Gastrocnemius Myoelectric Control of a Robotic Hip Exoskeleton Can Reduce the User's Lower-Limb Muscle Activities at Push Off.
We present a novel assistive control strategy for a robotic hip exoskeleton for assisting hip flexion/extension, based on a proportional Electromyography (EMG) strategy. The novelty of the proposed controller relies on the use of the Gastrocnemius Medialis (GM) EMG signal instead of a hip flexor muscle, to control the hip flexion torque. This strategy has two main advantages: first, avoiding the placement of the EMG electrodes at the human-robot interface can reduce discomfort issues for the user and motion artifacts of the recorded signals; second, using a powerful signal for control, such as the GM, could improve the reliability of the control system. The control strategy has been tested on eight healthy subjects, walking with the robotic hip exoskeleton on the treadmill. We evaluated the controller performance and the effect of the assistance on muscle activities. The tuning of the assistance timing in the controller was subject dependent and varied across subjects. Two muscles could benefit more from the assistive strategy, namely the Rectus Femoris (directly assisted) and the Tibialis Anterior (indirectly assisted). A significant correlation was found between the timing of the delivered assistance (i.e., synchronism with the biological hip torque), and reduction of the hip flexors muscular activity during walking; instead, no significant correlations were found for peak torque and peak power. Results suggest that the timing of the assistance is the most significant parameter influencing the effectiveness of the control strategy. The findings of this work could be important for future studies aimed at developing assistive strategies for walking assistance exoskeletons.


'Life then', 'life interrupted', 'life reclaimed': The fluctuation of agency in teenagers and young adults with cancer.
This paper presents findings from an in-depth study exploring agency in decision making when young people experience cancer. Exploratory case studies were utilised to examine all aspects of decision making, beginning with the onset of symptoms followed by diagnosis and treatment. Interviews, observations and documentary analysis were used to generate data. Multiple sources were selected to generate further insights and these included family, partners, friends and healthcare professionals who were close to the young people during their experience. Three overarching themes were identified during analysis of the data: 'life then', 'life interrupted' and 'life reclaimed'. Key elements of these themes included a number of complex and interrelating factors which were interwoven within the everyday lives of the young people. In the 'life then' phase, 'holding on' to agency prior to diagnosis and the importance of close and intimate relationships was illuminated. In 'life interrupted', agentic power during treatment, in terms of the range of decision making and the complexity of the parental role, were prominent. In 'life reclaimed' the 'different but determined' nature of young people's behaviour and re-aligned agency was transparent as they were near to completing treatment. This study has culminated in the development of a model of individual cancer trajectories relating to the fluctuation of agency during young people's cancer experiences. These trajectories could be applied in future healthcare practice.


Isolated trigeminal nerve sarcoid granuloma mimicking trigeminal schwannoma: case report.
Sarcoidosis most commonly presents as a systemic disorder. Infrequently, sarcoidosis can manifest itself in the central nervous system, with granulomas involving the leptomeninges and presenting with facial nerve weakness. Sarcoid of the trigeminal nerve is exceedingly rare and can mimic trigeminal schwannoma. We review the literature on sarcoid granulomas of the trigeminal nerve and compare their radiological features with the more common schwannoma. A 33-year-old woman presented with a history of left-sided facial pain and numbness for 11 months, which was presumed to be trigeminal neuralgia. A trial of carbamazepine had been unsuccessful in relieving the facial pain. Her neurological examination revealed decreased facial sensation in the V(1)-V(2) distribution. Preoperative magnetic resonance imaging demonstrated a contrast-enhancing mass centered in the left cavernous sinus with extension along the cisternal portion of the left trigeminal nerve. The patient underwent a left frontotemporal orbitozygomatic craniotomy with intraoperative neurophysiological monitoring of Cranial Nerves III, V, and VI and image guidance for subtotal microsurgical resection of what appeared, grossly and on frozen section, to be a neurofibroma. The final pathology report, however, revealed a sarcoid granuloma of the trigeminal nerve. The differential diagnosis of contrast-enhancing lesions in the lateral wall of the cavernous sinus should include inflammatory conditions such as sarcoidosis. We recommend that surgery for biopsy or decompression be used only for those patients in whom a diagnosis cannot be confirmed with noninvasive testing. If surgery is performed, intraoperative frozen pathology is very useful in guiding the extent of resection.


International Variation in Outcomes Among People with Cardiovascular Disease or Cardiovascular Risk Factors and Impaired Glucose Tolerance: Insights from the NAVIGATOR Trial.
Regional differences in risk of diabetes mellitus and cardiovascular outcomes in people with impaired glucose tolerance are poorly characterized. Our objective was to evaluate regional variation in risk of new-onset diabetes mellitus, cardiovascular outcomes, and treatment effects in participants from the NAVIGATOR (Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research) trial. NAVIGATOR randomized people with impaired glucose tolerance and cardiovascular risk factors or with established cardiovascular disease to valsartan (or placebo) and to nateglinide (or placebo) with a median 5-year follow-up. Data from the 9306 participants were categorized by 5 regions: Asia (n=552); Europe (n=4909); Latin America (n=1406); North America (n=2146); and Australia, New Zealand, and South Africa (n=293). Analyzed outcomes included new-onset diabetes mellitus; cardiovascular death; a composite cardiovascular outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke; and treatment effects of valsartan and nateglinide. Respective unadjusted 5-year risks for new-onset diabetes mellitus, cardiovascular death, and the composite cardiovascular outcome were 33%, 0.4%, and 4% for Asia; 34%, 2%, and 6% for Europe; 37%, 4%, and 8% for Latin America; 38%, 2%, and 6% for North America; and 32%, 4%, and 8% for Australia, New Zealand, and South Africa. After adjustment, compared with North America, European participants had a lower risk of new-onset diabetes mellitus (hazard ratio 0.86, 95% CI 0.78-0.94; P=0.001), whereas Latin American participants had a higher risk of cardiovascular death (hazard ratio 2.68, 95% CI 1.82-3.96; P<0.0001) and the composite cardiovascular outcome (hazard ratio 1.48, 95% CI 1.15-1.92; P=0.003). No differential interactions between treatment and geographic location were identified. Major regional differences regarding the risk of new-onset diabetes mellitus and cardiovascular outcomes in NAVIGATOR participants were identified. These differences should be taken into account when planning global trials. URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00097786.


Free radical-mediated lipid peroxidation and systemic nitric oxide bioavailability: implications for postexercise hemodynamics.
The metabolic vasodilator mediating postexercise hypotension (PEH) is poorly understood. Recent evidence suggests an exercise-induced reliance on pro-oxidant-stimulated vasodilation in normotensive young human subjects, but the role in the prehypertensive state is not known. Nine prehypertensives (mean arterial pressure (MAP), 106 ± 5 mm Hg; 50 ± 10 years old) performed 30 minutes of cycle exercise and a nonexercise trial. Arterial distensibility was characterized by simultaneously recording upper- and lower-limb pulse wave velocity (PWV) via oscillometry. Systemic vascular resistance and conductance were determined by MAP/Q and Q/MAP, respectively. Venous blood was assayed for indirect markers of oxidative stress (lipid hydroperoxides (LOOH); spectrophotometry), plasma nitric oxide (NO) and S-nitrosothiols (fluorometry), atrial natriuretic peptide (ANP), and angiotensin II (ANG-II) (radioimmunoassay). Exercise reduced MAP (6mm Hg) and vascular resistance (15%) at 60 minutes after exercise, whereas conductance was elevated (20%) (P < 0.05). The hypotension resulted in a lower MAP at 60 and 120 minutes after exercise compared with nonexercise (P < 0.05). Upper-limb PWV was also 18% lower after exercise compared with baseline (P < 0.05). Exercise increased LOOH coincident with the nadir in hypotension and vascular resistance but failed to affect plasma NO or S-nitrosothiols. Exercise-induced increases in LOOH were related to ANG-II (r = 0.97; P < 0.01) and complemented by elevated ANP concentrations. These data indicate attenuated vascular resistance after exercise with increased oxidative stress and unchanged NO. Whether free radicals are obligatory for PEH requires further investigation, although it seems that oxidative stress occurs during the hyperemia underlying PEH.


Hierarchies of host factor dynamics at the entry site of Shigella flexneri during host cell invasion.
Shigella flexneri, the causative agent of bacillary dysentery, induces massive cytoskeletal rearrangement, resulting in its entry into nonphagocytic epithelial cells. The bacterium-engulfing membrane ruffles are formed by polymerizing actin, a process activated through injected bacterial effectors that target host small GTPases and tyrosine kinases. Once inside the host cell, S. flexneri escapes from the endocytic vacuole within minutes to move intra- and intercellularly. We quantified the fluorescence signals from fluorescently tagged host factors that are recruited to the site of pathogen entry and vacuolar escape. Quantitative time lapse fluorescence imaging revealed simultaneous recruitment of polymerizing actin, small GTPases of the Rho family, and tyrosine kinases. In contrast, we found that actin surrounding the vacuole containing bacteria dispersed first from the disassembling membranes, whereas other host factors remained colocalized with the membrane remnants. Furthermore, we found that the disassembly of the membrane remnants took place rapidly, within minutes after bacterial release into the cytoplasm. Superresolution visualization of galectin 3 through photoactivated localization microscopy characterized these remnants as small, specular, patchy structures between 30 and 300 nm in diameter. Using our experimental setup to track the time course of infection, we identified the S. flexneri effector IpgB1 as an accelerator of the infection pace, specifically targeting the entry step, but not vacuolar progression or escape. Together, our studies show that bacterial entry into host cells follows precise kinetics and that this time course can be targeted by the pathogen.


Sertraline inhibits increases in body fat and carbohydrate dysregulation in adult female cynomolgus monkeys.
Selective serotonin reuptake inhibitor (SSRI) antidepressants are widely prescribed for depression and other disorders. SSRIs have become one of the most commonly used drugs in the United States, particularly by women. Acute effects on body composition and carbohydrate metabolism have been reported, but little is known regarding the effects of chronic SSRI use. We evaluated the effects of chronic administration of a commonly prescribed SSRI, sertraline HCl, on body weight and composition, fat distribution, carbohydrate metabolism, as well as activity, in adult female depressed and nondepressed cynomolgus monkeys (Macaca fascicularis; n=42) using a placebo-controlled, longitudinal, randomized study design. Phenotypes were evaluated prior to and after 18 months of oral sertraline (20mg/kg) or placebo. Over the 18 month treatment period, the placebo group experienced increases in body weight, body fat (visceral and subcutaneous) fasting insulin concentrations, and homeostasis model assessment of insulin resistance scores (HOMA-IR). Sertraline treatment prevented increases in body weight, fat, insulin, and HOMA-IR (all p<0.05), without significantly altering activity levels. Sertraline treatment altered adiponectin in an unusual way - reducing circulating adiponectin in depressed monkeys without affecting fat mass or body weight. Deleterious effects on adiponectin, a potentially insulin-sensitizing and atheroprotective protein, may result in adverse effects on cardiovascular health despite otherwise beneficial effects on body composition and carbohydrate metabolism.


Constraining upper limb synergies of hemiparetic patients using a robotic exoskeleton in the perspective of neuro-rehabilitation.
The aim of this paper was to explore how an upper limb exoskeleton can be programmed to impose specific joint coordination patterns during rehabilitation. Based on rationale which emphasizes the importance of the quality of movement coordination in the motor relearning process, a robot controller was developed with the aim of reproducing the individual corrections imposed by a physical therapist on a hemiparetic patient during pointing movements. The approach exploits a description of the joint synergies using principal component analysis (PCA) on joint velocities. This mathematical tool is used both to characterize the patient's movements, with or without the assistance of a physical therapist, and to program the exoskeleton during active-assisted exercises. An original feature of this controller is that the hand trajectory is not imposed on the patient: only the coordination law is modified. Experiments with hemiparetic patients using this new active-assisted mode were conducted. Obtained results demonstrate that the desired inter-joint coordination was successfully enforced, without significantly modifying the trajectory of the end point.


A novel mesh processing based technique for 3D plant analysis.
In recent years, imaging based, automated, non-invasive, and non-destructive high-throughput plant phenotyping platforms have become popular tools for plant biology, underpinning the field of plant phenomics. Such platforms acquire and record large amounts of raw data that must be accurately and robustly calibrated, reconstructed, and analysed, requiring the development of sophisticated image understanding and quantification algorithms. The raw data can be processed in different ways, and the past few years have seen the emergence of two main approaches: 2D image processing and 3D mesh processing algorithms. Direct image quantification methods (usually 2D) dominate the current literature due to comparative simplicity. However, 3D mesh analysis provides the tremendous potential to accurately estimate specific morphological features cross-sectionally and monitor them over-time. In this paper, we present a novel 3D mesh based technique developed for temporal high-throughput plant phenomics and perform initial tests for the analysis of Gossypium hirsutum vegetative growth. Based on plant meshes previously reconstructed from multi-view images, the methodology involves several stages, including morphological mesh segmentation, phenotypic parameters estimation, and plant organs tracking over time. The initial study focuses on presenting and validating the accuracy of the methodology on dicotyledons such as cotton but we believe the approach will be more broadly applicable. This study involved applying our technique to a set of six Gossypium hirsutum (cotton) plants studied over four time-points. Manual measurements, performed for each plant at every time-point, were used to assess the accuracy of our pipeline and quantify the error on the morphological parameters estimated. By directly comparing our automated mesh based quantitative data with manual measurements of individual stem height, leaf width and leaf length, we obtained the mean absolute errors of 9.34%, 5.75%, 8.78%, and correlation coefficients 0.88, 0.96, and 0.95 respectively. The temporal matching of leaves was accurate in 95% of the cases and the average execution time required to analyse a plant over four time-points was 4.9 minutes. The mesh processing based methodology is thus considered suitable for quantitative 4D monitoring of plant phenotypic features.


Long-term results of the implantation of the AMS 800 artificial sphincter for post-prostatectomy incontinence: a single-center experience.
Report the long-term outcomes of the AMS 800 artificial sphincer (AS) for the treatment post-prostatectomy incontinence (PPI) in a single center in Brazil. Clinical data from patients who underwent the procedure were retrieved from the medical records of individuals with more than 1 year of follow-up from May 2001 to January 2016. Continence status (number of pads that was used), complications (erosion or extrusion, urethral atrophy, and infection), malfunctions, and need for secondary implantation were evaluated. The relationship between complications and prior or subsequent radiation therapy (RT) was also examined. From May 2001 to January 2016, 121 consecutive patients underwent AS implantation for PPI at an oncological referral center in Brazil. At the last visit, the AS remained implanted in 106 patients (87.6%), who reported adequate continence status (maximum of 1 pad/day). Eight-two subjects (67.8%) claimed not to be using pads on a regular basis at the final visit (completely dry). Revision occurred in 24 patients (19.8%).Radiation therapy (RT) for prostate cancer following radical prostatectomy was used in 47 patients before or after AS placement. Twelve patients with a history of RT had urethral erosion compared with 3 men without RT (p=0.004). Considering our outcomes, we conclude that AS implantation yields satisfactory results for the treatment of PPI and should remain the standard procedure for these patients. Radiation therapy is a risk factor for complication.


Glutamate oxidation in astrocytes: Roles of glutamate dehydrogenase and aminotransferases.
The cellular distribution of transporters and enzymes related to glutamate metabolism led to the concept of the glutamate-glutamine cycle. Glutamate is released as a neurotransmitter and taken up primarily by astrocytes ensheathing the synapses. The glutamate carbon skeleton is transferred back to the presynaptic neurons as the nonexcitatory amino acid glutamine. The cycle was initially thought to function with a 1:1 ratio between glutamate released and glutamine taken up by neurons. However, studies of glutamate metabolism in astrocytes have shown that a considerable proportion of glutamate undergoes oxidative degradation; thus, quantitative formation of glutamine from the glutamate taken up is not possible. Oxidation of glutamate is initiated by transamination catalyzed by an aminotransferase, or oxidative deamination catalyzed by glutamate dehydrogenase (GDH). We discuss methods available to elucidate the enzymes that mediate this conversion. Methods include pharmacological tools such as the transaminase inhibitor aminooxyacetic acid, studies using GDH knockout mice, and siRNA-mediated knockdown of GDH in astrocytes. Studies in brain slices incubated with [15 N]glutamate demonstrated activity of GDH in astrocytes in situ. These results, in conjunction with reports in the literature, support the conclusion that GDH is active in astrocytes both in culture and in vivo and that this enzyme plays a significant role in glutamate oxidation. Oxidative metabolism of glutamate, primarily mediated by GDH, but also by transamination by aspartate aminotransferase, provides considerably more energy than is required to maintain the activity of the high-affinity glutamate transporters needed for efficient removal of glutamate from the synaptic cleft. © 2016 Wiley Periodicals, Inc.


Transmembrane helix 6 observed at the interface of β2AR homodimers in blind docking studies.
Peptide- and protein-protein dockings were carried out on β2-adrenergic receptor (β2AR) to confirm the presence of transmembrane helix 6 (TM6) at the interface region between two β2AR monomers, thereby its possible role in dimerization as suggested in numerous experimental and computational studies. Initially, a portion of TM6 was modeled as a peptide consisting of 23 residues and blindly docked to β2AR monomer using a rigid body approach. Interestingly, all highest score conformations preferred to be near TM5 and TM6 regions of the receptor. Furthermore, longer peptides generated from a whole TM region were blindly docked to β2AR using the same rigid body approach. This yielded a total of seven docked peptides, each derived from one TM helix. Most interestingly, for each peptide, TM6 was among the most preferred binding site region in the receptor. Besides the peptide dockings, two β2AR monomers were blindly docked to each other using a full rigid-body search of docking orientations, which yielded a total of 16,000 dimer conformations. Each dimer was then filtered according to a fitness value based on the membrane topology. Among 149 complexes that met the topology requirements, 102 conformers were composed of two monomers oriented in opposite directions, whereas in the remaining 47, the monomers were arranged in parallel. Lastly, all 149 conformers were clustered based on a root mean-squared distance value of 6 Å. In agreement with the peptide results, the clustering yielded the largest population of conformers with the highest Z-score value having TM6 at the interface region.


Phone-delivered mindfulness training for patients with implantable cardioverter defibrillators: results of a pilot randomized controlled trial.
The reduction in adrenergic activity and anxiety associated with meditation may be beneficial for patients with implantable cardioverter defibrillators. This study aims to determine the feasibility of a phone-delivered mindfulness intervention in patients with defibrillators and to obtain preliminary indications of efficacy on mindfulness and anxiety. Clinically stable outpatients were randomized to a mindfulness intervention (eight weekly individual phone sessions) or to a scripted follow-up phone call. We used the Hospital Anxiety and Depression Scale and the Five Facets of Mindfulness to measure anxiety and mindfulness, and multivariate linear regression to estimate the intervention effect on pre-post-intervention changes in these variables. We enrolled 45 patients (23 mindfulness and 22 control; age, 43-83; 30 % women). Retention was 93 %; attendance was 94 %. Mindfulness (beta = 3.31; p = 0.04) and anxiety (beta = -1.15; p = 0.059) improved in the mindfulness group. Mindfulness training can be effectively phone-delivered and may improve mindfulness and anxiety in cardiac defibrillator outpatients.


Evolutionary Pareto-optimization of stably folding peptides.
As a rule, peptides are more flexible and unstructured than proteins with their substantial stabilizing hydrophobic cores. Nevertheless, a few stably folding peptides have been discovered. This raises the question whether there may be more such peptides that are unknown as yet. These molecules could be helpful in basic research and medicine. As a method to explore the space of conformationally stable peptides, we have developed an evolutionary algorithm that allows optimization of sequences with respect to several criteria simultaneously, for instance stability, accessibility of arbitrary parts of the peptide, etc. In a proof-of-concept experiment we have perturbed the sequence of the peptide Villin Headpiece, known to be stable in vitro. Starting from the perturbed sequence we applied our algorithm to optimize peptide stability and accessibility of a loop. Unexpectedly, two clusters of sequences were generated in this way that, according to our criteria, should form structures with higher stability than the wild-type. The structures in one of the clusters possess a fold that markedly differs from the native fold of Villin Headpiece. One of the mutants predicted to be stable was selected for synthesis, its molecular 3D-structure was characterized by nuclear magnetic resonance spectroscopy, and its stability was measured by circular dichroism. Predicted structure and stability were in good agreement with experiment. Eight other sequences and structures, including five with a non-native fold are provided as bona fide predictions. The results suggest that much more conformationally stable peptides may exist than are known so far, and that small fold classes could comprise well-separated sub-folds.


Analysis of the enantiomers of 3,4-methylenedioxy-N-ethylamphetamine (MDE, "Eve") and its metabolite 3,4-methylenedioxyamphetamine (MDA) in rat brain.
The methylenedioxy analogues of amphetamine are used recreationally despite concerns raised regarding potential neurotoxicity of the parent compounds and a number of metabolites. Much has been written regarding 3,4-methylenedioxymethamphetamine (MDMA; 3,4-methylenedioxy-N-ethylamphetamine (MDE; "Eve"), despite recent reports indicating the abuse of this drug and its potentially serious side effects. An assay procedure was developed for the simultaneous quantitation of both enantiomers of MDE and its metabolite MDA; the method involves derivatization with an optically pure reagent and analysis on a gas chromatograph equipped with a capillary column and a nitrogen-phosphorus detector. Brain levels of the enantiomers of MDE and MDA were examined in the rat at different time periods after acute i.p. injections of racemic MDE and the results were compared with levels of MDMA and MDA obtained after i.p. injection of MDMA in a previous study from our laboratories. The levels of the enantiomers of MDE and MDA achieved at 1, 4, and 8 hr were lower than in the case of MDMA. Stereoselective differences in brain levels of enantiomers of the parent drug and metabolite were much less marked with MDE than with MDMA, but where these small differences did exist in the case of MDE, the (R)-(-) vs (S)-(+) relationship was opposite to that reported for MDMA.


Biological effect of an alternating electric field on cell proliferation and synergistic antimitotic effect in combination with ionizing radiation.
Alternating electric fields at an intermediate frequency (100~300 kHz), referred to as tumour-treating fields (TTF), are believed to interrupt the process of mitosis via apoptosis and to act as an inhibitor of cell proliferation. Although the existence of an antimitotic effect of TTF is widely known, the proposed apoptotic mechanism of TTF on cell function and the efficacy of TTF are controversial issues among medical experts. To resolve these controversial issues, a better understanding of the underlying molecular mechanisms of TTF on cell function and the differences between the effects of TTF alone and in combination with other treatment techniques is essential. Here, we report experimental evidence of TTF-induced apoptosis and the synergistic antimitotic effect of TTF in combination with ionizing radiation (IR). For these experiments, two human Glioblastoma multiforme (GBM) cells (U373 and U87) were treated either with TTF alone or with TTF followed by ionizing radiation (IR). Cell apoptosis, DNA damage, and mitotic abnormalities were quantified after the application of TTF, and their percentages were markedly increased when TTF was combined with IR. Our experimental results also suggested that TTF combined with IR synergistically suppressed both cell migration and invasion, based on the inhibition of MMP-9 and vimentin.


Relation of lipid gene scores to longitudinal trends in lipid levels and incidence of abnormal lipid levels among individuals of European ancestry: the Atherosclerosis Risk in Communities (ARIC) study.
Multiple genetic loci have been associated with blood lipid levels. We tested the hypothesis that persons with an unfavorable lipid gene profile would experience a greater increase in lipid levels and a higher incidence of abnormal lipid levels relative to those with more-favorable lipid gene profiles. A total of 9328 individuals of European descent (aged 45-64 years) in the ARIC (Atherosclerosis Risk in Communities) study were followed for 9 years. Separate gene scores were created for each lipid phenotype on the basis of 95 loci identified in a published genome-wide association study of >100 000 people of European-descent. Adjusted linear and survival models were used to estimate associations with lipid levels and incidence of lipid-lowering medication or abnormal lipid levels. Age and sex interactions were also explored. The cross-sectional difference (mg/dL) per 1 SD was -1.89 for high-density lipoprotein cholesterol (HDL-C), 9.5 for low-density lipoprotein cholesterol (LDL-C), and 22.8 for triglycerides (P<5×10(-34) for all). Longitudinally, overall triglyceride levels rose over time, and each 1-SD greater triglyceride gene score was associated with an average increase in triglyceride levels of 0.3 mg/dL (P=0.003) over 3 years. The HDL-C, LDL-C, and total cholesterol gene scores were not related to change. All lipid gene scores were positively related to incidence of abnormal lipid levels over follow-up (hazard ratios per SD range, 1.15-1.36). Associations of genetic variants with lipid levels over time are complex. The triglyceride gene score was positively related to change in triglycerides levels, but similar longitudinal results were not observed for LDL-C or HDL-C levels. Unfavorable gene scores were nevertheless related to higher incidence of abnormal levels.


S. mansoni-T. cruzi co-infection modulates arginase-1/iNOS expression, liver and heart disease in mice.
Although Schistosoma species and Trypanosoma cruzi share common endemic areas, co-infections by these parasites remains overlooked. By using a murine model of S. mansoni and T. cruzi co-infection, we investigated if and to what extent these infections might interact to change the pathological outcomes typically observed when the host is infected by a single parasite species. Swiss mice were randomized into four groups: uninfected (NI) and those infected by S. mansoni (SM), T. cruzi (TC) or co-infected (SM + TC). After 120 days of S. mansoni infection, T. cruzi was concurrently inoculated and the infection occurred for 30 days. Taken together, we identified that the overlap of Th2 (schistosomiasis) and Th1 (Chagas disease) immunological patterns changes the host resistance against both pathogens. Beyond impairing the control of granulomatous inflammation, T. cruzi parasitemia and parasitism in co-infected animals, the Th2 inflammatory response against S. mansoni elicits the activation of the arginase-1 pathway to the detriment of inducible oxide nitric synthase (iNOS) expression and nitric oxide (NO) production, contributing to the liver damage, with minor effects on heart pathology.


Exogenous interleukin-33 targets myeloid-derived suppressor cells and generates periphery-induced Foxp3⁺ regulatory T cells in skin-transplanted mice.
Interleukin-33 (IL-33) has been a focus of study because of its variety of functions shaping CD4(+) T-cell biology. In the present work, we evaluated the modulatory effect of IL-33 on suppressor cells in an in vivo transplantation model. C57BL/6 wild-type mice were grafted with syngeneic or allogeneic skin transplants and treated with exogenous IL-33 daily. After 10 days of treatment, we analysed draining lymph node cellularity and found in allogeneic animals an increment in myeloid-derived suppressor cells, which co-express MHC-II, and become enriched upon IL-33 treatment. In line with this observation, inducible nitric oxide synthase and arginase 1 expression were also increased in allogeneic animals upon IL-33 administration. In addition, IL-33 treatment up-regulated the number of Foxp3(+) regulatory T (Treg) cells in the allogeneic group, complementing the healthier integrity of the allografts and the increased allograft survival. Moreover, we demonstrate that IL-33 promotes CD4(+) T-cell expansion and conversion of CD4(+) Foxp3(-) T cells into CD4(+) Foxp3(+) Treg cells in the periphery. Lastly, the cytokine pattern of ex vivo-stimulated draining lymph nodes indicates that IL-33 dampens interferon-γ and IL-17 production, stimulating IL-10 secretion. Altogether, our work complements previous studies on the immune-modulatory activity of IL-33, showing that this cytokine affects myeloid-derived suppressor cells at the cell number and gene expression levels. More importantly, our research demonstrates for the first time that IL-33 allows for in vivo Foxp3(+) Treg cell conversion and favours an anti-inflammatory or tolerogenic state by skewing cytokine production. Therefore, our data suggest a potential use of IL-33 to prevent allograft rejection, bringing new therapeutics to the transplantation field.


Placement of implants into ridges grafted with bioplant HTR synthetic bone: histological long-term case history reports.
Following alveolar ridge grafting procedures for ridge preservation, for example, the immediate filling of extraction sockets, and ridge augmentation, for example, the building up of the atrophic jawbone, punch biopsies were obtained at various times postextraction prior to the placement of endosseous root-form implants. These histological sections provided an opportunity to study the bony regenerative response to an osteoconductive synthetic graft material and longer term interactions over a period from 8 months to 12 years. The formation and remodeling of healthy dense lamina of bone in areas where bone voids previously existed either from healed or immediate extraction sockets or where there was jawbone atrophy resulting from multiple tooth loss was observed. The grafting procedures enabled dentists to place implants into sites that would have been impossible if not for these preimplant grafting procedures. The jawbone areas studied involved grafted single sites and quadrants as well as full arch augmentation with a calcified microporous copolymer (Bioplant HTR Synthetic Bone, Bioplant Inc, South Norwalk, Conn) graft material. Retrospective case reports of 24 patients were followed radiographically and clinically to 12 years post-alveolar-ridge grafting and subsequently to 5 years after implants were placed into these augmented ridges. Implant and grafting histories from 4.7 months to 17 years are reported for three of these patients. General applications of synthetic bone grafting before implant placement are recommended.


Olanzapine-induced pancreatitis: a case report.
The antipsychotic agent clozapine has been linked to several cases of pancreatitis. The newer, but related, olanzapine was believed to have fewer side effects. A 42-year-old man in good physical condition gradually developed hypertriglyceridemia, hypercholesterolemia, elevated alanine aminotransferase, diabetes and, ultimately, acute pancreatitis after 19 months of olanzapine monotherapy. Due to multiorgan failure, he was in the intensive care unit and surgical ward for 29 days. He made a full recovery. The olanzapine was discontinued. Glucose, triglyceride and cholesterol levels normalized as did pancreas and liver function. We report olanzapine as the probable cause of acute pancreatitis in a patient without any known predisposing factors. Olanzapine-treated patients should be monitored with glucose, lipid, pancreatic function and liver function tests, and the olanzapine should be discontinued if the results of these tests worsen.


Prostate-specific antigen and related isoforms in the diagnosis and management of prostate cancer.
Despite its unparalleled merits for prostate cancer detection and staging, prostate-specific antigen (PSA) is not a marker for prostate cancer only, but also is expressed in benign conditions. For early detection, limitations of PSA are obvious. Its widespread use has led to an extensive amount of expensive and often unnecessary diagnostic procedures associated with significant morbidity. Total PSA derivatives may enhance the accuracy of prostate cancer diagnosis. The ratio of free-to-total PSA improves specificity while maintaining a high sensitivity for prostate cancer detection for men with a total PSA of 2.5 to 10 ng/mL. Human glandular kallikrein also has the potential to be a valuable tool in combination with total and free PSA for early diagnosis of prostate cancer. Complex PSA seems to be a reliable tool to improve specificity at high sensitivity levels in men with suspected prostate cancer (mainly in PSA levels below 4 ng/mL). Newly discovered isoforms of free PSA also may impact early detection of prostate cancer with encouraging preliminary results that warrant further clinical investigation.


The effects of multiple scattering to optical forces on a sphere in an evanescent field.
In this paper we discuss the effects of multiple scattering to the optical forces on a particle by an evanescent field. We show that the iterative method to process the effects of the interaction between the particle and a plane surface is invalid when the radius of particle is large or when the structural resonance of the particle occurs. By using the generalized minimum residual method to solve the set of equations directly, the divergence appears in the iterative method can be removed completely. As an illustrative example, we discussed the effects of multiple scattering to optical forces on a particle in an evanescent field from an incident plane wave. The interpretations of numerical results are presented in detail.


Atomistic-Scale Simulations of Defect Formation in Graphene under Noble Gas Ion Irradiation.
Despite the frequent use of noble gas ion irradiation of graphene, the atomistic-scale details, including the effects of dose, energy, and ion bombardment species on defect formation, and the associated dynamic processes involved in the irradiations and subsequent relaxation have not yet been thoroughly studied. Here, we simulated the irradiation of graphene with noble gas ions and the subsequent effects of annealing. Lattice defects, including nanopores, were generated after the annealing of the irradiated graphene, which was the result of structural relaxation that allowed the vacancy-type defects to coalesce into a larger defect. Larger nanopores were generated by irradiation with a series of heavier noble gas ions, due to a larger collision cross section that led to more detrimental effects in the graphene, and by a higher ion dose that increased the chance of displacing the carbon atoms from graphene. Overall trends in the evolution of defects with respect to a dose, as well as the defect characteristics, were in good agreement with experimental results. Additionally, the statistics in the defect types generated by different irradiating ions suggested that the most frequently observed defect types were Stone-Thrower-Wales (STW) defects for He(+) irradiation and monovacancy (MV) defects for all other ion irradiations.


The Leadership Case for Investing in Continuing Professional Development.
Continuing medical education (CME) has the power and capacity to address many challenges in the health care environment, from clinician well-being to national imperatives for better health, better care, and lower cost. Health care leaders who recognize the strategic value of education and engage their people in education can expect a meaningful return on their investment-not only in terms of the quality and safety of their clinicians' work but also in the spirit and cohesiveness of the clinicians who work at their institution. To optimize the benefits of education, clinical leaders need to think of accredited CME as the professional development vehicle that can help them drive change and achieve goals, in consort with quality improvement efforts, patient safety projects, and other systems changes. An empowered CME program, with its multiprofessional scope and educational expertise, can contribute to initiatives focused on both clinical and nonclinical areas, such as quality and safety, professionalism, team communication, and process improvements. In this Invited Commentary, the author describes principles and action steps for aligning leadership and educational strategy and urges institutional leaders to embrace the continuing professional development of their human capital as an organizational responsibility and opportunity and to view engagement in education as an investment in people.


Cladosporium Avr2 inhibits tomato Rcr3 protease required for Cf-2-dependent disease resistance.
How plants recognize pathogens and activate defense is still mysterious. Direct interaction between pathogen avirulence (Avr) proteins and plant disease resistance proteins is the exception rather than the rule. During infection, Cladosporium fulvum secretes Avr2 protein into the apoplast of tomato leaves and, in the presence of the extracellular leucine-rich repeat receptor-like Cf-2 protein, triggers a hypersensitive response (HR) that also requires the extracellular tomato cysteine protease Rcr3. We show here that Avr2 binds and inhibits Rcr3 and propose that the Rcr3-Avr2 complex enables the Cf-2 protein to activate an HR.


Individual differences in responses to provocation and frequent victimization by peers.
This study examined associations between victimization by peers and intention to respond to provocative events as a function of anger arousal and motivation to improve the situation in a cross-sectional sample of school-age children (N = 506, 260 males, 246 females). Results demonstrated that more intense anger and more retaliatory motivation were positively associated with intentions to aggress and with frequency of victimization. The association between aggressive intentions to respond to anger provocation and victimization could be accounted for by subjective feelings of anger and motivation to retaliate. The contribution of emotion processes was stronger for boys than for girls. A post hoc examination of non-bullying participants revealed that motivation accounted for aggressive intentions among the non-bullies. Results support including anger management programs in prevention efforts that target the school climate and victims' risk for psychopathology.


Early infectious outcomes after addition of fluoroquinolone or aminoglycoside to posttrauma antibiotic prophylaxis in combat-related open fracture injuries.
We examined combat-related open extremity fracture infections as a function of whether posttrauma antimicrobial prophylaxis included expanded Gram-negative (EGN) coverage. Military personnel with open extremity fractures sustained in Iraq and Afghanistan (2009-2014) who transferred to participating hospitals in the United States were assessed. The analysis was restricted to patients with a U.S. hospitalization period of ≥7 days. Prophylaxis was classified as narrow (e.g., IV cefazolin, clindamycin, and/or amoxicillin-clavulanate) or EGN, if the prophylactic regimen included fluoroquinolones and/or aminoglycosides. The study population included 1,044 patients, of which 585 (56%) and 459 (44%) received narrow and EGN coverage, respectively (p < 0.001). Skin and soft-tissue infections (SSTIs) were more common among patients who received narrow prophylaxis compared to EGN coverage (28% vs. 22%; p = 0.029), whereas osteomyelitis rates were comparable between regimens (8%). Similar findings were noted when endpoints were measured at 2 and 4 weeks postinjury. There was no significant difference related to length of hospitalization between narrow and EGN regimens (median: 34 and 32 days, respectively) or operating room visits (median: 5 and 4). A higher proportion of EGN coverage patients had Gram-negative organisms isolated that were not susceptible to fluoroquinolones and/or aminoglycosides (49% vs. 40%; p < 0.001). In a Cox proportional model, narrow prophylaxis was independently associated with an increased risk of extremity SSTIs (hazard ratio: 1.41; 95% confidence interval: 1.09-1.83). Despite seeing a small benefit with EGN coverage related to a reduction of SSTIs, it does not decrease the risk of osteomyelitis, and there seems to be a cost of increased antibiotic resistance associated with use. Overall, our findings support the current post-combat trauma antibiotic prophylaxis guidelines, which recommend the use of cefazolin or clindamycin with open fractures. Prognostic/Epidemiological, Level II; Therapy, level IV.


SMC1: an essential yeast gene encoding a putative head-rod-tail protein is required for nuclear division and defines a new ubiquitous protein family.
The smc1-1 mutant was identified initially as a mutant of Saccharomyces cerevisiae that had an elevated rate of minichromosome nondisjunction. We have cloned the wild-type SMC1 gene. The sequence of the SMC1 gene predicts that its product (Smc1p) is a 141-kD protein, and antibodies against Smc1 protein detect a protein with mobility of 165 kD. Analysis of the primary and putative secondary structure of Smc1p suggests that it contains two central coiled-coil regions flanked by an amino-terminal nucleoside triphosphate (NTP)-binding head and a conserved carboxy-terminal tail. These analyses also indicate that Smc1p is an evolutionary conserved protein and is a member of a new family of proteins ubiquitous among prokaryotes and eukaryotes. The SMC1 gene is essential for viability. Several phenotypic characteristics of the mutant alleles of smc1 gene indicate that its product is involved in some aspects of nuclear metabolism, most likely in chromosome segregation. The smc1-1 and smc1-2 mutants have a dramatic increase in mitotic loss of a chromosome fragment and chromosome III, respectively, but have no increase in mitotic recombination. Depletion of SMC1 function in the ts mutant, smc1-2, causes a dramatic mitosis-related lethality. Smc1p-depleted cells have a defect in nuclear division as evidenced by the absence of anaphase cells. This phenotype of the smc1-2 mutant is not RAD9 dependent. Based upon the facts that Smc1p is a member of a ubiquitous family, and it is essential for yeast nuclear division, we propose that Smc1p and Smc1p-like proteins function in a fundamental aspect of prokaryotic and eukaryotic cell division.


How the brain heals emotional wounds: the functional neuroanatomy of forgiveness.
IN LIFE, EVERYONE GOES THROUGH HURTFUL EVENTS CAUSED BY SIGNIFICANT OTHERS: a deceiving friend, a betraying partner, or an unjustly blaming parent. In response to painful emotions, individuals may react with anger, hostility, and the desire for revenge. As an alternative, they may decide to forgive the wrongdoer and relinquish resentment. In the present study, we examined the brain correlates of forgiveness using functional Magnetic Resonance Imaging (fMRI). Healthy participants were induced to imagine social scenarios that described emotionally hurtful events followed by the indication to either forgive the imagined offenders, or harbor a grudge toward them. Subjects rated their imaginative skills, levels of anger, frustration, and/or relief when imagining negative events as well as following forgiveness. Forgiveness was associated with positive emotional states as compared to unforgiveness. Granting forgiveness was associated with activations in a brain network involved in theory of mind, empathy, and the regulation of affect through cognition, which comprised the precuneus, right inferior parietal regions, and the dorsolateral prefrontal cortex. Our results uncovered the neuronal basis of reappraisal-driven forgiveness, and extend extant data on emotional regulation to the resolution of anger and resentment following negative interpersonal events.


Multidisciplinary lymphedema treatment program.
Lymphedema is an underrecognized and undertreated condition that requires a multidisciplinary approach in an individualized program that will address the special needs of each patient. In an ideal setting of an outpatient management program the team should be composed of a vascular surgeon, a dermatologist, a physiotherapist, a dietician, a psychologist, a social worker, and an office employee, working together in the assessment and management of all aspects of lymphedema. All treatment strategies and actions taken should ultimately focus on the improvement of the quality of life of patients suffering from lymphedema and on the prevention of lymphedema in high-risk patients.


In situ growth of well-dispersed CdS nanocrystals in semiconducting polymers.
A straight synthetic route to fabricate hybrid nanocomposite films of well-dispersed CdS nanocrystals (NCs) in poly[2-methoxy-5-(2'-ethyl-hexyloxy)-1,4-phenylene vinylene] (MEH-PPV) is reported. A soluble cadmium complex [Cd(SBz)2]2·MI, obtained by incorporating a Lewis base (1-methylimidazole, MI) on the cadmium bis(benzyl)thiol, is used as starting reagent in an in situ thermolytic process. CdS NCs with spherical shape nucleate and grow well below 200°C in a relatively short time (30 min). Photoluminescence spectroscopy measurements performed on CdS/MEH-PPV nanocomposites show that CdS photoluminescence peaks are totally quenched inside MEH-PPV, if compared to CdS/PMMA nanocomposites, as expected due to overlapping of the polymer absorption and CdS emission spectra. The CdS NCs are well-dispersed in size and homogeneously distributed within MEH-PPV matrix as proved by transmission electron microscopy. Nanocomposites with different precursor/polymer weight ratios were prepared in the range from 1:4 to 4:1. Highly dense materials, without NCs clustering, were obtained for a weight/weight ratio of 2:3 between precursor and polymer, making these nanocomposites particularly suitable for optoelectronic and solar energy conversion applications.


Isolation of colonial variants of Bacteroides gingivalis W50 with a reduced virulence.
The spontaneous appearance of unusual colony forms was observed during prolonged growth of Bacteroides gingivalis W50 in a chemostat. Two variants were selected for further study which could be distinguished from the parent strain by the rate and intensity of pigmentation of their colonies. For example, after anaerobic incubation for 14 days, variant W50/BR1 produced brown colonies whereas those of the parent strain were black; in contrast, variant W50/BE1 did not show signs of pigmentation until incubation had continued for 21 days. In subsequent studies in the chemostat, variant W50/BE1 bred true even after prolonged growth whereas other colony forms appeared after incubation of variant W50/BR1 for 14 days. The relatedness of W50/BR1 and W50/BE1 to the parent strain was confirmed by comparisons of the whole-cell fatty-acid profiles, the patterns of pre-formed enzymes and by the metabolic end products after growth. However, the variants did differ from the parent strain in their virulence in a mouse pathogenicity model. The parent strain killed all mice given infective doses greater than 5 x 10(8) cfu whereas W50/BR1 was much less virulent (2 out of 10 mice killed and higher infective doses needed for higher mortality rates) and W50/BE1 was avirulent at all infective doses tested.


Erythropoietin in traumatic brain injury associated acute kidney injury: A randomized controlled trial.
Acute kidney injury (AKI) in traumatic brain injury (TBI) is poorly understood and it is unknown if it can be attenuated using erythropoietin (EPO). Pre-planned analysis of patients included in the EPO-TBI (ClinicalTrials.gov NCT00987454) trial who were randomized to weekly EPO (40 000 units) or placebo (0.9% sodium chloride) subcutaneously up to three doses or until intensive care unit (ICU) discharge. Creatinine levels and urinary output (up to 7 days) were categorized according to the Kidney Disease Improving Global Outcome (KDIGO) classification. Severity of TBI was categorized with the International Mission for Prognosis and Analysis of Clinical Trials in TBI. Of 3348 screened patients, 606 were randomized and 603 were analyzed. Of these, 82 (14%) patients developed AKI according to KDIGO (60 [10%] with KDIGO 1, 11 [2%] patients with KDIGO 2, and 11 [2%] patients with KDIGO 3). Male gender (hazard ratio [HR] 4.0 95% confidence interval [CI] 1.4-11.2, P = 0.008) and severity of TBI (HR 1.3 95% CI 1.1-1.4, P < 0.001 for each 10% increase in risk of poor 6 month outcome) predicted time to AKI. KDIGO stage 1 (HR 8.8 95% CI 4.5-17, P < 0.001), KDIGO stage 2 (HR 13.2 95% CI 3.9-45.2, P < 0.001) and KDIGO stage 3 (HR 11.7 95% CI 3.5-39.7, P < 0.005) predicted time to mortality. EPO did not influence time to AKI (HR 1.08 95% CI 0.7-1.67, P = 0.73) or creatinine levels during ICU stay (P = 0.09). Acute kidney injury is more common in male patients and those with severe compared to moderate TBI and appears associated with worse outcome. EPO does not prevent AKI after TBI.


Effect of dietary flaxseed oil level on the growth performance and fatty acid composition of fingerlings of rainbow trout, Oncorhynchus mykiss.
This study evaluated the suitability of flaxseed oil as a source of supplemental dietary lipid for fingerlings of rainbow trout (Oncorhynchus mykiss). Triplicate groups of the 30 fingerlings held under identical culture conditions were fed twice daily by iso-nitrogenous, iso-calorific and iso-lipidic diets for 8 weeks. Experimental diets consisted of 30.2% protein, 18.6 kJ g(-1) energy and 16.5% lipid from fish oil (FO), flaxseed oil (FxO) and 1:1 blends of the oils (FFxO). Moisture, ash, protein, final body weight, specific growth rate, weight gain, feed conversion ratio, survival and hepatosomatic index were not affected by treatments but the percent of lipids was significantly highest in fish fed the flaxseed oil diet (FxOD). The condition factors of fingerlings reared on FxOD and fish and flaxseed oils diet (FFxOD) were significantly lower than those fed the fish oil diet (FOD). Protein efficiency ratio (PER) was significantly higher than those fed the FOD and FFxOD. Whole body fatty acid compositions mirrored those of diet treatments. The highest amounts of highly unsaturated fatty acids (HUFAs) were detected in fish fed 100% FO, which was significantly different from other treatments. In all treatments polyunsaturated fatty acids/saturated fatty acids (PUFAs/SFAs) and n-6/n-3 ratios were higher than 0.45 and lower than 4, respectively. Present results indicate the fingerlings can be reared on diets in which FO has been replaced with FxO, with no significant effects on fish performance.


Prolonged intestinal transit and diarrhea in patients with an activating GUCY2C mutation.
Increased intestinal hydration by activation of the epithelial enzyme linked receptor guanylate cyclase C (GC-C) is a pharmacological principle for treating constipation. Activating mutations in the GUCY2C gene encoding GC-C cause Familial GUCY2C diarrhea syndrome (FGDS) which has been diagnosed with severe dysmotility. To investigate gut motility and hormones before and after a meal in FGDS patients and compare with healthy controls (HC). Bristol stool chart and stool frequency was assessed. Before and after a meal occlusive and non-occlusive contractions were obtained using ultrasound. A wireless motility capsule (WMC) recorded gut transit time, pH, contractions and pressure. Plasma levels of selected gut hormones were measured at different time points. The FGDS patients had 4 (range 1-10) loose stools/day and prolonged total gut transit time compared to HC, 55.5 h vs 28.5 h, respectively,with significantly increased colon transit time. In FGDS patients, pH in duodenum, small bowel and colon was increased and the number of contractions and the intraluminal pressure were significantly decreased, measured by WMC. Ultrasound showed in small bowel increased number of non-occlusive contractions in the FGDS patients. Serotonin (5-HT) plasma levels in the HC peaked 30 min after the meal, while the FGDS patients had no response. Despite having diarrhea, the FGDS patients have prolonged transit time through the gut compared to HC, particularly in colon. The reduced number of intestinal contractions and lack of 5-HT release after a meal in FGDS patients surprisingly resemble colonic motility disturbances seen in patients with constipation.


Studies on neuropeptide Y receptors in a mouse adrenocortical cell line.
The mouse adrenocortical Y-1 cell line has been found to express high affinity binding sites for neuropeptide Y (NPY). Pharmacological studies have shown that these NPY binding sites are of the Y1 type. Reverse transcription-polymerase chain reaction using primers specific for the rat Y1 receptor revealed that the NPY Y1 receptor mRNA is present in Y-1 cells. The Kd of the receptor for NPY was found to be 1.75 +/- 0.20 nM and the Bmax was 265 +/- 18 fmol/mg. The NPY Y1 receptors in this adrenocortical cell line were shown to be coupled to pertussis toxin-sensitive G proteins. Stimulation of Y1 receptors resulted in the inhibition of forskolin- and adrenocorticotropic hormone (ACTH)-stimulated cAMP synthesis. NPY had no effect on basal steroid release from the Y-1 cells. At an ACTH concentration of 0.1 microM, NPY did not affect ACTH-stimulated steroid release, although NPY did inhibit cAMP production under the same hormonal conditions. cAMP profoundly affected the density of the NPY receptors in Y-1 cells. Treatment of the cells with N6,2'-O-dibutyryl-cAMP or ACTH reduced the Y1 receptor density by > 50%. On the other hand the steroid dexamethasone increased the density of Y1 receptors by 35%. Although additional detailed studies are necessary, these results may have interesting implications for the functions of ACTH, steroids, and NPY in the pituitary-adrenocortical axis.


Macrolide-Resistant Mycoplasma pneumoniae in the United States as Determined from a National Surveillance Program.
There are sparse data to indicate the extent that macrolide-resistant Mycoplasma pneumoniae (MRMp) occurs in the United States or its clinical significance. Between 2015 and 2018, hospitals in 8 states collected and stored respiratory specimens that tested positive for M. pneumoniae and sent them to the University of Alabama at Birmingham, where real-time PCR was performed for detection of 23S rRNA mutations known to confer macrolide resistance. MRMp was detected in 27 of 360 specimens (7.5%). MRMp prevalence was significantly higher in the South and East (18.3%) than in the West (2.1%). A2063G was the predominant 23S rRNA mutation detected. MICs for macrolide-susceptible M. pneumoniae (MSMp) were ≤0.008 μg/ml, whereas MICs for MRMp were 16 to 32 μg/ml. Patients with MRMp infection were more likely to have a history of immunodeficiency or malignancy. Otherwise, there were no other significant differences in the clinical features between patients infected with MRMp and those infected with MSMp, nor were there any differences in radiographic findings, hospitalization rates, viral coinfections, the mean duration of antimicrobial treatment, or clinical outcomes. There was no significant change in MRMp incidence over time or according to age, sex, race/ethnicity, or status as an inpatient or an outpatient. Patients with MRMp were more likely to have received a macrolide prior to presentation, and their treatment was more likely to have been changed to a fluoroquinolone after presentation. This is the first national surveillance program for M. pneumoniae in the United States. Additional surveillance is needed to assess the clinical significance of MRMp and to monitor changes in MRMp prevalence.


Au3(μ3-S)(0e) elementary block: new insights into ligated gold clusters with μ3-sulfido motifs.
An understanding of the structural stability and formation mechanism of ligated gold nanoclusters with triply coordinated μ3-sulfido (μ3-S) motifs is important not only for gold chemistry but also for the design of more effective catalysts or drug carriers for various applications. In this article, a new elementary block Au3(μ3-S) with zero valence electrons [referred to as Au3(μ3-S)(0e)] has been identified, which describes all crystallized ligated gold clusters with μ3-S motifs, in conjunction with the previously reported Au3(2e) and Au4(2e) elementary blocks, in a grand unified model (GUM). This Au3(μ3-S)(0e) elementary block has a tripod structure with the S atom bonding to three Au atoms in a μ3 bridging mode, and can be considered as a μ3-S atom balancing out the 2e valence electrons of the Au3(2e) block. Using Au3(μ3-S) as a building block, a special group of quasi-fullerene hollow-cage [Au3n(μ3-S)2n]n- gold(i) μ3-S clusters are designed, which exhibit high stabilities. In addition, a series of theoretical structures are predicted to be increasingly stable after introducing μ3-S atoms, based on the crystallized clusters. Overall, the introduction of a Au3(μ3-S)(0e) elementary block can help with the understanding of diverse structures of ligated gold clusters with μ3-S motifs, thereby assisting the rational design of new forms of gold nanoclusters.


Hidden conflicts: explanations make inconsistencies harder to detect.
A rational response to an inconsistent set of propositions is to revise it in a minimal way to restore consistency. A more important psychological goal is usually to create an explanation that resolves the inconsistency. We report five studies showing that once individuals have done so, they find inconsistencies harder to detect. Experiment 1 established the effect when participants explained inconsistencies, and Experiment 2 eliminated the possibility that the effect was a result of demand characteristics. Experiments 3a and 3b replicated the result, and showed that it did not occur in control groups that evaluated (or justified) which events in the pairs of assertions were more surprising. Experiment 4 replicated the previous findings, but the participants carried out all the conditions acting as their own controls. In all five studies, control conditions established that participants were able to detect comparable inconsistencies. Their explanations led them to re-interpret the generalizations as holding by default, and so they were less likely to treat the pairs of assertions as inconsistent. Explanations can accordingly undo the devastating consequences of logical inconsistencies, but at the cost of a subsequent failure to detect them.


SepA, the major extracellular protein of Shigella flexneri: autonomous secretion and involvement in tissue invasion.
In addition to Ipa proteins and IcsA, which are involved in entry into epithelial cells and intercellular spread, respectively, Shigella secretes a 110 kDa protein, designated SepA. We report the identification, cloning, and nucleotide sequence determination of the sepA gene, analysis of SepA secretion, and construction and characterization of a sepA mutant. The sepA gene is carried by the virulence plasmid and codes for a 150 kDa precursor. Upon secretion, which does not involve accessory proteins encoded by the virulence plasmid, the precursor is converted to a mature protein of 110 kDa by two cleavages removing an N-terminal signal sequence and a C-terminal fragment. Extensive similarities were detected between the sequence of the first 500 residues of mature SepA and the N-terminal region of IgA1 proteases from Neisseria gonorrhoeae and Haemophilus influenzae, the Tsh haemagglutinin of an avian pathogenic Escherichia coli, and the Hap protein involved in adhesion and penetration of H. influenzae. The C-terminal domain of the SepA precursor, which is not present in the secreted protein, exhibits sequence similarity with pertactin of Bordetella pertussis and the ring-forming protein of Helicobacter mustelae. Construction and phenotypic characterization of a sepA mutant indicated that SepA is required neither for entry into cultured epithelial cells nor for intercellular dissemination. However, in the rabbit ligated ileal loop model, the sepA mutant exhibited an attenuated virulence, which suggests that SepA might play a role in tissue invasion.


Mediators and theories of change in psychotherapy with adolescents: a systematic review protocol.
Approximately 75% of mental disorders emerge before the age of 25 years but less than half receive appropriate treatment. Little is known about the mechanisms underlying the therapeutic change of adolescents in psychotherapy. The 'European Network of Individualised Psychotherapy Treatment of Young People with Mental Disorders', funded by the European Cooperation in Science and Technology, will conduct the first systematic review to summarise the existing knowledge on mediators and theories of change in psychotherapy for adolescents. A systematic review will be conducted, conforming to the reporting guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement recommendations. Electronic databases (PubMed and PsycINFO) have been systematically searched on 23 February 2020, for prospective, longitudinal and case-control designs which examine mediators of change. Participants will be adolescents between 10 and 19 years of age who suffer from a mental disorder or psychological difficulties and receive an intervention that aims at preventing, ameliorating and/or treating psychological problems. Ethical approval is not required for this systematic review as no primary data will be collected. The results will be published in a peer-reviewed journals and at conference presentations and will be shared with stakeholder groups. The whole data set will be offered to other research groups following recommendations of the open science initiative. Databases with the systematic search will be made openly available following open science initiatives. CRD42020177535.


Reflexive Gaze Shifts and Fear Recognition Deficits in Children with Callous-Unemotional Traits and Impulsivity/Conduct Problems.
The ability to efficiently recognize the emotions on others' faces is something that most of us take for granted. Children with callous-unemotional (CU) traits and impulsivity/conduct problems (ICP), such as attention-deficit hyperactivity disorder, have been previously described as being "fear blind". This is also associated with looking less at the eye regions of fearful faces, which are highly diagnostic. Previous attempts to intervene into emotion recognition strategies have not had lasting effects on participants' fear recognition abilities. Here we present both (a) additional evidence that there is a two-part causal chain, from personality traits to face recognition strategies using the eyes, then from strategies to rates of recognizing fear in others; and (b) a pilot intervention that had persistent effects for weeks after the end of instruction. Further, the intervention led to more change in those with the highest CU traits. This both clarifies the specific mechanisms linking personality to emotion recognition and shows that the process is fundamentally malleable. It is possible that such training could promote empathy and reduce the rates of antisocial behavior in specific populations in the future.


Exosomes from drug-resistant breast cancer cells transmit chemoresistance by a horizontal transfer of microRNAs.
Adriamycin and docetaxel are two agents commonly used in treatment of breast cancer, but their efficacy is often limited by the emergence of chemoresistance. Recent studies indicate that exosomes act as vehicles for exchange of genetic cargo between heterogeneous populations of tumor cells, engendering a transmitted drug resistance for cancer development and progression. However, the specific contribution of breast cancer-derived exosomes is poorly understood. Here we reinforced other's report that human breast cancer cell line MCF-7/S could acquire increased survival potential from its resistant variants MCF-7/Adr and MCF-7/Doc. Additionally, exosomes of the latter, A/exo and D/exo, significantly modulated the cell cycle distribution and drug-induced apoptosis with respect to S/exo. Exosomes pre-treated with RNase were unable to regulate cell cycle and apoptosis resistance, suggesting an RNA-dependent manner. Microarray and polymerase chain reaction for the miRNA expression profiles of A/exo, D/exo, and S/exo demonstrated that they loaded selective miRNA patterns. Following A/exo and D/exo transfer to recipient MCF-7/S, the same miRNAs were significantly increased in acquired cells. Target gene prediction and pathway analysis showed the involvement of miR-100, miR-222, and miR-30a in pathways implicated in cancer pathogenesis, membrane vesiculation and therapy failure. Furthermore, D/exo co-culture assays and miRNA mimics transfection experiments indicated that miR-222-rich D/exo could alter target gene expression in MCF-7/S. Our results suggest that drug-resistant breast cancer cells may spread resistance capacity to sensitive ones by releasing exosomes and that such effects could be partly attributed to the intercellular transfer of specific miRNAs.


A modified SPIHT algorithm for image coding with a joint MSE and classification distortion measure.
The set partitioning in hierarchical trees (SPIHT) algorithm is an efficient wavelet-based progressive image-compression technique, designed to minimize the mean-squared error (MSE) between the original and decoded imagery. However, the MSE-based distortion measure is not in general well correlated with image-recognition quality, especially at low bit rates. Specifically, low-amplitude wavelet coefficients that may be important for classification are given low priority by conventional SPIHT. In this paper, we use the kernel matching pursuits (KMP) method to autonomously estimate the importance of each wavelet subband for distinguishing between different textures, with textural segmentation first performed via a hidden Markov tree. Based on subband importance determined via KMP, we scale the wavelet coefficients prior to SPIHT coding, with the goal of minimizing a Lagrangian distortion based jointly on the MSE and classification error. For comparison we consider Bayes tree-structured vector quantization (B-TSVQ), also designed to obtain a tradeoff between MSE and classification error. The performances of the original SPIHT, the modified SPIHT, and B-TSVQ are compared.


Sex differences in fracture outcomes within Taiwan population: A nationwide matched study.
Because the sex difference in outcomes of fracture was incompletely understood, we evaluated the post-fracture complications and mortality of female and male patients. We conducted a nationwide study of 498,586 fracture patients who received inpatient care using Taiwan's National Health Insurance Research Database 2008-2013 claims data. Female and male fracture patients were selected for comparison by using a propensity-score matching procedure. Age, low income, types of fracture, fracture with surgery, several medical conditions, number of hospitalization and emergency visits were considered as potential confounding factors. Multivariate logistic regressions were used to calculate the adjusted odds ratios (OR), the 95% CI of post-fracture complications and 30-day in-hospital mortality differences between women and men. Male patients had a higher risk of post-fracture pneumonia (OR 1.96, 95% CI 1.83-2.11), acute renal failure (OR 1.85, 95% CI 1.60-2.15), deep wound infection (OR 1.63, 95% CI 1.51-1.77), stroke (OR 1.58, 95% CI 1.49-1.67), septicemia (OR 1.51, 95% CI 1.42-1.61), acute myocardial infarction (OR 1.38, 95% CI 1.09-1.75) and 30-day in-hospital mortality (OR 1.69, 95% CI 1.48-1.93) compared with female patients. However, a lower risk of post-fracture urinary tract infection (OR 0.69, 95% CI 0.65-0.72) was found in men than in women. Male patients also had longer hospital stays and higher medical expenditures due to fracture admission than did the female patients. Higher rates of post-fracture adverse events in male patients were noted in all age groups and all types of fractures. We raised the possibility that male patients showed more complications and higher mortality rates after fracture admission compared with female patients, with the exception of urinary tract infections.


Modulation of flagellar expression in Escherichia coli by acetyl phosphate and the osmoregulator OmpR.
During the search for unknown factors involved in motility, we have found that expression of the flagellar master operon flhDC is affected by mutations of the pta and ackA genes, encoding phosphotransacetylase and acetate kinase, respectively (S. Shin, J. Sheen, and C. Park, Korean J. Microbiol. 31:504-511, 1993). Here we describe results showing that this effect is modulated by externally added acetate, except when both pta and ackA are mutated, suggesting the role of acetyl phosphate, an intermediate of acetate metabolism, as a regulatory effector. Furthermore, the following evidence indicates that the phosphorylation of OmpR, a trans factor for osmoregulation, regulates flagellar expression. First, in a strain lacking ompR, the expression of flhDC is no longer responsive to a change in the level of acetyl phosphate. Second, an increase in medium osmolarity does not decrease flhDC expression in an ompR mutant. It is known that such an increase normally enhances OmpR phosphorylation. Third, OmpR protein binds to the DNA fragment containing the flhDC promoter, and its affinity is increased with phosphorylation by acetyl phosphate. DNase I footprinting revealed the regions of the flhDC promoter protected by OmpR in the presence or absence of phosphorylation. Therefore, we propose that the phosphorylated OmpR, generated by either osmolarity change or the internal level of acetyl phosphate, negatively regulates the expression of flagella.


β-Amyloid Clustering around ASC Fibrils Boosts Its Toxicity in Microglia.
Alzheimer's disease is the world's most common neurodegenerative disorder. It is associated with neuroinflammation involving activation of microglia by β-amyloid (Aβ) deposits. Based on previous studies showing apoptosis-associated speck-like protein containing a CARD (ASC) binding and cross-seeding extracellular Aβ, we investigate the propagation of ASC between primary microglia and the effects of ASC-Aβ composites on microglial inflammasomes and function. Indeed, ASC released by a pyroptotic cell can be functionally built into the neighboring microglia NOD-like receptor protein (NLRP3) inflammasome. Compared with protein-only application, exposure to ASC-Aβ composites amplifies the proinflammatory response, resulting in pyroptotic cell death, setting free functional ASC and inducing a feedforward stimulating vicious cycle. Clustering around ASC fibrils also compromises clearance of Aβ by microglia. Together, these data enable a closer look at the turning point from acute to chronic Aβ-related neuroinflammation through formation of ASC-Aβ composites.


Why superhydrophobicity is crucial for a water-jumping microrobot? Experimental and theoretical investigations.
This study reported for the first time a novel microrobot that could continuously jump on the water surface without sinking, imitating the excellent aquatic locomotive behaviors of a water strider. The robot consisted of three supporting legs and two actuating legs made from superhydrophobic nickel foam and a driving system that included a miniature direct-current motor and a reduction gear unit. In spite of weighing 11 g, the microrobot jumped 14 cm high and 35 cm long at each leap. In order to better understand the jumping mechanism on the water surface, the variation of forces exerted on the supporting legs was carefully analyzed and calculated based on numerical models and computational simulations. Results demonstrated that superhydrophobicity was crucial for increasing the upward force of the supporting legs and reducing the energy consumption in the process of jumping. Although bionic microrobots mimicking the horizontal skating motions of aquatic insects have been fabricated in the past years, few studies reported a miniature robot capable of continuously jumping on the water surface as agile as a real water strider. Therefore, the present finding not only offers a possibility for vividly imitating and better understanding the amazing water-jumping capability of aquatic insects but also extends the application of porous and superhydrophobic materials to advanced robotic systems.


Trends in "avoidable" mortality in Sweden, 1974-1985.
The aim was to analyse trends in "avoidable" mortality in Sweden, and to contribute to the methodology of avoidable mortality as an index of the quality of care. All deaths of Swedish citizens and other residents in Sweden during the period 1974-1985 were analysed as to causes of death between ages 0 and 64 years. Total mortality delined during the 12 year period studied. Avoidable causes of death were grouped into preventable and treatable causes according to Rutstein's classification. In men, treatable diseases declined more during the 12 year period studied than did total mortality. When lung cancer was excluded, preventable diseases declined for both sexes. Certain avoidable causes of death decreased compared to total mortality, while some others showed an increase. The death rate increased for some avoidable causes of death such as pneumonia other than viral. In women death rates increased for chronic bronchitis and emphysema as well as for malignant neoplasms of trachea, bronchus, and lung, while for boys aged 1-14 years bronchitis NOS and asthma showed an increasing death rate. The study indicates that the avoidable mortality method is sensitive enough to describe important changes in the mortality pattern. The explicit definition of treatable and preventable causes of death constitutes a methodological development in epidemiological analysis of this type. Further studies on the quality of care should combine this method with other methods examining the structure and process of health care.


Influence of host diversity on development of epidemics: an evaluation and elaboration of mixture theory.
ABSTRACT A spatiotemporal/integro-difference equation model was developed and utilized to study the progress of epidemics in spatially heterogeneous mixtures of susceptible and resistant host plants. The effects of different scales and patterns of host genotypes on the development of focal and general epidemics were investigated using potato late blight as a case study. Two different radial Laplace kernels and a two-dimensional Gaussian kernel were used for modeling the dispersal of spores. An analytical expression for the apparent infection rate, r, in general epidemics was tested by comparison with dynamic simulations. A genotype connectivity parameter, q, was introduced into the formula for r. This parameter quantifies the probability of pathogen inoculum produced on a certain host genotype unit reaching the same or another unit of the same genotype. The analytical expression for the apparent infection rate provided accurate predictions of realized r in the simulations of general epidemics. The relationship between r and the radial velocity of focus expansion, c, in focal epidemics, was linear in accordance with theory for homogeneous genotype mixtures. The findings suggest that genotype mixtures that are effective in reducing general epidemics of Phytophthora infestans will likewise curtail focal epidemics and vice versa.


Immunologic memory in Haemophilus influenzae type b conjugate vaccine failure.
To compare the convalescent antibody response to invasive Haemophilus influenzae type b (Hib) disease between conjugate vaccine immunised and unimmunised children, to look for evidence of priming for immunologic memory. Unmatched case-control study in the UK and Eire 1992-2001 and Victoria, Australia 1988-1990. A total of 93 children were identified as having invasive Hib disease following three doses of conjugate vaccine in infancy through post licensure surveillance throughout the UK and Eire; 92 unvaccinated children admitted to an Australian paediatric hospital with invasive Hib disease were used as historical controls. Convalescent serum was taken for measurement of Hib antibody concentration, and clinical information relating to potential disease risk factors was collected. The geometric mean concentrations of convalescent Hib antibodies were compared between immunised and unimmunised children, using raw and adjusted data. Hib conjugate vaccine immunised children had higher serum Hib antibody responses to disease (geometric mean concentration (GMC) 10.81 microg/ml (95% CI 6.62 to 17.66) than unimmunised children (1.06 microg/ml (0.61 to 1.84)) (p < 0.0001). However, following adjustment for the significant confounding influences of age at presentation and timing of serum collection, a difference persisted only in children presenting with meningitis (vaccinated GMC 3.78 microg/ml (2.78 to 5.15); unvaccinated GMC 1.48 microg/ml (0.90 to 2.21); p = 0.003). Higher antibody responses to invasive Hib disease in vaccinated children with meningitis reflect priming for immunologic memory by the vaccine. Although a majority of children in the UK are protected from Hib disease by immunisation, the relative roles of immunologic memory and other immune mechanisms in conferring protection remain unclear.


Investigation of a New Version of the Liquid Embolic Agent PHIL with Extra-Low-Viscosity in an Endovascular Embolization Model.
The type and composition of an embolic agent have a relevant influence on the performance of endovascular embolization. The aim of this study was to investigate a new version of the liquid embolic agent precipitating hydrophobic injectable liquid (PHIL) with extra-low-viscosity in an in vivo embolization model. Twenty-four embolization procedures were performed in the porcine rete mirabile. Eight embolizations were performed with PHIL 25% low viscosity, Squid 12, and standard PHIL 25%, respectively. Procedure time, required volume of embolic agent, visibility of the embolic agent, embolization control, embolization extent (ie, penetration of the rete mirabile), amount of reflux, and degree of embolization distal to the rete mirabile were assessed. All embolic agents were adequately visible. The embolization extent was not significantly different among the 3 investigated agents; however, there was a tendency toward a higher embolization extent for PHIL 25% low viscosity (median embolization extent: 88% [PHIL 25% low viscosity]; 65% [Squid 12]; 60% [PHIL 25%]; P = .146). The amount of reflux was significantly lower for the extra-low-viscosity agents PHIL 25% low viscosity and Squid 12 compared with the standard PHIL 25% (median reflux distance: 8 mm [PHIL 25% low viscosity]; 6 mm [Squid 12]; 17 mm [PHIL 25%]; P = .011). All other embolization features did not differ among agents. PHIL 25% low viscosity is a promising liquid embolic agent for endovascular embolization, featuring effective distal penetration, adequate visibility, a low amount of reflux, and good flow control.


Well-differentiated liposarcoma, an atypical lipomatous tumor, of the mesentery: a case report and review of the literature.
Mesenteric liposarcoma is a rare neoplasm. Here, we report the case of a 73-year-old Japanese man with a well-differentiated (WD) liposarcoma of the mesentery. Due to rapid growth of the abdominal mass and abdominal insufficiency, a tumorectomy was performed. The excised tumor was 12.4 × 9.6 cm in size and weighed 548 g. Cut sections showed a lobulated yellow and/or grayish-colored appearance. The histological features were predominantly those of the sclerotic and lipoma-like variants of WD liposarcoma. The cytoplasm of most spindle cells was diffusely immunoreactive for CD34, while fat cells were positive for S-100 protein. Some spindle cell nuclei were positive for CDK4, and a few were positive for MDM2. The average Ki-67 proliferation index in tumor cells was 10%, and androgen receptor expression was detected in tumor cell nuclei. The present case and 11 cases identified from a literature search were reviewed. The WD mesenteric liposarcomas developed in patients in the fourth to seventh decades of life (mean age 57.9 years). The patients consisted of 7 men and 5 women. All tumors were larger than 10 cm in diameter at the time of surgery. Complete resection might be the only curative therapy for WD liposarcomas of the mesentery, but long-term follow-up is needed because of the possibility of a local recurrence of the tumor.


Hip-abductor fatigue and single-leg landing mechanics in women athletes.
Reduced hip-abductor strength and muscle activation may be associated with altered lower extremity mechanics, which are thought to increase the risk for anterior cruciate ligament injury. However, experimental evidence supporting this relationship is limited. To examine the changes in single-leg landing mechanics and gluteus medius recruitment that occur after a hip-abductor fatigue protocol. Descriptive laboratory study. Twenty physically active women (age = 21.0 ± 1.3 years). Participants were tested before (prefatigue) and after (postfatigue) a hip-abductor fatigue protocol consisting of repetitive side-lying hip abduction. Outcome measures included sagittal-plane and frontal-plane hip and knee kinematics at initial contact and at 60 milliseconds after initial contact during 5 single-leg landings from a height of 40 cm. Peak hip and knee sagittal-plane and frontal-plane joint moments during this time interval were also analyzed. Measures of gluteus medius activation, including latency, peak amplitude, and integrated signal, were recorded. A small (<1°) increase in hip-abduction angle at initial contact and a small (<1°) decrease in knee-abduction (valgus) angle at 60 milliseconds after contact were observed in the postfatigue landing condition. No other kinematic changes were noted for the knee or hip at initial contact or at 60 milliseconds after initial contact. Peak external knee-adduction moment decreased 27% and peak hip adduction moment decreased 24% during the postfatigue landing condition. Gluteus medius activation was delayed after the protocol, but no difference in peak or integrated signal was seen during the landing trials. Changes observed during single-leg landings after hip-abductor fatigue were not generally considered unfavorable to the integrity of the anterior cruciate ligament. Further work may be justified to study the role of hip-abductor activation in protecting the knee during landing.


Sodium valproate versus phenytoin monotherapy for epilepsy: an individual participant data review.
Epilepsy is a common neurological condition in which abnormal electrical discharges from the brain cause recurrent unprovoked seizures. It is believed that with effective drug treatment up to 70% of individuals with active epilepsy have the potential to become seizure-free, and to go into long-term remission shortly after starting drug therapy with a single antiepileptic drug in monotherapy.Worldwide, sodium valproate and phenytoin are commonly used antiepileptic drugs for monotherapy treatment. It is generally believed that phenytoin is more effective for focal onset seizures, and that sodium pvalproate is more effective for generalised onset tonic-clonic seizures (with or without other generalised seizure types). This review is one in a series of Cochrane Reviews investigating pair-wise monotherapy comparisons. This is the latest updated version of the review first published in 2001, and updated in 2013 and 2016. To review the time to treatment failure, remission and first seizure of sodium valproate compared to phenytoin when used as monotherapy in people with focal onset seizures or generalised tonic-clonic seizures (with or without other generalised seizure types). We searched the Cochrane Epilepsy Group's Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform ICTRP on 19 February 2018. We handsearched relevant journals, contacted pharmaceutical companies, original trial investigators and experts in the field. Randomised controlled trials (RCTs) comparing monotherapy with either sodium valproate or phenytoin in children or adults with focal onset seizures or generalised onset tonic-clonic seizures DATA COLLECTION AND ANALYSIS: This was an individual participant data (IPD) review. Our primary outcome was time to treatment failure and our secondary outcomes were time to first seizure post-randomisation, time to six-month, and 12-month remission, and incidence of adverse events. We used Cox proportional hazards regression models to obtain trial-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs), using the generic inverse variance method to obtain the overall pooled HR and 95% CI. We included 11 trials in this review and IPD were available for 669 individuals out of 1119 eligible individuals from five out of 11 trials, 60% of the potential data. Results apply to focal onset seizures (simple, complex and secondary generalised tonic-clonic seizures), and generalised tonic-clonic seizures, but not other generalised seizure types (absence or myoclonus seizure types). For remission outcomes, a HR of less than 1 indicates an advantage for phenytoin, and for first seizure and treatment failure outcomes a HR of less than 1 indicates an advantage for sodium valproate.The main overall results were: time to treatment failure for any reason related to treatment (pooled HR adjusted for seizure type 0.88, 95% CI 0.61 to 1.27; 5 studies; 528 participants; moderate-quality evidence), time to treatment failure due to adverse events (pooled HR adjusted for seizure type 0.77, 95% CI 0.44 to 1.37; 4 studies; 418 participants; moderate-quality evidence), time to treatment failure due to lack of efficacy (pooled HR for all participants 1.16 (95% CI 0.71 to 1.89; 5 studies; 451 participants; moderate-quality evidence). These results suggest that treatment failure for any reason related to treatment and treatment failure due to adverse events may occur earlier on phenytoin compared to sodium valproate, while treatment failure due to lack of efficacy may occur earlier on sodium valproate than phenytoin; however none of these results were statistically significant.Results for time to first seizure (pooled HR adjusted for seizure type 1.08, 95% CI 0.88 to 1.33; 5 studies; 639 participants; low-quality evidence) suggest that first seizure recurrence may occur slightly earlier on sodium valproate compared to phenytoin. There were no clear differences between drugs in terms of time to 12-month remission (pooled HR adjusted for seizure type 1.02, 95% CI 0.81 to 1.28; 4 studies; 514 participants; moderate-quality evidence) and time to six-month remission (pooled HR adjusted for seizure type 1.05, 95% CI 0.86 to 1.27; 5 studies; 639 participants; moderate-quality evidence).Limited information was available regarding adverse events in the trials and we could not make comparisons between the rates of adverse events on sodium valproate and phenytoin. Some adverse events reported with both drugs were drowsiness, rash, dizziness, nausea and gastrointestinal problems. Weight gain was also reported with sodium valproate and gingival hypertrophy/hyperplasia was reported on phenytoin.The methodological quality of the included trials was generally good, however four out of the five trials providing IPD for analysis were of an open-label design, therefore all results were at risk of detection bias. There was also evidence that misclassification of seizure type may have confounded the results of this review, particularly for the outcome 'time to first seizure' and heterogeneity was present in analysis of treatment failure outcomes which could not be explained by subgroup analysis by epilepsy type or by sensitivity analysis for misclassification of seizure type. Therefore, for treatment failure outcomes we judged the quality of the evidence to be moderate to low, for 'time to first seizure' we judged the quality of the evidence to be low, and for remission outcomes we judged the quality of the evidence to be moderate. We have not found evidence that a significant difference exists between valproate and phenytoin for any of the outcomes examined in this review. However detection bias, classification bias and heterogeneity may have impacted on the results of this review. We did not find any outright evidence to support or refute current treatment policies. We recommend that future trials be designed to the highest quality possible with consideration of masking, choice of population, classification of seizure type, duration of follow-up, choice of outcomes and analysis, and presentation of results.


Coronary arterial lesions and myocardial necrosis in stillbirths and infants.
In a detailed study of the coronary arterial tree and myocardium in 256 stillbirths and infants, abnormalities of the coronary arterial tree were noticed in 79 infants, and necrotic lesions of the myocardium in 111 infants. Of the 79 infants with arterial lesions, 70 had associated myocardial necrosis or scarring, or both; the group with coronary arterial lesions, therefore, accounted for the majority of cases with myocardial damage. The myocardial lesions varied from small zones of subendocardial damage, to larger 'geographical' zones of necrosis scattered haphazardly through the myocardium, and a small group where massive necrotic lesions of the papillary muscles were present. While the coronary arterial lesions were associated with all three patterns, they were particularly found in association with the 'geographical' and papillary muscle changes. The coronary arterial lesions varied from zones of acute focal, medial necrosis to severe proliferative intimal lesions and medial defects, with a distinct progression of changes from the acute to the more established lesions. The coronary arterial lesions were seen most commonly in association with conditions that could produce severe hypoxia, and it is argued that they result from hypoxia. It is suggested further that the myocardial damage, so commonly associated with the coronary arterial lesions, could compromise the ability of the hypoxic infant to respond to such an insult. The coronary arterial lesions seen in this group of young infants could offer one explanation for the later development of a variety of other pathological conditions seen in adolescents and young adults.


Endovascular treatment of thoracic aortic pathology: lessons learned.
Endovascular repair has emerged as a very important treatment modality in the management of thoracic aortic diseases due to its reduced invasiveness especially in patients at increased risk for open surgery. Aim of this study is to analyze the lessons learned in our experience of thoracic aortic endografting. From June 1999 to January 2006, 145 selected patients (121 men and 24 women with a mean age of 70 +/- 9 years) with thoracic aorta disease received endovascular treatment with one of four different commercially produced stent grafts (Cook, Gore, Endomed, Medtronic). Indications for treatment included disease of the descending thoracic aorta in 92 cases, of the aortic arch in 43 cases and of the thoracoabdominal aorta in 10 cases. In 48 patients, an hybrid surgical and endovascular approach was required. Primary technical success was achieved in 137/145 (94.5%) cases. One patient died intraoperatively and seven patients had a type "I a" endoleak. In-hospital complications included perioperative stroke in three patients, acute renal failure in two patients, acute respiratory failure in one. Initial clinical success was obtained in 128/145 patients (88.3%) with a mortality rate of 9/145 (6.2%). At 38 +/- 16 months, mid-term clinical success was obtained in 89.5% of the followed patients. Two patients died from fatal aneurysm rupture. One type I endoleak was successfully treated with a rescue endovascular procedure, four cases of type I endoleak resolved completely without any further intervention, no new onset endoleak was discovered. One patient underwent a successful open conversion. Aneurysm expansion was observed in one patient. Endovascular surgery is changing the management of complex aortic disease. Synergy between endovascular and surgical procedures may provide a solution for many challenging clinical problems.


An overview of assistive technology products and services provided in Malawi.
Assistive technology is the products and services used by individuals with functional limitations to enable participation in society and realisation of rights afforded by the United Nations Convention on the Rights of Persons with Disabilities. The Assistive Product List is a comprehensive list of products identified as essential for access through universal health coverage. Key stakeholders, including organisations of persons with disabilities, civil service organisations, academic organisations and government ministries are collaborating to integrate assistive technology into policy and develop a priority assistive products list for Malawi. To understand the organisational characteristics of, and assistive products provided by, key stakeholders working in AT in Malawi. Online survey of representatives from key stakeholder organisations. We surveyed representatives of key stakeholder organisations to gather information regarding assistive technology product and service provision in Malawi. Responses were analysed using counts for closed-ended questions, and conventional content analysis for open-ended questions. A total of 36 of the 50 APL products were provided by eight organisations. Related services were provided for 36 of the 50 APL products by twelve organisations. Five organisations reported providing both products and services. Products and services are largely funded by donation and provided free to those who require them. A range of organisations in Malawi play a role in assistive product delivery and related services. Coordinated AP delivery and service provision is required at a national level which is sustainable and inclusive, and is based on identified needs of the Malawian population.Implications for rehabilitationPolicies supporting assistive product and service provision must acknowledge the contextual needs of the communities where they are implemented.Coordination is required for assistive product and service provision at the national and subnational level.Existing and potential gaps in service provision must be addressed when implementing a national assistive products list.