeffects on vascular growth and the use of ultrasound for the targeted stimulation of blood vessel growth via drug and gene delivery have been performed and published over the years. In this review article, we first discuss the basic principles of therapeutic ultrasound for stimulating angiogenesis and arteriogenesis. We then follow this with a comprehensive cataloging of studies that have used ultrasound for stimulating revascularization to date. Finally, we offer a brief perspective on the future of such approaches, in the context of both further research development and possible clinical translation.


An atypical bHLH protein encoded by POSITIVE REGULATOR OF GRAIN LENGTH 2 is involved in controlling grain length and weight of rice through interaction with a typical bHLH protein APG.
Grain size is an important yield component in rice, however, genes controlling the trait remain poorly understood. Previously, we have shown that an antagonistic pair of basic helix-loop-helix (bHLH) proteins, POSITIVE REGULATOR OF GRAIN LENGTH 1 (PGL1) and ANTAGONIST OF PGL1 (APG), is involved in controlling rice grain length. Here, we report the involvement of another atypical bHLH protein gene, POSITIVE REGULATOR OF GRAIN LENGTH 2 (PGL2), in the regulation of rice grain length. Over-expression of PGL2 in the lemma/palea increased grain length and weight in correlation with the level of transgene expression. Observation of the inner epidermal cells of lemma of PGL2-overexpressing lines revealed that the long grain size is caused by an increase in cell length. PGL2 interacts with a typical bHLH protein APG, a negative regulator of rice grain length and weight, in vitro and in vivo. It was reported that overexpression of BU1 (BRASSINOSTEROID UPREGULATED 1), the closest homolog of PGL2, caused an increase in grain length. However, we detected no interaction between BU1 and APG. These findings suggest that PGL2 and PGL1 redundantly suppress the function of APG by forming heterodimers to positively regulate the rice grain length, while the pathway through which BU1, the closest homolog of PGL2, controls grain length is independent of APG.


Terahertz polarization converter and one-way transmission based on double-layer magneto-plasmonics of magnetized InSb.
In this work, we investigate the nonreciprocal circular dichroism for terahertz (THz) waves in magnetized InSb by the theoretical calculation and numerical simulation, which indicates that longitudinally magnetized InSb can be applied to the circular polarizer and nonreciprocal one-way transmission for the circular polarization THz waves. Furthermore, we propose a double-layer magnetoplasmonics based on the longitudinally magnetized InSb, and find two MO enhancement mechanisms in this device: the magneto surface plasmon resonance on the InSb-metal surface and Fabry-Pérot resonances between two orthogonal metallic gratings. These two resonance mechanisms enlarge the MO polarization rotation and greatly reduce the external magnetic field below 0.1T. The one-way transmission and perfect linear polarization conversion can be realized over 70dB, of which the transmittance can be modulated from 0 to 80% when the weak magnetic field changes from 0 to 0.1T under the low temperature around 200K. This magnetoplasmonic device has broad potential as a THz isolator, modulator, polarization convertor, and filter in the THz application systems.


The physical and genetic framework of the maize B73 genome.
Maize is a major cereal crop and an important model system for basic biological research. Knowledge gained from maize research can also be used to genetically improve its grass relatives such as sorghum, wheat, and rice. The primary objective of the Maize Genome Sequencing Consortium (MGSC) was to generate a reference genome sequence that was integrated with both the physical and genetic maps. Using a previously published integrated genetic and physical map, combined with in-coming maize genomic sequence, new sequence-based genetic markers, and an optical map, we dynamically picked a minimum tiling path (MTP) of 16,910 bacterial artificial chromosome (BAC) and fosmid clones that were used by the MGSC to sequence the maize genome. The final MTP resulted in a significantly improved physical map that reduced the number of contigs from 721 to 435, incorporated a total of 8,315 mapped markers, and ordered and oriented the majority of FPC contigs. The new integrated physical and genetic map covered 2,120 Mb (93%) of the 2,300-Mb genome, of which 405 contigs were anchored to the genetic map, totaling 2,103.4 Mb (99.2% of the 2,120 Mb physical map). More importantly, 336 contigs, comprising 94.0% of the physical map ( approximately 1,993 Mb), were ordered and oriented. Finally we used all available physical, sequence, genetic, and optical data to generate a golden path (AGP) of chromosome-based pseudomolecules, herein referred to as the B73 Reference Genome Sequence version 1 (B73 RefGen_v1).


Engaging stakeholders in rehabilitation research: a scoping review of strategies used in partnerships and evaluation of impacts.
To describe how stakeholder engagement has been undertaken and evaluated in rehabilitation research. A scoping review of the scientific literature using five search strategies. Quantitative and qualitative analyses using extracted data. Interpretation of results was iteratively discussed within the team, which included a parent stakeholder. Searches identified 101 candidate papers; 28 were read in full to assess eligibility and 19 were included in the review. People with disabilities and their families were more frequently involved compared to other stakeholders. Stakeholders were often involved in planning and evaluating service delivery. A key issue was identifying stakeholders; strategies used to support their involvement included creating committees, organizing meetings, clarifying roles and offering training. Communication, power sharing and resources influenced how stakeholders could be engaged in the research. Perceived outcomes of stakeholder engagement included the creation of partnerships, facilitating the research process and the application of the results, and empowering stakeholders. Stakeholder engagement outcomes were rarely formally evaluated. There is a great interest in rehabilitation to engage stakeholders in the research process. However, further evidence is needed to identify effective strategies for meaningful stakeholder engagement that leads to more useful research that positively impacts practice. Implications for Rehabilitation Using several strategies to engage various stakeholders throughout the research process is thought to increase the quality of the research and the rehabilitation process by developing proposals and programs responding better to their needs. Engagement strategies need to be better reported and evaluated in the literature. Engagement facilitate uptake of research findings by increasing stakeholders' awareness of the evidence, the resources available and their own ability to act upon a situation. Factors influencing opportunities for stakeholder engagement need to be better understood.


Circulating serum interleukin-6, serum chitinase-3-like protein-1, and plasma vascular endothelial growth factor are not predictive for remission and radiographic progression in patients with early rheumatoid arthritis: post-hoc explorative and validation studies based on the CIMESTRA and OPERA trials.
To investigate serum interleukin-6 (IL-6), serum chitinase-3-like protein-1 (YKL-40), and plasma vascular endothelial growth factor (VEGF) as measures of disease activity and predictors of clinical remission and radiographic progression in two early rheumatoid arthritis (RA) randomized controlled trials (RCTs). Treatment-naïve patients with early RA (< 6 months' duration) and active disease, participating in two investigator-initiated RCTs, were treated according to a predefined treat-to-target algorithm aiming at inflammatory control, using methotrexate (MTX) + cyclosporine versus MTX + placebo (CIMESTRA study, n = 150, 5 year follow-up) or MTX + adalimumab versus MTX + placebo (OPERA study, n = 180, 2 year follow-up). The 28-joint Disease Activity Score (DAS28) and conventional radiography [bilateral hands and feet at baseline, 2 years and 5 years (only CIMESTRA)] were obtained at baseline and during follow-up. Serum IL-6, serum YKL-40, and plasma VEGF were measured in baseline blood samples and during follow-up. Hypotheses regarding the biomarkers' relation with DAS28 and ability to predict clinical remission (DAS28 < 2.6) and radiographic progression (change in total Sharp van der Heijde score ≥ 2) were generated in CIMESTRA and validated in OPERA, by Spearman's correlation and logistic regression analyses. Baseline IL-6, YKL-40, and VEGF correlated significantly with DAS28 in CIMESTRA (r = 0.50, r = 0.36, r = 0.36, respectively, all p < 0.01) and these results were confirmed in OPERA patients (r = 0.52, p < 0.01; r = 0.18, p = 0.01; r = 0.23, p = 0.002, respectively). None of the biomarkers (absolute values or change) was predictive of clinical remission or radiographic progression at 2 or 5 years in either study. Serum IL-6, serum YKL-40, and plasma VEGF were significantly correlated with DAS28 at baseline, but did not have consistent predictive value for clinical remission or radiographic progression in two early RA RCTs.


FastSKAT: Sequence kernel association tests for very large sets of markers.
The sequence kernel association test (SKAT) is widely used to test for associations between a phenotype and a set of genetic variants that are usually rare. Evaluating tail probabilities or quantiles of the null distribution for SKAT requires computing the eigenvalues of a matrix related to the genotype covariance between markers. Extracting the full set of eigenvalues of this matrix (an n×n matrix, for n subjects) has computational complexity proportional to n3 . As SKAT is often used when n>104 , this step becomes a major bottleneck in its use in practice. We therefore propose fastSKAT, a new computationally inexpensive but accurate approximations to the tail probabilities, in which the k largest eigenvalues of a weighted genotype covariance matrix or the largest singular values of a weighted genotype matrix are extracted, and a single term based on the Satterthwaite approximation is used for the remaining eigenvalues. While the method is not particularly sensitive to the choice of k, we also describe how to choose its value, and show how fastSKAT can automatically alert users to the rare cases where the choice may affect results. As well as providing faster implementation of SKAT, the new method also enables entirely new applications of SKAT that were not possible before; we give examples grouping variants by topologically associating domains, and comparing chromosome-wide association by class of histone marker.


Mortality Reduction for Fever, Hyperglycemia, and Swallowing Nurse-Initiated Stroke Intervention: QASC Trial (Quality in Acute Stroke Care) Follow-Up.
Implementation of nurse-initiated protocols to manage fever, hyperglycemia, and swallowing dysfunction decreased death and disability 90 days poststroke in the QASC trial (Quality in Acute Stroke Care) conducted in 19 Australian acute stroke units (2005-2010). We now examine long-term all-cause mortality. Mortality was ascertained using Australia's National Death Index. Cox proportional hazards regression compared time to death adjusting for correlation within stroke units using the cluster sandwich (Huber-White estimator) method. Primary analyses included treatment group only unadjusted for covariates. Secondary analysis adjusted for age, sex, marital status, education, and stroke severity using multiple imputation for missing covariates. One thousand and seventy-six participants (intervention n=600; control n=476) were followed for a median of 4.1 years (minimum 0.3 to maximum 70 months), of whom 264 (24.5%) had died. Baseline demographic and clinical characteristics were generally well balanced by group. The QASC intervention group had improved long-term survival (>20%), but this was only statistically significant in adjusted analyses (unadjusted hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.58-1.07; P=0.13; adjusted HR, 0.77; 95% CI, 0.59-0.99; P=0.045). Older age (75-84 years; HR, 4.9; 95% CI, 2.8-8.7; P<0.001) and increasing stroke severity (HR, 1.5; 95% CI, 1.3-1.9; P<0.001) were associated with increased mortality, while being married (HR, 0.70; 95% CI, 0.49-0.99; P=0.042) was associated with increased likelihood of survival. Cardiovascular disease (including stroke) was listed either as the primary or secondary cause of death in 80% (211/264) of all deaths. Our results demonstrate the potential long-term and sustained benefit of nurse-initiated multidisciplinary protocols for management of fever, hyperglycemia, and swallowing dysfunction. These protocols should be a routine part of acute stroke care. URL: http://www.anzctr.org.au. Unique identifier: ACTRN12608000563369.


THE IMPACT OF GLP-1 RECEPTOR AGONISTS ON PATIENTS WITH DIABETES ON INSULIN THERAPY.
Objective: The clinical benefit of adding a glucagon-like peptide-1 receptor agonist (GLP-1RA) to basal-bolus or very high dose insulin regimens is unclear. This study investigated the impact of adding a GLP-1RA to a spectrum of insulin regimens (basal, basal-bolus, and U-500) to determine the impact on hemoglobin A1c (HbA1c), weight loss, and total daily insulin dose (TDD) over the course of 12 months. Methods: A retrospective chart review was conducted on 113 participants with type 2 diabetes mellitus using insulin therapy. Each participant's HbA1c, body weight, and TDD were recorded prior to initiation of GLP-1RA therapy and at the 3, 6, and 12-month time points while on combination therapy. Results: Across all participants, the HbA1c values decreased significantly from a baseline of 8.9 (74 mmol/mol) ± 0.14% to 8.2 (66 mmol/mol) ± 0.14% (P<.01) in the first 3 months, 8.0 (64 mmol/mol) ± 0.12% (P<.01) at 6 months, to 8.3 (67 mmol/mol) ± 0.14% (P<.01) at 12 months. There was no significant decrease in weight or TDD with the addition of a GLP-1RA overall or in different insulin groups. However, there was a clinically significant decrease in weight over the study duration. Conclusion: The results of this study suggest that adding a GLP-1RA to various insulin regimens may help to achieve glycemic goals while avoiding the less desirable side effects of weight gain and increasing insulin regimens. However, the expected weight loss and decrease in TDD may not be as sizable in the clinical setting. Abbreviations: DCOE = Diabetes Center of Excellence; DM = diabetes mellitus; GLP-1RA = glucagon-like peptide-1 receptor agonist; HbA1c = hemoglobin A1c; RCT = randomized controlled trial; TDD = total daily dose.