Inhibition of FLT3 and PIM Kinases by EC-70124 Exerts Potent Activity in Preclinical Models of Acute Myeloid Leukemia.
Internal tandem duplication (ITD) or tyrosine kinase domain mutations of FLT3 is the most frequent genetic alteration in acute myelogenous leukemia (AML) and are associated with poor disease outcome. Despite considerable efforts to develop single-target FLT3 drugs, so far, the most promising clinical response has been achieved using the multikinase inhibitor midostaurin. Here, we explore the activity of the indolocarbazole EC-70124, from the same chemical space as midostaurin, in preclinical models of AML, focusing on those bearing FLT3-ITD mutations. EC-70124 potently inhibits wild-type and mutant FLT3, and also other important kinases such as PIM kinases. EC-70124 inhibits proliferation of AML cell lines, inducing cell-cycle arrest and apoptosis. EC-70124 is orally bioavailable and displays higher metabolic stability and lower human protein plasma binding compared with midostaurin. Both in vitro and in vivo pharmacodynamic analyses demonstrate inhibition of FLT3-STAT5, Akt-mTOR-S6, and PIM-BAD pathways. Oral administration of EC-70124 in FLT3-ITD xenograft models demonstrates high efficacy, reaching complete tumor regression. Ex vivo, EC-70124 impaired cell viability in leukemic blasts, especially from FLT3-ITD patients. Our results demonstrate the ability of EC-70124 to reduce proliferation and induce cell death in AML cell lines, patient-derived leukemic blast and xenograft animal models, reaching best results in FLT3 mutants that carry other molecular pathways' alterations. Thus, its unique inhibition profile warrants EC-70124 as a promising agent for AML treatment based on its ability to interfere the complex oncogenic events activated in AML at several levels. Mol Cancer Ther; 17(3); 614-24. ©2018 AACR.


Pedestrians: the daily underestimated victims on the road.
Traffic-related pedestrian injuries (TRPI) are vulnerable to road users. In this study, we aimed to evaluate the demographic pattern of injury and outcome of TRPI. Patients with TRPI admitted between November 2007 and March 2010 to the only level 1 trauma centre in Qatar were included. A retrospective analysis was based on medical records and Emergency Medical Services run sheets. The spreadsheet included demographic data and pre-hospital transport, service admissions and injuries by system and mortality. Of 4077 patients who were admitted, 420 (10.3%) had TRPI. The mode of transportation included ambulances (91%), private vehicles (6%) and helicopters (3%). The direct dispositions were trauma intensive care units (38%), surgical wards (42%) and operating rooms (17%). Patients were classified according to Injury Severity Score (1-8 in 28%, 9-15 in 25%, 16-24 in 20% and 25-75 in 17% cases). Multisystem injuries were most characteristic. Of 804 injures, injury of extremities was predominant followed by head, thorax and abdomen. The overall mortality was 8%. Pedestrian injuries are a significant cause of serious trauma in Qatar. Motor vehicle/pedestrian interface contributes to this ongoing public health problem. Reducing pedestrian trauma requires recognition of the problem and implementing programmes to mitigate these largely preventable injuries.


[Differences in occupational accidents in Spain according to the worker's country of origin].
Compare the occupational accidents between autochthonous and immigrant workers in Spain. Data were obtained from the Spanish Survey of Working Conditions. Nationality was considered as an explicative variable, and the country of origin was regrouped according to the Human Development Index-HDI. Occupational accidents were the outcome. Other variables included were sociodemographic and employment conditions. Prevalences were calculated as well as simple and adjusted odds ratio (OR) (logistic regression) with a 95% confidence interval (CI 95%). The prevalence of occupational accidents was 12.7% (women, 11.1%) for workers from low HDI countries and 10.3% (women, 8.1%) for Spaniards. A higher risk of occupational accidents was observed among women from low HDI countries compared to Spaniards (adjusted OR 1.66; 95%CI 1.21-2.28). It is necessary to conduct a more thorough causal analysis of occupational accidents among immigrants in order to identify risk factors and strengthen prevention and control strategies.


Overview of methodologies for T-cell receptor repertoire analysis.
The T-cell receptor (TCR), located on the surface of T cells, is responsible for the recognition of the antigen-major histocompatibility complex, leading to the initiation of an inflammatory response. Analysing the TCR repertoire may help to gain a better understanding of the immune system features and of the aetiology and progression of diseases, in particular those with unknown antigenic triggers. The extreme diversity of the TCR repertoire represents a major analytical challenge; this has led to the development of specialized methods which aim to characterize the TCR repertoire in-depth. Currently, next generation sequencing based technologies are most widely employed for the high-throughput analysis of the immune cell repertoire. Here, we report on the latest methodological advancements in the field by describing and comparing the available tools; from the choice of the starting material and library preparation method, to the sequencing technologies and data analysis. Finally, we provide a practical example and our own experience by reporting some exemplary results from a small internal benchmark study, where current approaches from the literature and the market are employed and compared. Several valid methods for clonotype identification and TCR repertoire analysis exist, however, a gold standard method for the field has not yet been identified. Depending on the purpose of the scientific study, some approaches may be more suitable than others. Finally, due to possible method specific biases, scientists must be careful when comparing results obtained using different methods.


Miscarriage Occurrence and Prevention Efforts by Disability Status and Type in the United States.
Background: Very little is known about early pregnancy loss in women with disabilities. To address this gap, we analyzed nationally representative data on miscarriage and receipt of care focused on miscarriage prevention among women with and without disabilities. Materials and Methods: We used 2011-2015 National Survey of Family Growth data on women with at least one completed pregnancy within the past 5 years. Bivariate and multivariate analyses assessed the association of six disability categories (any, hearing, vision, cognitive, physical, independent living) with miscarriage occurrence and receipt of services intended to prevent miscarriage. Results: Our analytic sample included 3,843 women with 5,776 completed pregnancies within the past 5 years. Overall, 31.63% of women with disabilities and 21.83% of women without disabilities had had a miscarriage within the past 5 years. Compared to women without disabilities, women with any, cognitive, physical, and independent living disability had higher adjusted odds of experiencing miscarriage (any disability aOR = 1.65 [95% CI: 1.21-2.25]). These women also had higher odds of receiving services to prevent miscarriage compared with women without disabilities (any disability aOR = 1.71 [95% CI: 1.20-2.45]). Among women who received services, higher proportions of women with any, vision, physical, or independent living disability received recommendations for bed rest (e.g., 65.007% of women with independent living disability vs. 33.98% of women without disability, p = 0.018). Conclusions: In a representative sample of U.S. women, we found significant differences in the odds of miscarriage and in receipt of care to prevent miscarriage between women with and without disabilities. Further research is needed to understand why women with disabilities are more likely to experience a miscarriage. Such research is important for informing care recommendations.


Laboratory Markers in Incomplete Kawasaki Disease according to Coronary Artery Outcome.
We defined laboratory marker profiles typical of incomplete Kawasaki disease (iKD) during illness, especially with respect to the presence of a coronary artery abnormality such as coronary artery dilation or aneurysm. This retrospective study examined the clinical and laboratory markers of patients with iKD over time, along with those of patients with complete KD (cKD) and febrile controls. Of 795 patients, 178 had iKD, 504 had cKD and 113 were febrile controls. During the transition from the acute to subacute phase, the age-adjusted hemoglobin levels and platelet counts were significantly lower and higher, respectively, in the subacute phase than in the acute phase in both iKD and cKD patients, which differed from those of febrile controls. Lower levels of acute and subacute age-adjusted hemoglobin levels in iKD patients (odds ratio [OR], 0.538 and 0.583; p=0.006 and 0.018, respectively) and higher subacute platelet counts in cKD patients (OR, 1.004; p=0.014) were correlated with the risk of coronary dilation. A higher acute neutrophil-to-lymphocyte ratio was associated with aneurysm only in cKD patients (OR, 1.059; p=0.044). The iKD patients share KD-specific laboratory marker profiles in terms of complete blood cell counts and acute phase reactant levels with cKD patients. However, the factors predicting coronary dilation differ according to the phenotype; lower acute and subacute age-adjusted hemoglobin levels predict coronary dilation only in iKD patients.


Ulceration, unsteadiness, and uncertainty: the biomechanical consequences of diabetes mellitus.
Diabetes mellitus, which results from a failure of the endocrine system to control blood glucose levels within normal limits, affects approximately 15% of the population over the age of 65 in developed countries. Between 20-50% of people with diabetes for more than 10 years will experience symmetrical distal sensory neuropathy resulting in a progressive, distal to proximal, loss of sensation in the lower extremities. The most common consequence is plantar ulceration that too often results in partial or total amputation of the foot. While neuropathy is a major permissive factor, plantar ulcers occur at locations of high plantar pressures. The measurement of pressure using tools developed and refined in the field of biomechanics has been shown to be a valuable asset to the management of the foot at risk for ulceration. In particular, the use of in-shoe measuring techniques has the potential to revolutionize the prescription of therapeutic footwear. Biomechanical techniques have also helped to evaluate other consequences of diabetic neuropathy on the foot such as callus formation, foot deformity, limited joint mobility and bony abnormalities. The reduction of afferent information from the lower extremities implies a lack of active feedback thought to be necessary for the control of human movements such as posture and gait. Our results show that diabetic neuropathy results in a significant increase in sway during standing that is not compensated for by other sensory systems. The study of the sagittal plane movements of the same individuals walking on a treadmill showed little effect on the kinematic control of gait when compared to age matched nonneuropathic control groups. This may indicate the dominance of efferent input over afferent feedback during gait. We believe that the study of the biomechanical consequences of diabetes can act as a model for many other diseases that have yet to come under the scrutiny of a multidisciplinary team.


Psilocybin as a Treatment for Psychiatric Illness: A Meta-Analysis.
Psilocybin is an emerging potential therapy for the treatment of psychiatric illnesses. Microdosing has been shown to result in an overall improvement in patients with anxiety, depression, obsessive-compulsive disorder, post-traumatic stress disorder, and substance abuse. This meta-analysis explores and compiles prior research to make further inferences regarding psilocybin and its use for the treatment of psychiatric illness along with its safety and efficacy. Database searches were conducted to identify peer-reviewed randomized controlled trials and clinical trials mentioning psilocybin use and psychiatric illness. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram was created and analysis was run on the nine articles that met all established inclusion criteria. An event is defined as a participant who showed improvement, in a quantitative method, from baseline after the use of psilocybin. Another analysis was done using depression severity (Quick Inventory of Depressive Symptomatology 16-Item Self Report, QIDS-SR16) at baseline and after the use of psilocybin. Analyses of the original data and the nine articles showed a great deal of heterogeneity with an I2 value of 73.68%, suggesting that the studies in this meta-analysis cannot be considered to be studies of the same population. The Q value of 30.4 was higher than 15.507, which is the critical value for eight degrees of freedom found in a chi-square distribution. This Q value showed a high degree of variation and lacked significance. The second meta-run on QIDS-SR16 scores from three studies showed a Q value of 1.16 which was lower than 5.991, the critical value for two degrees of freedom found in a chi-square distribution. The I2 statistic for this second meta-analysis was -73% which can be equated to zero. This indicated that the data were homogeneous or that there was no observed heterogeneity. Due to low heterogeneity, the fixed-effects model was used. Based on this meta-analysis, psilocybin seems to show symptom improvement in some psychiatric illnesses. The effectiveness of psilocybin microdosing and the use of psilocybin, in general, need to be studied further to determine the efficacy and safety of potential applications in psychiatry.


Transcriptome profiling of developmental and xenobiotic responses in a keystone soil animal, the oligochaete annelid Lumbricus rubellus.
Natural contamination and anthropogenic pollution of soils are likely to be major determinants of functioning and survival of keystone invertebrate taxa. Soil animals will have both evolutionary adaptation and genetically programmed responses to these toxic chemicals, but mechanistic understanding of such is sparse. The clitellate annelid Lumbricus rubellus is a model organism for soil health testing, but genetic data have been lacking. We generated a 17,000 sequence expressed sequence tag dataset, defining ~8,100 different putative genes, and built an 8,000-element transcriptome microarray for L. rubellus. Strikingly, less than half the putative genes (43%) were assigned annotations from the gene ontology (GO) system; this reflects the phylogenetic uniqueness of earthworms compared to the well-annotated model animals. The microarray was used to identify adult- and juvenile-specific transcript profiles in untreated animals and to determine dose-response transcription profiles following exposure to three xenobiotics from different chemical classes: inorganic (the metal cadmium), organic (the polycyclic aromatic hydrocarbon fluoranthene), and agrochemical (the herbicide atrazine). Analysis of these profiles revealed compound-specific fingerprints which identify the molecular responses of this annelid to each contaminant. The data and analyses are available in an integrated database, LumbriBASE. L. rubellus has a complex response to contaminant exposure, but this can be efficiently analysed using molecular methods, revealing unique response profiles for different classes of effector. These profiles may assist in the development of novel monitoring or bioremediation protocols, as well as in understanding the ecosystem effects of exposure.


Agonists of peroxisome-proliferator activated receptor-alpha (clofibrate and WY14643) reduce renal ischemia/reperfusion injury in the rat.
The aim of this study was to investigate the effects of peroxisome-proliferator activated receptor-alpha (PPAR-alpha) agonists, clofibrate and WY14643 on the renal dysfunction and injury caused by bilateral ischemia/reperfusion (I/R) of rat kidneys in vivo. Male Wistar rats were anesthetized with sodium thiopentone (120 mg/kg i.v.) and subjected to bilateral renal ischemia (45 min) followed by reperfusion (6 h). Serum and urinary biochemical indicators of renal dysfunction and injury were measured; serum creatinine (sCr, glomerular dysfunction), fractional excretion of Na+ (FENa, tubular dysfunction), and urinary N-acetyl-b-D-glucosaminidase (uNAG, tubular injury). Additionally, renal sections were used for histological grading of renal injury and for RT-PCR analysis of the expression of PPAR-isoforms in kidneys obtained from rats prior to or after I/R. In addition, expression of intercellular adhesion molecule-1 (ICAM-1) was determined using Northern blot analysis. Using RT-PCR, we document here the expression of PPAR-alpha, PPAR-beta and PPAR-gamma1 (but not PPAR-gamma2) in the kidney of the rat. I/R resulted in the down-regulation of PPAR-alpha without modulation of any other PPAR. Clofibrate and WY14643 significantly reduced the increases in sCr, FENa and uNAG caused by renal I/R, indicating attenuation of renal dysfunction and injury. Expression of ICAM-1 caused by I/R of the kidney was not modulated by PPAR-alpha agonists. We show here that (i) renal I/R results in the down-regulation of PPAR-alpha in the kidney, and (ii) that the PPAR-alpha agonists clofibrate and WY14643 reduce the renal dysfunction and injury associated with I/R of the kidney.


Multiobjective immune algorithm with nondominated neighbor-based selection.
Abstract Nondominated Neighbor Immune Algorithm (NNIA) is proposed for multiobjective optimization by using a novel nondominated neighbor-based selection technique, an immune inspired operator, two heuristic search operators, and elitism. The unique selection technique of NNIA only selects minority isolated nondominated individuals in the population. The selected individuals are then cloned proportionally to their crowding-distance values before heuristic search. By using the nondominated neighbor-based selection and proportional cloning, NNIA pays more attention to the less-crowded regions of the current trade-off front. We compare NNIA with NSGA-II, SPEA2, PESA-II, and MISA in solving five DTLZ problems, five ZDT problems, and three low-dimensional problems. The statistical analysis based on three performance metrics including the coverage of two sets, the convergence metric, and the spacing, show that the unique selection method is effective, and NNIA is an effective algorithm for solving multiobjective optimization problems. The empirical study on NNIA's scalability with respect to the number of objectives shows that the new algorithm scales well along the number of objectives.


Community-acquired, non-occupational needlestick injuries treated in US Emergency Departments.
The escalating number of persons self-injecting medications, predominantly insulin, has generated concerns that the public is at risk of acquiring blood-borne infections from discarded needles/syringes. Communities have developed disposal guidelines but a debate continues over the need for further legislation and/or at-home safety devices. This study examines the number, characteristics, treatment and costs of community-acquired needlestick injuries (CANSIs). US-representative CANSI rates and characteristics were derived from 2001-08 National Electronic Injury Surveillance System All Injury Program data on product-related injuries treated at US emergency departments (EDs). CANSI-related medical care was examined using 2003-09 National Hospital Ambulatory Medical Care Surveys, representing all US ED visits. Cost analyses used 2010 Current Procedural Terminology Coding and Medicare rates. In 2001-08, an estimated 16 677 CANSIs were treated in US EDs, with an associated annual rate of 0.7 per 100 000 US citizens (95% CI 0.6-0.8) and no observable temporal trend. The estimated maximum annual medical cost of ED-treated CANSIs was $9.8 million, or $0.03 per citizen, $1.66 per insulin-injecting person and $0.0018 per insulin injection. US ED-treated CANSI rates are extremely low. Stricter disposal programs and the at-home use of safety devices do not appear to be needed at this time.


An oil spill decision matrix in response to surface spills of various bitumen blends.
Canada's production, transport, and sale of diluted bitumen (dilbit) products are expected to increase by a million barrels per day over the next decade. The anticipated growth in oil production and transport increases the risk of oil spills in aquatic areas and places greater demands on oil spill capabilities to respond to spills, which have raised stakeholder concerns. Current oil spill models only predict the transport of bitumen blends that are used in contingency plans and oil spill response strategies, rather than changes in the oil's physical properties that are relevant to spill response. We conducted weathering studies of five oil products (two conventional oils and three bitumen blends) in the Department of Fisheries and Oceans' flume tank. We also considered two initial oil slick thicknesses, 4.0 mm and 7.0 mm. We found that there is a major difference in the time evolution of oil properties (density and viscosity), raising doubts on weathering models that do not consider the thickness of oil. We also developed empirical expressions for the evolution of the density and viscosity of these oil products. The findings from the 4.0 mm results were incorporated with data from the literature to provide an update on the factors to consider during the decision making for spills of diluted bitumen products. The matrix indicated that most response options, including chemical dispersants, work much more effectively within 48 hours of the initiation of weathering. After this window of opportunity closes, natural attenuation or in situ burning is the only option remaining, but containment of oil is a limiting factor for in situ burning.


Characterizing the morphology of organic aerosols at ambient temperature and pressure.
The aerosol direct effect, which characterizes the interaction of radiation with aerosol particles, remains poorly understood. By determining aerosol composition, shape, and internal structure, we can predict aerosol optical properties. In this study, we performed a feasibility study to determine if tapping-mode atomic force microscopy (TM-AFM) and Raman microscopy can be effectively used to obtain information on aerosol composition, shape, and structure. These techniques are advantageous because they operate under ambient pressure and temperature. We worked with model aerosol particles composed of organic components of varying solubility mixed with ammonium sulfate. In particular, we explored whether aerosols could be differentiated on the basis of the solubility of the organic component. We also characterized the aerosol internal structure and investigated how this structure changes as the solubility of the organic compound is varied. To obtain indirect chemical information from AFM, we imaged particles supported on both polar, SiO(x)/Si(100), and nonpolar, highly ordered pyrolytic graphite, surfaces. We have found that AFM can be used to differentiate the solubility of the organic component. In some cases, AFM can also be used to identify internal structure. With Raman microscopy, we can differentiate between core-shell structures and homogeneous structures. Surprisingly, we find that even for the most soluble compounds, core-shell structures are observed. To discuss consequences of our results for climate studies, we calculate the difference in radiative forcing caused by having a core-shell aerosol rather than a homogeneous particle. Overall, these techniques are promising for characterizing composition, shape, and internal structure of atmospheric particles.


Sleep disorders, obesity, and aging: the role of orexin.
The hypothalamic neuropeptides orexin A and B (hypocretin 1 and 2) are important homeostatic mediators of central control of energy metabolism and maintenance of sleep/wake states. Dysregulation or loss of orexin signaling has been linked to narcolepsy, obesity, and age-related disorders. In this review, we present an overview of our current understanding of orexin function, focusing on sleep disorders, energy balance, and aging, in both rodents and humans. We first discuss animal models used in studies of obesity and sleep, including loss of function using transgenic or viral-mediated approaches, gain of function models using exogenous delivery of orexin receptor agonist, and naturally-occurring models in which orexin responsiveness varies by individual. We next explore rodent models of orexin in aging, presenting evidence that orexin loss contributes to age-related changes in sleep and energy balance. In the next section, we focus on clinical importance of orexin in human obesity, sleep, and aging. We include discussion of orexin loss in narcolepsy and potential importance of orexin in insomnia, correlations between animal and human studies of age-related decline, and evidence for orexin involvement in age-related changes in cognitive performance. Finally, we present a summary of recent studies of orexin in neurodegenerative disease. We conclude that orexin acts as an integrative homeostatic signal influencing numerous brain regions, and that this pivotal role results in potential dysregulation of multiple physiological processes when orexin signaling is disrupted or lost.


Effects of Gradient Coil Noise and Gradient Coil Replacement on the Reproducibility of Resting State Networks.
The stability of the MRI scanner throughout a given study is critical in minimizing hardware-induced variability in the acquired imaging data set. However, MRI scanners do malfunction at times, which could generate image artifacts and would require the replacement of a major component such as its gradient coil. In this article, we examined the effect of low intensity, randomly occurring hardware-related noise due to a faulty gradient coil on brain morphometric measures derived from T1-weighted images and resting state networks (RSNs) constructed from resting state functional MRI. We also introduced a method to detect and minimize the effect of the noise associated with a faulty gradient coil. Finally, we assessed the reproducibility of these morphometric measures and RSNs before and after gradient coil replacement. Our results showed that gradient coil noise, even at relatively low intensities, could introduce a large number of voxels exhibiting spurious significant connectivity changes in several RSNs. However, censoring the affected volumes during the analysis could minimize, if not completely eliminate, these spurious connectivity changes and could lead to reproducible RSNs even after gradient coil replacement.


Manipulative interplay of two adozelesin molecules with d(ATTAAT)₂achieving ligand-stacked Watson-Crick and Hoogsteen base-paired duplex adducts.
Previous structural studies of the cyclopropapyrroloindole (CPI) antitumor antibiotics have shown that these ligands bind covalently edge-on into the minor groove of double-stranded DNA. Reversible covalent modification of the DNA via N3 of adenine occurs in a sequence-specific fashion. Early nuclear magnetic resonance and molecular modeling studies with both mono- and bis-alkylating ligands indicated that the ligands fit tightly within the minor groove, causing little distortion of the helix. In this study, we propose a new binding model for several of the CPI-based analogues, in which the aromatic secondary rings form π-stacked complexes within the minor groove. One of the adducts, formed with adozelesin and the d(ATTAAT)(2) sequence, also demonstrates the ability of these ligands to manipulate the DNA of the binding site, resulting in a Hoogsteen base-paired adduct. Although this type of base pairing has been previously observed with the bisfunctional CPI analogue bizelesin, this is the first time that such an observation has been made with a monoalkylating nondimeric analogue. Together, these results provide a new model for the design of CPI-based antitumor antibiotics, which also has a significant bearing on other structurally related and structurally unrelated minor groove-binding ligands. They indicate the dynamic nature of ligand-DNA interactions, demonstrating both DNA conformational flexibility and the ability of two DNA-bound ligands to interact to form stable covalent modified complexes.


Polymer simulations guide the detection and quantification of chromatin loop extrusion by imaging.
Genome-wide chromosome conformation capture (Hi-C) has revealed the organization of chromatin into topologically associating domains (TADs) and loops, which are thought to help regulate genome functions. TADs and loops are understood as the result of DNA extrusion mediated by the cohesin complex. However, despite recent efforts, direct visualization and quantification of this process in single cells remains an open challenge. Here, we use polymer simulations and dedicated analysis methods to explore if, and under which conditions, DNA loop extrusion can be detected and quantitatively characterized by imaging pairs of fluorescently labeled loci located near loop or TAD anchors in fixed or living cells. We find that under realistic conditions, extrusion can be detected and the frequency of loop formation can be quantified from fixed cell images alone, while the lifetime of loops and the speed of extrusion can be estimated from dynamic live-cell data. Our delineation of appropriate imaging conditions and the proposed analytical methods lay the groundwork for a systematic quantitative characterization of loop extrusion in fixed or living cells.


Pathway mapping of leukocyte transcriptome in influenza patients reveals distinct pathogenic mechanisms associated with progression to severe infection.
Influenza infections produce a spectrum of disease severity, ranging from a mild respiratory illness to respiratory failure and death. The host-response pathways associated with the progression to severe influenza disease are not well understood. To gain insight into the disease mechanisms associated with progression to severe infection, we analyzed the leukocyte transcriptome in severe and moderate influenza patients and healthy control subjects. Pathway analysis on differentially expressed genes was performed using a topology-based pathway analysis tool that takes into account the interaction between multiple cellular pathways. The pathway profiles between moderate and severe influenza were then compared to delineate the biological mechanisms underpinning the progression from moderate to severe influenza. 107 patients (44 severe and 63 moderate influenza patients) and 52 healthy control subjects were included in the study. Severe influenza was associated with upregulation in several neutrophil-related pathways, including pathways involved in neutrophil differentiation, migration, degranulation and neutrophil extracellular trap (NET) formation. The degree of upregulation in neutrophil-related pathways were significantly higher in severely infected patients compared to moderately infected patients. Severe influenza was also associated with downregulation in immune response pathways, including pathways involved in antigen presentation such as CD4+ T-cell co-stimulation, CD8+ T cell and Natural Killer (NK) cells effector functions. Apoptosis pathways were also downregulated in severe influenza patients compare to moderate and healthy controls. These findings showed that there are changes in gene expression profile that may highlight distinct pathogenic mechanisms associated with progression from moderate to severe influenza infection.


Surgical training and research in the Netherlands.
In contrast to many other countries, training of medical specialists is funded by the Department of Health. The curriculum of medical specialist training including general surgery is well structured and lasts 6 years. Specialist (trainers) and hospitals involved in surgical training have been accredited by the Dutch Association of Surgeons. Surgical training includes 4 years of general surgery followed by two years of differentiation in one of the sub-specialities. These are gastrointestinal, oncological, vascular, pediatric and trauma surgery. The training program is competency based: there are key procedures and so called EPA (entrusted professional activities) that are defined to monitor the progress of an individual. Unique in the Dutch system is the quality control and governance of surgical training that will be discussed in my lecture.The number of positions available for surgical trainees is limited and determined by the government each year. Hence, to enter surgical training has always been very competitive and not easy for young doctors. This is one of the reasons why many students start a PhD program after medical school and to gain experience in basic or clinical research. These young and talented students usually work for 3-4 years full time and are well capable of coordinating trials. This is just one of the reasons that many clinical (randomised) studies come from the Netherlands. Besides this strong academic environment, lack of private practice, strong multidisciplinary working parties and the geographical situation in our small country facilitates multicenter studies. Some more crucial factors for success will be discussed in the lecture.(Presented at the 1983th Meeting, July 10, 2019).


Using machine learning to predict 30-day readmissions after posterior lumbar fusion: an NSQIP study involving 23,264 patients.
Unplanned preventable hospital readmissions within 30 days are a great burden to patients and the healthcare system. With an estimated $41.3 billion spent yearly, reducing such readmission rates is of the utmost importance. With the widespread adoption of big data and machine learning, clinicians can use these analytical tools to understand these complex relationships and find predictive factors that can be generalized to future patients. The object of this study was to assess the efficacy of a machine learning algorithm in the prediction of 30-day hospital readmission after posterior spinal fusion surgery. The authors analyzed the distribution of National Surgical Quality Improvement Program (NSQIP) posterior lumbar fusions from 2011 to 2016 by using machine learning techniques to create a model predictive of hospital readmissions. A deep neural network was trained using 177 unique input variables. The model was trained and tested using cross-validation, in which the data were randomly partitioned into training (n = 17,448 [75%]) and testing (n = 5816 [25%]) data sets. In training, the 17,448 training cases were fed through a series of 7 layers, each with varying degrees of forward and backward communicating nodes (neurons). Mean and median positive predictive values were 78.5% and 78.0%, respectively. Mean and median negative predictive values were both 97%, respectively. Mean and median areas under the curve for the model were 0.812 and 0.810, respectively. The five most heavily weighted inputs were (in order of importance) return to the operating room, septic shock, superficial surgical site infection, sepsis, and being on a ventilator for > 48 hours. Machine learning and artificial intelligence are powerful tools with the ability to improve understanding of predictive metrics in clinical spine surgery. The authors' model was able to predict those patients who would not require readmission. Similarly, the majority of predicted readmissions (up to 60%) were predicted by the model while retaining a 0% false-positive rate. Such findings suggest a possible need for reevaluation of the current Hospital Readmissions Reduction Program penalties in spine surgery.


Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial.
Survival outcomes are poor for patients with metastatic urothelial carcinoma who receive standard, first-line, platinum-based chemotherapy. We assessed the overall survival of patients who received durvalumab (a PD-L1 inhibitor), with or without tremelimumab (a CTLA-4 inhibitor), as a first-line treatment for metastatic urothelial carcinoma. DANUBE is an open-label, randomised, controlled, phase 3 trial in patients with untreated, unresectable, locally advanced or metastatic urothelial carcinoma, conducted at 224 academic research centres, hospitals, and oncology clinics in 23 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. We randomly assigned patients (1:1:1) to receive durvalumab monotherapy (1500 mg) administered intravenously every 4 weeks; durvalumab (1500 mg) plus tremelimumab (75 mg) administered intravenously every 4 weeks for up to four doses, followed by durvalumab maintenance (1500 mg) every 4 weeks; or standard-of-care chemotherapy (gemcitabine plus cisplatin or gemcitabine plus carboplatin, depending on cisplatin eligibility) administered intravenously for up to six cycles. Randomisation was done through an interactive voice-web response system, with stratification by cisplatin eligibility, PD-L1 status, and presence or absence of liver metastases, lung metastases, or both. The coprimary endpoints were overall survival compared between the durvalumab monotherapy versus chemotherapy groups in the population of patients with high PD-L1 expression (the high PD-L1 population) and between the durvalumab plus tremelimumab versus chemotherapy groups in the intention-to-treat population (all randomly assigned patients). The study has completed enrolment and the final analysis of overall survival is reported. The trial is registered with ClinicalTrials.gov, NCT02516241, and the EU Clinical Trials Register, EudraCT number 2015-001633-24. Between Nov 24, 2015, and March 21, 2017, we randomly assigned 1032 patients to receive durvalumab (n=346), durvalumab plus tremelimumab (n=342), or chemotherapy (n=344). At data cutoff (Jan 27, 2020), median follow-up for survival was 41·2 months (IQR 37·9-43·2) for all patients. In the high PD-L1 population, median overall survival was 14·4 months (95% CI 10·4-17·3) in the durvalumab monotherapy group (n=209) versus 12·1 months (10·4-15·0) in the chemotherapy group (n=207; hazard ratio 0·89, 95% CI 0·71-1·11; p=0·30). In the intention-to-treat population, median overall survival was 15·1 months (13·1-18·0) in the durvalumab plus tremelimumab group versus 12·1 months (10·9-14·0) in the chemotherapy group (0·85, 95% CI 0·72-1·02; p=0·075). In the safety population, grade 3 or 4 treatment-related adverse events occurred in 47 (14%) of 345 patients in the durvalumab group, 93 (27%) of 340 patients in the durvalumab plus tremelimumab group, and in 188 (60%) of 313 patients in the chemotherapy group. The most common grade 3 or 4 treatment-related adverse event was increased lipase in the durvalumab group (seven [2%] of 345 patients) and in the durvalumab plus tremelimumab group (16 [5%] of 340 patients), and neutropenia in the chemotherapy group (66 [21%] of 313 patients). Serious treatment-related adverse events occurred in 30 (9%) of 345 patients in the durvalumab group, 78 (23%) of 340 patients in the durvalumab plus tremelimumab group, and 50 (16%) of 313 patients in the chemotherapy group. Deaths due to study drug toxicity were reported in two (1%) patients in the durvalumab group (acute hepatic failure and hepatitis), two (1%) patients in the durvalumab plus tremelimumab group (septic shock and pneumonitis), and one (<1%) patient in the chemotherapy group (acute kidney injury). This study did not meet either of its coprimary endpoints. Further research to identify the patients with previously untreated metastatic urothelial carcinoma who benefit from treatment with immune checkpoint inhibitors, either alone or in combination regimens, is warranted. AstraZeneca.


Nanocubes for real-time exploration of spatiotemporal datasets.
Consider real-time exploration of large multidimensional spatiotemporal datasets with billions of entries, each defined by a location, a time, and other attributes. Are certain attributes correlated spatially or temporally? Are there trends or outliers in the data? Answering these questions requires aggregation over arbitrary regions of the domain and attributes of the data. Many relational databases implement the well-known data cube aggregation operation, which in a sense precomputes every possible aggregate query over the database. Data cubes are sometimes assumed to take a prohibitively large amount of space, and to consequently require disk storage. In contrast, we show how to construct a data cube that fits in a modern laptop's main memory, even for billions of entries; we call this data structure a nanocube. We present algorithms to compute and query a nanocube, and show how it can be used to generate well-known visual encodings such as heatmaps, histograms, and parallel coordinate plots. When compared to exact visualizations created by scanning an entire dataset, nanocube plots have bounded screen error across a variety of scales, thanks to a hierarchical structure in space and time. We demonstrate the effectiveness of our technique on a variety of real-world datasets, and present memory, timing, and network bandwidth measurements. We find that the timings for the queries in our examples are dominated by network and user-interaction latencies.


Phylogenomic analyses and distribution of terpene synthases among Streptomyces.
Terpene synthases are widely distributed among microorganisms and have been mainly studied in members of the genus Streptomyces. However, little is known about the distribution and evolution of the genes for terpene synthases. Here, we performed whole-genome based phylogenetic analysis of Streptomyces species, and compared the distribution of terpene synthase genes among them. Overall, our study revealed that ten major types of terpene synthases are present within the genus Streptomyces, namely those for geosmin, 2-methylisoborneol, epi-isozizaene, 7-epi-α-eudesmol, epi-cubenol, caryolan-1-ol, cyclooctat-9-en-7-ol, isoafricanol, pentalenene and α-amorphene. The Streptomyces species divide in three phylogenetic groups based on their whole genomes for which the distribution of the ten terpene synthases was analysed. Geosmin synthases were the most widely distributed and were found to be evolutionary positively selected. Other terpene synthases were found to be specific for one of the three clades or a subclade within the genus Streptomyces. A phylogenetic analysis of the most widely distributed classes of Streptomyces terpene synthases in comparison to the phylogenomic analysis of this genus is discussed.


Analysis of Voluntary User Feedback of the Swedish National PAEHR Service.
"Journalen" is a patient accessible electronic health record (PAEHR) and the national eHealth service for Sweden's citizens to gain access to their EHR. The Swedish national eHealth organization Inera, responsible for Journalen, created an inbox to receive voluntary user feedback about Journalen in order to improve the service from the user perspective. Based on voluntary user feedback via email. This study explored patients' experiences of using the national eHealth service and identified pros and cons. A mixed method content analysis was performed. In total, 1084 emails from 2016-2017 have been analyzed. 9 categories were identified, the most frequent ones related to questions about why some information was not accessible (due to regional differencies), feedback (including only positive or negative comments as well as constructive improvement suggestions), and emails about errors that user found in their record. These data can be successfully used to continuously improve an already implemented eHealth service.


Identifiability analysis for stochastic differential equation models in systems biology.
Mathematical models are routinely calibrated to experimental data, with goals ranging from building predictive models to quantifying parameters that cannot be measured. Whether or not reliable parameter estimates are obtainable from the available data can easily be overlooked. Such issues of parameter identifiability have important ramifications for both the predictive power of a model, and the mechanistic insight that can be obtained. Identifiability analysis is well-established for deterministic, ordinary differential equation (ODE) models, but there are no commonly adopted methods for analysing identifiability in stochastic models. We provide an accessible introduction to identifiability analysis and demonstrate how existing ideas for analysis of ODE models can be applied to stochastic differential equation (SDE) models through four practical case studies. To assess structural identifiability, we study ODEs that describe the statistical moments of the stochastic process using open-source software tools. Using practically motivated synthetic data and Markov chain Monte Carlo methods, we assess parameter identifiability in the context of available data. Our analysis shows that SDE models can often extract more information about parameters than deterministic descriptions. All code used to perform the analysis is available on Github.


ACTIVE SURVEILLANCE FOR PAPILLARY THYROID MICROCARCINOMA: NEW CHALLENGES AND OPPORTUNITIES FOR THE HEALTH CARE SYSTEM.
The dramatic increase in papillary thyroid carcinoma (PTC) is primarily a result of early diagnosis of small cancers. Active surveillance is a promising management strategy for papillary thyroid microcarcinomas (PTMCs). However, as this management strategy gains traction in the U.S., it is imperative that patients and clinicians be properly educated, patients be followed for life, and appropriate tools be identified to implement the strategy. We review previous active surveillance studies and the parameters used to identify patients who are good candidates for active surveillance. We also review some of the challenges to implementing active surveillance protocols in the U.S. and discuss how these might be addressed. Trials of active surveillance support nonsurgical management as a viable and safe management strategy. However, numerous challenges exist, including the need for adherence to protocols, education of patients and physicians, and awareness of the impact of this strategy on patient psychology and quality of life. The Thyroid Cancer Care Collaborative (TCCC) is a portable record keeping system that can manage a mobile patient population undergoing active surveillance. With proper patient selection, organization, and patient support, active surveillance has the potential to be a long-term management strategy for select patients with PTMC. In order to address the challenges and opportunities for this approach to be successfully implemented in the U.S., it will be necessary to consider psychological and quality of life, cultural differences, and the patient's clinical status.


Inteins: Nature's Gift to Protein Chemists.
Inteins are auto-processing domains found in organisms from all domains of life. These proteins carry out a process known as protein splicing, which is a multi-step biochemical reaction comprised of both the cleavage and formation of peptide bonds. While the endogenous substrates of protein splicing are specific essential proteins found in intein-containing host organisms, inteins are also functional in exogenous contexts and can be used to chemically manipulate virtually any polypeptide backbone. Given this, protein chemists have exploited various facets of intein reactivity to modify proteins in myriad ways for both basic biological research as well as potential therapeutic applications. Here, we review the intein field, first focusing on the biological context and phylogenetic diversity of inteins, followed by a description of intein structure and biochemical function. Finally, we discuss prevalent inteinbased technologies, focusing on their applications in chemical biology, followed by persistent caveats of intein chemistry and approaches to alleviate these shortcomings. The findings summarized herein describe two and a half decades of research, leading from a biochemical curiosity to the development of powerful protein engineering tools.


The effect of vitamin D and its metabolites on fracture repair in chicks.
One-day-old chicks were depleted of vitamin D. At 3 weeks their right tibiae, and those of a control group given vitamin D3, were fractured and pinned. After fracture the controls were kept on vitamin D3. Another group was left vitamin D-deficient. The remaining depleted chicks, divided into four groups, were given vitamin D3, 24,25-dihydroxyvitamin D3 [24,25(OH)2D3], 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] or a combination of 24,25(OH)2D3 and 1,25(OH)2D3. The callus obtained after 9 and 14 days was subjected to torsional stress. The callus of chicks given vitamin D continuously showed the greatest resistance, whereas that of vitamin D-deficient chicks showed the smallest resistance. Repletion with either vitamin D3 or its metabolites increased the strength of the callus. Repletion with the combination of 24,25(OH)2D3 and 1,25(OH)2D3 produced the most marked results, in that the callus was even stronger than that of chicks replete with vitamin D3. It is concluded that 24,25(OH)2D3 is essential for bone formation in addition to the known active vitamin D metabolite 1,25(OH)2D3, and the possible clinical implications of these findings are discussed.


Randomized trial of daily versus three-times-weekly prophylactic ganciclovir after lung and heart-lung transplantation.
Cytomegalovirus is an important cause of morbidity and mortality risk after lung transplantation. Ganciclovir, when given for a period of up to 3 months after lung transplantation, has been shown to reduce the incidence and severity of cytomegalovirus. However, daily prophylaxis is associated with considerable expense, inconvenience, and morbidity risk. The goal of this study was to determine whether 3-times-weekly dosage is as effective as daily prophylaxis with ganciclovir in preventing cytomegalovirus disease. Seventy-two consecutive subjects who had either donor or recipient cytomegalovirus seropositivity were randomized to the daily group (n = 35) or the 3-times-weekly group (n = 37). All subjects received twice-daily ganciclovir treatment for 2 weeks. Thereafter, subjects received either daily or 3-times-weekly ganciclovir dosing until 90 days after transplantation. Subjects were then monitored for 28 +/- 13 months to identify outcomes and complications. There were no significant differences between the daily and 3-times-weekly groups with respect to survival free from cytomegalovirus infection or survival free from cytomegalovirus disease. In both groups, cytomegalovirus infection and disease frequently emerged after the termination of prophylaxis. However, in most cases the cytomegalovirus syndromes observed were mild and in many cases could be treated on an outpatient basis. There was no significant difference between the groups in the incidence of obliterative bronchiolitis or time to onset of grade 2 bronchiolitis obliterans syndrome. Overall patient survival was better in the daily group, but the survival advantage did not appear to be related to a reduction in cytomegalovirus-related disease. Complications of ganciclovir prophylaxis included leukopenia in 2 subjects in the 3-times-weekly group and catheter-related sepsis in 6 subjects from each group. We conclude that intravenous ganciclovir given 3 times weekly for 3 months after transplantation is as effective as daily ganciclovir given for a similar time period. The 3-times-weekly dosing regimen did not result in increased infection, disease, or sequelae of cytomegalovirus infection when compared with the daily regimen.


The relationship between resilience and personality traits in doctors: implications for enhancing well being.
Objective. The health and well being of medical doctors is vital to their longevity and safe practice. The concept of resilience is recognised as a key component of well being and is an important factor in medical training to help doctors learn to cope with challenge, stress, and adversity. This study examined the relationship of resilience to personality traits and resilience in doctors in order to identify the key traits that promote or impair resilience. Methods. A cross sectional cohort of 479 family practitioners in practice across Australia was studied. The Temperament and Character Inventory measured levels of the seven basic dimensions of personality and the Resilience Scale provided an overall measure of resilience. The associations between resilience and personality were examined by Pearson product-moment correlation coefficients, controlling for age and gender (α = 0.05 with an accompanying 95% confidence level) and multiple regression analyses. Results. Strong to medium positive correlations were found between Resilience and Self-directedness (r = .614, p < .01), Persistence (r = .498, p < .01), and Cooperativeness (r = .363, p < .01) and negative with Harm Avoidance (r = .-555, p < .01). Individual differences in personality explained 39% of the variance in resilience [F(7, 460) = 38.40, p < .001]. The three traits which contributed significantly to this variance were Self-directedness (β = .33, p < .001), Persistence (β = .22, p < .001) and Harm Avoidance (β = .19, p < .001). Conclusion. Resilience was associated with a personality trait pattern that is mature, responsible, optimistic, persevering, and cooperative. Findings support the inclusion of resilience as a component of optimal functioning and well being in doctors. Strategies for enhancing resilience should consider the key traits that drive or impair it.


Decay kinetics of human immunodeficiency virus-specific CD8+ T cells in peripheral blood after initiation of highly active antiretroviral therapy.
We measured the longitudinal responses to 95 HLA class I-restricted human immunodeficiency virus (HIV) epitopes and an immunodominant HLA A2-restricted cytomegalovirus (CMV) epitope in eight treatment-naive HIV-infected individuals, using intracellular cytokine staining. Patients were treated with highly active antiretroviral therapy (HAART) for a median of 78 weeks (range, 34 to 121 weeks). Seven of eight patients maintained an undetectable viral load for the duration of therapy. A rapid decline in HIV-specific CD8(+) T-cell response was observed at initiation of therapy. After an undetectable viral load was achieved, a slower decrease in HIV-specific CD8(+) T-cell response was observed that was well described by first-order kinetics. The median half-life for the rate of decay was 38.8 (20.3 to 68.0) weeks when data were expressed as percentage of peripheral CD8(+) T cells. In most cases, data were similar when expressed as the number of responding CD8(+) T cells per microliter of blood. In subjects who responded to more than one HIV epitope, rates of decline in response to the different epitopes were similar and varied by a factor of 2.2 or less. Discontinuation of treatment resulted in a rapid increase in HIV-specific CD8(+) T cells. Responses to CMV increased 1.6- and 2.8-fold within 16 weeks of initiation of HAART in two of three patients with a measurable CMV response. These data suggest that HAART quickly starts to restore CD8(+) T-cell responses to other chronic viral infections and leads to a slow decrease in HIV-specific CD8(+) T-cell response in HIV-infected patients. The slow decrease in the rate of CD8(+) T-cell response and rapid increase in response to recurrent viral replication suggest that the decrease in CD8(+) T-cell response observed represents a normal memory response to withdrawal of antigen.


Effects of aggregation of drug and diagnostic codes on the performance of the high-dimensional propensity score algorithm: an empirical example.
The High-Dimensional Propensity Score (hd-PS) algorithm can select and adjust for baseline confounders of treatment-outcome associations in pharmacoepidemiologic studies that use healthcare claims data. How hd-PS performance is affected by aggregating medications or medical diagnoses has not been assessed. We evaluated the effects of aggregating medications or diagnoses on hd-PS performance in an empirical example using resampled cohorts with small sample size, rare outcome incidence, or low exposure prevalence. In a cohort study comparing the risk of upper gastrointestinal complications in celecoxib or traditional NSAIDs (diclofenac, ibuprofen) initiators with rheumatoid arthritis and osteoarthritis, we (1) aggregated medications and International Classification of Diseases-9 (ICD-9) diagnoses into hierarchies of the Anatomical Therapeutic Chemical classification (ATC) and the Clinical Classification Software (CCS), respectively, and (2) sampled the full cohort using techniques validated by simulations to create 9,600 samples to compare 16 aggregation scenarios across 50% and 20% samples with varying outcome incidence and exposure prevalence. We applied hd-PS to estimate relative risks (RR) using 5 dimensions, predefined confounders, ≤ 500 hd-PS covariates, and propensity score deciles. For each scenario, we calculated: (1) the geometric mean RR; (2) the difference between the scenario mean ln(RR) and the ln(RR) from published randomized controlled trials (RCT); and (3) the proportional difference in the degree of estimated confounding between that scenario and the base scenario (no aggregation). Compared with the base scenario, aggregations of medications into ATC level 4 alone or in combination with aggregation of diagnoses into CCS level 1 improved the hd-PS confounding adjustment in most scenarios, reducing residual confounding compared with the RCT findings by up to 19%. Aggregation of codes using hierarchical coding systems may improve the performance of the hd-PS to control for confounders. The balance of advantages and disadvantages of aggregation is likely to vary across research settings.


Characterization of a PET detector head based on continuous LYSO crystals and monolithic, 64-pixel silicon photomultiplier matrices.
The characterization of a PET detector head based on continuous LYSO crystals and silicon photomultiplier (SiPM) arrays as photodetectors has been carried out for its use in the development of a small animal PET prototype. The detector heads are composed of a continuous crystal and a SiPM matrix with 64 pixels in a common substrate, fabricated specifically for this project. Three crystals of 12 mm × 12 mm × 5 mm size with different types of painting have been tested: white, black and black on the sides but white on the back of the crystal. The best energy resolution, obtained with the white crystal, is 16% FWHM. The detector response is linear up to 1275 keV. Tests with different position determination algorithms have been carried out with the three crystals. The spatial resolution obtained with the center of gravity algorithm is around 0.9 mm FWHM for the three crystals. As expected, the use of this algorithm results in the displacement of the reconstructed position toward the center of the crystal, more pronounced in the case of the white crystal. A maximum likelihood algorithm has been tested that can reconstruct correctly the interaction position of the photons also in the case of the white crystal.


An efficient charge separation and photocurrent generation in the carbon dot-zinc oxide nanoparticle composite.
The development of light harvesting systems based on heterostructures for efficient conversion of solar energy to renewable energy is an emerging area of research. Here, we have designed heterostructures by using carbon dots (C-dots) and zinc oxide nanoparticles (ZnO NP) to develop an efficient light harvesting system. Interestingly, the conduction band and the valence band positions of ZnO NP are lower than the LUMO and HOMO positions of C-dots in this type II heterostructure of C dot-ZnO NP, which causes efficient charge separation and photocurrent generation. Steady state and time resolved spectroscopic studies reveal that an efficient photoinduced electron transfer occurs from C dots to ZnO NP and a simultaneous hole transfer occurs from the valence band of ZnO NP to the HOMO of C dots. The calculated rate of electron transfer is found to be 3.7 × 109 s-1 and the rate of hole transfer is found to be 3.6 × 107 s-1. The enhancement of photocurrent (11 fold) under solar light irradiation of the C dot-ZnO NP heterostructure opens up new possibilities to design efficient light harvesting systems.


Qualitative systematic review of barriers and facilitators to self-management of chronic obstructive pulmonary disease: views of patients and healthcare professionals.
Self-management interventions for chronic obstructive pulmonary disease (COPD) can improve quality of life, reduce hospital admissions, and improve symptoms. However, many factors impede engagement for patients and practitioners. Qualitative research, with its focus on subjective experience, can provide invaluable insights into such factors. Therefore, a systematic review and synthesis of qualitative evidence on COPD self-management from the perspective of patients, carers, and practitioners was conducted. Following a systematic search and screening, 31 studies were appraised and data extracted for analysis. This review found that patients can adapt to COPD; however, learning to self-manage is often a protracted process. Emotional needs are considerable; frustration, depression, and anxiety are common. In addition, patients can face an assortment of losses and limitations on their lifestyle and social interaction. Over time, COPD can consume their existence, reducing motivation. Support from family can prove vital, yet tinged with ambivalence and burden. Practitioners may not have sufficient time, resources, or appropriate skills or confidence to provide effective self-management support, particularly in regard to patients' psychosocial needs. This can compound patients' capability to engage in self-management. For COPD self-management to be effective, patients' psychosocial needs must be prioritised alongside medication and exacerbation management. In addition, patients' personal beliefs regarding COPD and its management should be reviewed periodically to avoid problematic behaviours and enhance positive adaptions to the disease. Patients with COPD are not a homogenous group and no one intervention will prove effective for all. Finally, practitioners require greater education, training, and support to successfully assist patients.


Relationships between malaria prevalence and malaria-related morbidity in school children from two villages in central Africa.
To investigate the relationship between parasite prevalence and malaria-related morbidity, we carried out a comparative study among cohorts of school children from two villages, Dienga, Gabon, and Pouma, Cameroon, both located in malaria-endemic areas. Seven to 17 year-old children attending primary schools were similarly followed-up at each site to evaluate the frequency of malaria attacks. Follow-up involved daily temperature recording (and blood smears in the case of fever) and preparation of blood smears every two weeks. In Pouma, 186 children were followed-up for six months. In Dienga, 228 children were followed-up for nine months. The mean prevalence rate of Plasmodium falciparum infections (as assessed by the blood smears) was twice as high in Pouma compared with Dienga (45.2% versus 26.8%; P < 0.0001), whereas the monthly malaria attack rate (as assessed by the daily surveillance) was twice as high in Dienga compared with Pouma (21.5% versus 41.4%; P = 0.003). The possible implication of several parameters that may differ between the two areas, such as the malaria transmission level, the economical and social status of the inhabitants, the characteristics of infecting parasite strains, and the genetic background of the population, is discussed.


Buprenorphine antagonism of mu opioids in the rhesus monkey tail-withdrawal procedure.
The apparent in vivo dissociation constant (KA) and relative efficacy values for alfentanil, etonitazene, morphine, and nalbuphine were determined by comparing the effects of these agonists in the presence of buprenorphine with the effects of these agonists alone in the rhesus monkey tail-withdrawal procedure. Initial time course studies of buprenorphine alone indicated that 3.2 and 10 mg/kg produced increases in tail-withdrawal latencies when studied with 48 degrees C water for 48 hr. No increases in tail-withdrawal latency were found with either dose studied with 55 degrees C water. Buprenorphine produced dose-dependent shifts to the right for the antinociceptive effects of alfentanil, etonitazene, morphine and nalbuphine 72 hr after administration and decreased the maximal effects of morphine in 48 degrees C water and those of alfentanil and etonitazene in 55 degrees C water. Buprenorphine administration decreased the receptors available for agonist interaction to approximately 2%. The average apparent in vivo dissociation constant (KA) values for alfentanil, etonitazene, morphine and nalbuphine were 3.3, 0.073, 60 and 31 mg/kg, respectively. High efficacy estimates were determined for alfentanil (149-203) and etonitazene (174-203), whereas lower efficacy estimates were determined for nalbuphine (57) and morphine (17). The apparent in vivo dissociation constant of a pseudoirreversible antagonist (KB) value for buprenorphine averaged 0.15 mg/kg across agonists, temperatures and buprenorphine doses. These data extend and emphasize the significance of in vivo estimates of affinity and relative efficacy for drug classification.


Feasibility of conducting HIV combination prevention interventions in fishing communities in Uganda: A pilot cluster randomised trial.
We assessed feasibility of an HIV-combination-prevention trial among fishing communities in Uganda. Cluster randomised trial in four fishing communities on Lake Victoria, Uganda. Two intervention communities received a combination-prevention-package (behaviour change communication, condom promotion, HIV testing, voluntary male medical circumcision and referral for anti-retroviral therapy if HIV-positive). All four communities received routine government HIV care services. Using household census data we randomly selected a cohort of consenting residents aged ≥18 years. A baseline sero-survey in July 2014 was followed by two repeat surveys in March and December 2015. We measured uptake of HIV prevention methods, loss-to-follow-up and HIV incidence, accounting for multistage survey design. A total of 862 participants were enrolled and followed for 15 months. Participation was 62% and 74% in the control and intervention arms respectively; Overall loss to follow up (LTFU) was 21.6% and was similar by arm. Self-reported abstinence/faithfulness increased between baseline and endline in both arms from 53% to 73% in the control arm, and 55% to 67% in the intervention arm. Reported condom use throughout the study period was 36% in the intervention arm vs 28% in the control arm; number of male participants reporting circumsicion in both arms from 58% to 79% in the intervention arm, and 39% to 46% in the control arm. Independent baseline predictors of loss-to-follow-up were: being HIV positive, residence in the community for <1 year, younger age, living in an urban area, and being away from the area for >1 month/year. Recruitment and retention of participants in longitudinal trials in highly mobile HIV fishing communities is challenging. Future research should investigate modes for locating and retaining participants, and delivery of HIV-combination prevention.


Cloning, sequence analysis, expression and inactivation of the Corynebacterium glutamicum pta-ack operon encoding phosphotransacetylase and acetate kinase.
The Corynebacterium glutamicum ack and pta genes encoding the acetate-activating enzymes acetate kinase and phosphotransacetylase were isolated, subcloned on a plasmid and re-introduced into Corynebacterium glutamicum. Relative to the wild-type, the recombinant strains showed about tenfold higher specific activities of both enzymes. Sequence analysis of a 3657 bp DNA fragment revealed that the ack and pta genes are contiguous in the corynebacterial chromosome, with pta upstream and the last nucleotide of the pta stop codon (TAA) overlapping the first of the ack start codon (ATG). The predicted gene product of pta consists of 329 amino acids (Mr 35242), that of ack consists of 397 amino acids (Mr 43098) and the amino acid sequences of the two polypeptides show up to 60 % (phosphotransacetylase) and 53% (acetate kinase) identity in comparison with respective enzymes from other organisms. Northern (RNA) blot hybridizations using pta- and ack-specific probes and transcriptional cat fusion experiments revealed that the two genes are transcribed as a 2.5 kb bicistronic mRNA and that the expression of this operon is induced when Corynebacterium glutamicum grows on acetate instead of glucose as a carbon source. Directed inactivation of the chromosomal pta and ack genes led to the absence of detectable phosphotransacetylase and acetate kinase activity in the respective mutants and to their inability to grow on acetate. These data indicate that no isoenzymes of acetate kinase and phosphotransacetylase are present in Corynebacterium glutamicum and that a functional acetate kinase/phosphotransacetylase pathway is essential for growth of this organism on acetate.


The relationship between interfacial bonding and radiation damage in adsorbed DNA.
We have performed a comparison of the radiation damage occurring in DNA adsorbed on gold in two different configurations, when the DNA is thiolated and bound covalently to the substrate and when it is unthiolated and interacts with the substrate through the bases. Both molecules were found to organize so as to protrude from the surface at ~45 degrees. Changes in the time-dependent C 1s and O 1s X-ray photoelectron (XP) spectra resulting from irradiation were interpreted to arise from cleavage of the phosphodiester bond and possibly COH desorption. By fitting the time-dependent XP spectra to a simple kinetic model, time constants were extracted, which were converted to cross sections and quantum yields for the damage reaction. The radiation induced damage is significantly higher for the thiolated DNA. N 1s X-ray absorption spectrum revealed the N-C=N LUMO is more populated in the unthiolated molecule, which is due to a higher degree of charge transfer from the substrate to this LUMO in the unthiolated case. Since the N-C=N LUMO of the thiolated molecule is comparatively less populated, it is more effective in capturing low energy electrons resulting in a higher degree of damage.


Revealing and acknowledging value judgments in health technology assessment.
Although value issues are increasingly addressed in health technology assessment (HTA) reports, HTA is still seen as a scientific endeavor and sometimes contrasted with value judgments, which are considered arbitrary and unscientific. This article aims at illustrating how numerous value judgments are at play in the HTA process, and why it is important to acknowledge and address value judgments. A panel of experts involved in HTA, including ethicists, scrutinized the HTA process with regard to implicit value judgments. It was analyzed whether these value judgments undermine the accountability of HTA results. The final results were obtained after several rounds of deliberation. Value judgments are identified before the assessment when identifying and selecting health technologies to assess, and as part of assessment. They are at play in the processes of deciding on how to select, frame, present, summarize or synthesize information in systematic reviews. Also, in economic analysis, value judgments are ubiquitous. Addressing the ethical, legal, and social issues of a given health technology involves moral, legal, and social value judgments by definition. So do the appraisal and the decision-making process. HTA by and large is a process of value judgments. However, the preponderance of value judgments does not render HTA biased or flawed. On the contrary they are basic elements of the HTA process. Acknowledging and explicitly addressing value judgments may improve the accountability of HTA.


Genome and transcriptome analysis of Bacillus velezensis BS-37, an efficient surfactin producer from glycerol, in response to d-/l-leucine.
Surfactin is one of the most widely studied biosurfactants due to its many potential applications in different fields. In the present study, Bacillus velezensis BS-37, initially identified as a strain of Bacillus subtilis, was used to efficiently produce surfactin with the addition of glycerol, an inexpensive by-product of biodiesel production. After 36 hr of growth in glycerol medium, the total surfactin concentration reached more than 1,000 mg/L, which was two times higher than that in sucrose medium. Moreover, the addition of l- and d-Leu to the culture medium had opposite effects on surfactin production by BS-37. While surfactin production increased significantly to nearly 2,000 mg/L with the addition of 10 mM l-Leu, it was dramatically reduced to about 250 mg/L with the addition of 10 mM d-Leu. To systemically elucidate the mechanisms influencing the efficiency of this biosynthesis process, we sequenced the genome of BS-37 and analyzed changes of the transcriptome in glycerol medium in response to d-/l-leucine. The RPKM analysis of the transcriptome of BS-37 showed that the transcription levels of genes encoding modular surfactin synthase, the glycerol utilization pathway, and branched-chain amino acid (BCAA) synthesis pathways were all at a relatively high level, which may offered an explanation why this strain can efficiently use glycerol to produce surfactin with a high yield. Neither l-Leu nor d-Leu had a significant effect on the expression of genes in these pathways, indicating that l-Leu plays an important role as a precursor or substrate involved in surfactin production, while d-Leu appears to act as a competitive inhibitor. The results of the present study provide new insights into the synthesis of surfactin and ways of its regulation, and enrich the genomic and transcriptomic resources available for the construction of high-producing strains.


TRICK2, a new alternatively spliced receptor that transduces the cytotoxic signal from TRAIL.
A subset of the tumour necrosis factor (TNF) receptor family contain a conserved intracellular motif, the death domain. Engagement of these receptors by their respective ligands initiates a signalling cascade that rapidly leads to cell death by apoptosis. We have cloned a new member of this family, TRICK2, the TRAIL (TNF-related apoptosis-inducing ligand) receptor inducer of cell killing 2. TRICK2 is expressed in a number of cell types, and to particularly high levels in lymphocytes and spleen. Two isoforms of the TRICK2 mRNA are generated by alternative pre-mRNA splicing and differ by a 29 amino-acid extension to the extracellular domain. Overexpression of TRICK2 rapidly induced apoptosis in 293T cells; this induction was dependent upon the presence of the death domain of TRICK2. Using a soluble molecule containing the TRICK2 extracellular domain, we demonstrated that TRICK2, like DR4 [1], is a receptor for TRAIL/APO-2L [2,3] and could inhibit TRAIL-induced killing of lymphocyte lines, such as the Jurkat T-cell line. TRAIL is upregulated upon lymphocyte activation, as is the intensively studied ligand for Fas, FasL [4]. TRAIL and its receptors might therefore provide another system for the regulation of lymphocyte selection and proliferation, as well as providing an additional weapon in the armoury of cytotoxic lymphocytes.


Visual Memories Bypass Normalization.
How distinct are visual memory representations from visual perception? Although evidence suggests that briefly remembered stimuli are represented within early visual cortices, the degree to which these memory traces resemble true visual representations remains something of a mystery. Here, we tested whether both visual memory and perception succumb to a seemingly ubiquitous neural computation: normalization. Observers were asked to remember the contrast of visual stimuli, which were pitted against each other to promote normalization either in perception or in visual memory. Our results revealed robust normalization between visual representations in perception, yet no signature of normalization occurring between working memory stores-neither between representations in memory nor between memory representations and visual inputs. These results provide unique insight into the nature of visual memory representations, illustrating that visual memory representations follow a different set of computational rules, bypassing normalization, a canonical visual computation.


Differences in the stimulus properties of 3,4-methylenedioxyamphetamine and 3,4- methylenedioxymethamphetamine in animals trained to discriminate hallucinogens from saline.
The stimulus properties of 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA) and several related compounds were compared to those of (+)-lysergic acid diethylamide (LSD) and mescaline (3,4,5-trimethoxyphenylethylamine) in a two-lever, water-reinforced, drug discrimination task. In animals trained to discriminate LSD (0.08 mg/kg) from saline (n = 8), LSD-like responding occurred during substitution (generalization) tests with sufficiently high doses of (+/- )-2,5-dimethoxy-4-methylamphetamine, LSD, mescaline, psilocybin and (-)-MDA; saline appropriate responding occurred after (+)-MDA and both (+)- and (+)- and (-)-MDMA. In animals trained to discriminate mescaline (10 mg/kg; n = 8), (-)-MDA, (+)-MDA, (-)-MDMA and (+)-MDMA as well as (+/- )-2,5-dimethoxy-4-methylamphetamine, LSD, mescaline and psilocybin mimicked the training drug. Neither (+)-amphetamine nor cocaine produced mescaline-like responding; fenfluramine substituted partially for mescaline but not LSD. Because all of the phenylisopropylamine enantiomers mimicked the potent hallucinogen mescaline (10 mg/kg), these results do not support suggestions that similarities in the behavioral effects of "designer" drugs such as MDA and MDMA to those of hallucinogens are limited to (-)-MDA. They also indicate that, although LSD and mescaline may be pharmacologically similar (in other assays), these compounds do not have identical stimulus properties.


RASSF1A-LATS1 signalling stabilizes replication forks by restricting CDK2-mediated phosphorylation of BRCA2.
Genomic instability is a key hallmark of cancer leading to tumour heterogeneity and therapeutic resistance. BRCA2 has a fundamental role in error-free DNA repair but also sustains genome integrity by promoting RAD51 nucleofilament formation at stalled replication forks. CDK2 phosphorylates BRCA2 (pS3291-BRCA2) to limit stabilizing contacts with polymerized RAD51; however, how replication stress modulates CDK2 activity and whether loss of pS3291-BRCA2 regulation results in genomic instability of tumours are not known. Here we demonstrate that the Hippo pathway kinase LATS1 interacts with CDK2 in response to genotoxic stress to constrain pS3291-BRCA2 and support RAD51 nucleofilaments, thereby maintaining genomic fidelity during replication stalling. We also show that LATS1 forms part of an ATR-mediated response to replication stress that requires the tumour suppressor RASSF1A. Importantly, perturbation of the ATR-RASSF1A-LATS1 signalling axis leads to genomic defects associated with loss of BRCA2 function and contributes to genomic instability and 'BRCA-ness' in lung cancers.


Greater impairment in negative emotion evaluation ability in patients with paranoid schizophrenia.
To explore whether or not patients with schizophrenia display a more profound impairment of negative emotion processing, we assessed the implicit evaluation of positive and negative emotional stimuli. Twenty patients with schizophrenia (9 paranoid, 11 non-paranoid) and 22 normal controls were instructed to classify emotional pictures according to the intrinsic valence if the pictures were black and white. If the stimuli were color-filtered, participants were instructed to press the positive/negative response key according to the extrinsic valence (assigned valence of color). The error rates of the color-filtered stimuli were used as dependent measures. Normal controls made more errors on trials of the positive pictures when the correct response was the negative response key than when the correct response was the positive response key. The reverse was true on trials of the negative pictures. Patients with schizophrenia, especially paranoid schizophrenia, committed more errors in trials of the positive pictures when the correct response key was the negative response key. However, the reverse was not true on trials of the negative pictures. These findings suggest that patients with paranoid schizophrenia might suffer from an impaired ability to evaluate negative emotions and have a loosening of association within their negative emotional networks.


The Acinetobacter baumannii Two-Component System AdeRS Regulates Genes Required for Multidrug Efflux, Biofilm Formation, and Virulence in a Strain-Specific Manner.
The opportunistic pathogen Acinetobacter baumannii is able to persist in the environment and is often multidrug resistant (MDR), causing difficulties in the treatment of infections. Here, we show that the two-component system AdeRS, which regulates the production of the AdeABC multidrug resistance efflux pump, is required for the formation of a protective biofilm in an ex vivo porcine mucosal model, which mimics a natural infection of the human epithelium. Interestingly, deletion of adeB impacted only on the ability of strain AYE to form a biofilm on plastic and only on the virulence of strain Singapore 1 for Galleria mellonella RNA-Seq revealed that loss of AdeRS or AdeB significantly altered the transcriptional landscape, resulting in the changed expression of many genes, notably those associated with antimicrobial resistance and virulence interactions. For example, A. baumannii lacking AdeRS displayed decreased expression of adeABC, pil genes, com genes, and a pgaC-like gene, whereas loss of AdeB resulted in increased expression of pil and com genes and decreased expression of ferric acinetobactin transport system genes. These data define the scope of AdeRS-mediated regulation, show that changes in the production of AdeABC mediate important phenotypes controlled by AdeRS, and suggest that AdeABC is a viable target for antimicrobial drug and antibiofilm discovery [corrected].


Surgical training 2.0: A systematic approach reviewing the literature focusing on oral maxillofacial surgery - Part I.
Many technologies are emerging in the medical field. Having an overview of the technological arsenal available to train new surgeons seems very interesting to guide subsequent surgical training protocols. This article is a systematic approach reviewing new technologies in surgical training, in particular in oral and maxillofacial surgery. This review explores what new technologies can do compared to traditional methods in the field of surgical education. A structured literature search of PubMed was performed in adherence to PRISMA guidelines. The articles were selected when they fell within predefined inclusion criteria while respecting the key objectives of this systematic review. We looked at medical students and more specifically in surgery and analysed whether exposure to new technologies improved their surgical skills compared to traditional methods. Each technology is reviewed by highlighting its advantages and disadvantages and studying the feasibility of integration into current practice. The results are encouraging. Indeed, all of these technologies make it possible to reduce the learning time, the operating times, the operating complications and increase the enthusiasm of the students compared to more conventional methods. The start-up cost, the complexity to develop new models, and the openness of mind necessary for the integration of these technologies are all obstacles to immediate development. The main limitations of this review are that many of the studies have been carried out on small numbers, they are not interested in acquiring knowledge or skills over the long term and obviously there is a publication bias. Surgical education methods will probably change in the years to come, integrating these new technologies into the curriculum seems essential so as not to remain on the side. This first part therefore reviews, open field camera, telemedicine and 3D printing. This systematic review is registered on PROSPERO.


A new pollination system: dung-beetle pollination discovered in Orchidantha inouei (Lowiaceae, Zingiberales) in Sarawak, Malaysia.
Lowiaceae, a family of the Zingiberales, comprise 11 species in the single genus Orchidantha. Here we present the first report on the pollination of Lowiaceae and describe a new system of dung-beetle pollination from Sarawak, Borneo. Orchidantha inouei has a zygomorphic flower located just above the ground. Observations revealed that the plant is visited frequently and is pollinated by scarabaeid dung beetles, mainly members of the genus Onthophagus. All four species of Onthophagus collected on O. inouei have also been caught using traps baited with dung or carrion in Borneo. Onthophagus was presumably attracted to the dung-like odor of the flower. Pollination of O. inouei is different from other examples of beetle pollination in that its flower provides neither reward nor protected space. Dung beetles are excellent at following a particular dung scent. Orchidantha is the only genus that includes species lacking floral nectar. It is interesting that this deception pollination using dung beetles was found in Zingiberales, in which all known species have mutual and specialized relationships with their long-distance, but costly, pollinators-bees, birds, and bats.


Multidisciplinary rehabilitation can impact on health-related quality of life outcome in radical cystectomy: secondary reported outcome of a randomized controlled trial.
Health related quality of life (HRQoL) is an important outcome in cancer care, although it is not well reported in surgical uro-oncology. Radical cystectomy (RC) with lymph-node dissection is the standard treatment of muscle-invasive bladder cancer and high-risk noninvasive bladder cancer. A wide range of impairments are reported postsurgery. The aims were to evaluate whether a standardized pre- and postoperative physical exercise program and enhanced mobilization can impact on HRQoL and inpatient satisfaction in RC, as defined by the European Organisation for Research and Treatment of Cancer (EORTC). Patients were randomized to fast-track RC and intervention (nI=50) or fast-track standard treatment (nS=57). HRQoL and inpatient satisfaction was measured using valid questionnaires: EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) combined with the disease-specific EORTC BLS24 (baseline), and EORTC BLM30 (follow-up), and IN-PATSAT32 inpatient-satisfaction survey at discharge. Efficacy was defined as the differences in HRQoL-scores between treatment groups at the 4-month follow-up. The intervention group significantly improved HRQoL scores in dyspnea (P≤0.05), constipation (P<0.02), and abdominal flatulence (P≤0.05) compared to the standard group. In contrast, the standard group reported significantly reduced symptoms in sleeping pattern (P≤0.04) and clinically relevant differences in role function, body function, and fatigue. The intervention did not compromise inpatient satisfaction. We found no overall impact on global HRQoL due to a physical rehabilitation program. However, pre- and postoperative physical rehabilitation can significantly and positively impact on HRQoL aspects related to bowel management and respiratory function (dyspnea) without compromising inpatient satisfaction. These results highlight the role of multimodal rehabilitation, including physical exercises in fast-track RC.


Contact lens wear is associated with decrease of meibomian glands.
Approximately 30% to 50% of contact lens (CL) wearers report dry eye symptoms. Meibomian gland dysfunction has been recognized as a possible cause of CL-related dry eye. This study investigated the influence of CL wear on the meibomian glands using a newly developed meibographic technique. Cross-sectional observational case series. Contact lens wearers (n=121; 47 men, 74 women; mean age+/-standard deviation, 31.8+/-8.0 years) and healthy volunteers (n=137; 71 men, 66 women; mean age+/-standard deviation, 31.4+/-15.1 years). The following tests were performed: slit-lamp examinations of the eyelids, corneal and conjunctival staining using fluorescein, measurement of the tear film breakup time, evaluation of the meibomian glands using noncontact meibography, and measurement of tear production using the Schirmer I test. Partial or complete loss of the meibomian glands was scored for each eyelid using 4 grades (meiboscores): grade 0 (no loss of meibomian glands) through grade 3 (the area characterized by gland dropout was more than 66% of the total area containing the meibomian glands). The meiboscores for the upper and lower eyelids were summed for each subject. Score of meibomian gland changes (meiboscore), tear film breakup time, and Schirmer test value. The meiboscore was significantly higher (P<0.0001) in CL wearers (mean, 1.72; 95% confidence interval, 1.47-1.96) than in the control group (mean, 0.96; 95% confidence interval, 0.73-1.19). The average meiboscore of CL wearers was similar to that of a 60- to 69-year-old age group from the normal population. A significant positive correlation was observed between the duration of CL wear and the meiboscore. Contact lens wear is associated with a decrease in the number of functional meibomian glands. This decrease is proportional to the duration of CL wear.


Assessment of pharmacological activities of two medicinal plant of Bangladesh: Launaea sarmentosa and Aegialitis rotundifolia roxb in the management of pain, pyrexia and inflammation.
The current study aims at evaluating the analgesic, anti-pyretic and anti-inflammatory properties of methanolic extract of the stem, bark and leaves of Launaea sarmentosa and Aegialitis rotundifolia roxb. The AELS and AEAR extract presented a significant (***p < 0.001) dose dependent increase in reaction time in writhing method and showed inhibition of 63.1% and 57.1% respectively at the doses of 400 mg/kg body weight while standard drug showed (P < 0.001) inhibition of 69.23%. In tail immersion method, AELS and AEAR showed maximum time of tail retention at 30 min in hot water i.e. 6.93 sec and 6.54 sec respectively at highest doses of 400 mg/kg body weight than lower dose while standard pentazocine showed reaction time of 7.62 sec. The AELS and AEAR extract also exhibited promising anti-inflammatory effect as demonstrated by statistically significant inhibition of paw volume by 32.48% and 26.75% respectively at the dose of 400 mg/kg body weight while the value at the dose of 200 mg/kg body weight were linear to higher dose at the 3rd hour of study. On the other hand, Standard indomethacin inhibited 40.13% of inflammation (***P < 0.001). In Cotton-pellet granuloma method, AELS and AEAR extract at the dose of 400 mg/kg body weight exhibited inhibition of inflammation of 34.7% and 29.1% respectively while standard drug showed (P < 0.001) inhibition of 63.22%. Intraperitoneal administration of AELS and AEAR showed dose dependent decrease in body temperature in brewer's yeast induced hyperthermia in rats at both doses. However, AELS significantly decreased body temperature (***p < 0.001) at 400 mg/kg compared to control. Present work propose that the methanolic extract of Launaea sarmentosa and Aegialitis rotundifolia roxb possesses dose dependent pharmacological action which supports its therapeutic use in folk medicine possibly mediated through the inhibition or blocking of release of prostaglandin and/or actions of vasoactive substances such as histamine, serotonin and kinins.


Intrathoracic Acute Cholecystitis.
The authors present the case of a 51-year-old woman with no history of surgical or traumatic injury or accident, who presented with right hypochondrium and epigastric discomfort, malaise, nausea, loss of appetite and episodes of dark urine and greenish stools. Initial laboratory work-up revealed elevated inflammatory markers including leucocytosis with left shift and C-reactive protein, and a slight elevation of gamma-glutamyltransferase and alkaline phosphatase, with no other significant alterations. Computed tomography (CT) showed intrathoracic acute cholecystitis with a large diaphragmatic hernia. A literature search revealed only one other case of acute cholecystitis complicated by intrathoracic gallbladder due to a non-traumatic diaphragmatic hernia. Symptoms are uncharacteristic and the absence of pain or fever, explained by the altered location of the gallbladder, makes the diagnosis a challenge. Only one other case of acute cholecystitis complicated by intrathoracic gallbladder due to a non-traumatic diaphragmatic hernia has been reported.Uncharacteristic symptoms make the diagnosis of intrathoracic acute cholecystitis a challenge.


Bimane fluorescent labels: labeling of normal human red cells under physiological conditions.
The bimane fluorescent labels, monobromobimane, dibromobimane, and monobromotrimethylammoniobimane, are derivatives of syn-9,10-dioxabimane:1,5-diazabicyclo[3.3.0]octa-3,6-diene-2,8-dione. They efficiently label hemoglobin (reactive thiol groups), membrane proteins, and glutathione of normal human red cells under physiological conditions. Monobromobimane and dibromobimane are effective on intact cells while red cell membranes may be impermeable to the positively charged monobromotrimethylammoniobimane, the latter being effective only on lysed cells. These bimane labels provide a class of labeling agents that may have wide applicability in biological materials.


Predictive factors of major adverse cardiac events in acute myocardial infarction patients complicated by cardiogenic shock undergoing primary percutaneous coronary intervention.
The aim of this study was to assess in-hospital mortality and major adverse cardiac events (MACE) during long-term clinical follow-up of patients who developed cardiogenic shock (CS) after acute myocardial infarction (AMI) and who underwent primary percutaneous coronary intervention (PCI). The data from 147 patients with CS after AMI (61.7 +/-10.4 years, M:F =156:99) who underwent primary PCI at Chonnam National University Hospital between January 1999 and December 2002 were analyzed: clinical characteristics, coronary angiographic findings and mortality during admission, and MACE during a 1-year clinical follow-up. Of the enrolled patients, 121 patients survived (group I, M:F =94:27) and 26 died (group II, M:F =14:12) during admission. By binary logistic regression analysis, in-hospital death was associated with low Thrombolysis In Myocardial Infarction (TIMI) flow after coronary revascularization (p=0.02, odds ratio (OR) =1.3). Eighty-nine patients (60.5%) survived without MACE during the 1-year clinical follow-up and MACE was associated with a C-reactive protein (CRP) of more than 1 mg/dl (p=0.002, OR =6.3) and low TIMI flow after coronary revascularization (p<0.001, OR =7.8). Primary PCI achieving TIMI 3 flow reduces in-hospital death in AMI with CS. High concentration of CRP and low TIMI flow are associated with MACE during long-term clinical follow-up.


Clinical utility of array comparative genomic hybridisation for prenatal diagnosis: a cohort study of 3171 pregnancies.
To evaluate the clinical value of prenatal array comparative genomic hybridisation (CGH) in screening for submicroscopic genomic imbalances. Cross-sectional study. Tertiary referral centre. From June 2008 to February 2011, 3171 fetuses underwent prenatal array CGH testing and karyotyping at the National Taiwan University Hospital. Indications for invasive prenatal diagnosis included abnormal karyotype, abnormal ultrasound, advanced maternal age and parental anxiety. In all, 2497 fetuses were screened with 1-Mb resolution bacterial artificial chromosome array-based CGH, and 674 fetuses with 60-K oligonucleotide array-based CGH. Multiplex ligation-dependent probe amplification, fluorescence in situ hybridization, or 105-K oligonucleotide array CGH provided further confirmation. Copy number variations identified by array CGH. Array CGH detected numerical chromosome anomalies in 37 (1.2%) fetuses, microdeletion/duplication in 34 (1.1%) fetuses, large deletion/duplication in 13 (0.4%) fetuses, benign copy number changes in 13 (0.4%) fetuses and variation of unknown clinical significance in five (0.2%) fetuses. Array CGH was effective in identifying submicroscopic genomic imbalance in fetuses with de novo balance translocations (2/17, 1.8%), supernumerary marker chromosomes (3/6, 50%), and abnormal prenatal ultrasound findings (33/194, 17.0%). Array CGH detected microdeletions/duplications in 12 fetuses with normal karyotype. Prenatal array CGH is effective in screening for submicroscopic genomic imbalance. Array CGH may add 8.2% to the diagnostic field, compared with conventional karyotyping, for fetuses with abnormal ultrasound results, and is particularly useful in fetuses with karyotypic balanced translocation or marker chromosomes. There is a 0.52% baseline risk of submicroscopic genomic imbalance, even in women with an uneventful prenatal examination.