Integrative taxonomy delimits and diagnoses cryptic arboreal species of the Cyrtodactylusbrevipalmatus group (Squamata, Gekkonidae) with descriptions of four new species from Thailand.
Species delimitation and species diagnosis must remain separate operations to avoid constructing taxonomies comprised of non-monophyletic species based on morphological similarity as opposed to phylogenetic propinquity. This is particularly true for highly specialized species such as the range-restricted upland taxa in the Cyrtodactylusbrevipalmatus group of Indochina where strong selection pressure for an arboreal lifestyle has contributed to morphologically similar but distantly related species. This in turn, has resulted in a history of erroneous taxonomies that have actually obscured rather than revealed the diversity within this group. A Bayesian phylogeny of the C.brevipalmatus group recovered at least 15 putative species-level lineages, at least seven of which are undescribed, and of which four are described herein. A total evidence morphological data set comprised of 16 normalized morphometric, 15 meristic, and seven categorical characters scored across 51 individuals was subjected to a multiple factor analysis (MFA) and an analysis of variance (ANOVA) to diagnose the putative species. These new species descriptions contribute to focusing attention to the unrealized diversity in upland tropical ecosystems, which due to climate change, are some of the most impearled ecosystems on the planet. Thus, it is paramount that taxonomies do not conflate species identities and underrepresent true diversity.


Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.
We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.


Functional morphology of undulatory pectoral fin locomotion in the stingray taeniura lymma (Chondrichthyes: dasyatidae)
Rajiform locomotion is a unique swimming style found in the batoid fishes (skates and rays) in which thrust is generated by undulatory waves passing down the enlarged pectoral fins. We examined the kinematic patterns of fin motion and the motor patterns of pectoral fin muscles driving the locomotor system in the blue-spot stingray Taeniura lymma. Our goals in this study were to determine overall patterns of fin motion and motor control during undulatory locomotion, to discover how these patterns change with swimming velocity and to correlate muscle function with kinematics and pectoral morphology. Kinematic data were recorded from five individuals over a range of swimming speeds from 22 to 55 cm s(-)(1) (0.9-3.0 DL s(-)(1), where DL is body disc length). Electromyographic (EMG) data were recorded from three individuals over a range of velocities (1.2-3.0 DL s(-)(1)) at seven locations (four dorsal, three ventral) along the pectoral fin. As swimming velocity increases, fin-beat frequency, wavespeed and stride length increase, number of waves and reduced frequency decrease and fin amplitude remains constant. There is variability among individuals in frequency and amplitude at a given speed. An inverse relationship was found in which a high fin-beat frequency is associated with a low fin amplitude and a low fin-beat frequency is associated with a high fin amplitude. The motor pattern of undulatory locomotion is alternate firing activity in the dorsal and ventral muscles as the wave moves along the fin from anterior to posterior. Fin muscles are active along the entire length of the fin except at the lowest speeds. As swimming velocity and fin-beat frequency increase, the time of activation of posterior muscles becomes earlier relative to the onset of activity in the anterior dorsal muscles. The duration of muscle activity is longer in the ventral muscles than in the dorsal muscles, indicating that they play a central role in the power stroke of the fin-beat cycle. The anterior muscles (dorsal and ventral) are active for a relatively longer part of the stride cycle than the posterior muscles. Both the anterior position and the large duty factor of the anterior muscles reflect the role of these muscles in initial wave generation. Synchronous recordings of kinematic data with EMG data reveal that the anterior dorsal and middle ventral muscles do mostly positive work, whereas the dorsal and ventral posterior muscles do negative work at most swimming speeds.


Capturing the pattern of physical activity and sedentary behavior: exposure variation analysis of accelerometer data.
Capturing the complex time pattern of physical activity (PA) and sedentary behavior (SB) using accelerometry remains a challenge. Research from occupational health suggests exposure variation analysis (EVA) could provide a meaningful tool. This paper (1) explains the application of EVA to accelerometer data, (2) demonstrates how EVA thresholds and derivatives could be chosen and used to examine adherence to PA and SB guidelines, and (3) explores the validity of EVA outputs. EVA outputs are compared with accelerometer data from 4 individuals (Study 1a and 1b) and 3 occupational groups (Study 2): seated workstation office workers (n = 8), standing workstation office workers (n = 8), and teachers (n = 8). Line graphs and related EVA graphs highlight the use of EVA derivatives for examining compliance with guidelines. EVA derivatives of occupational groups confirm no difference in bouts of activity but clear differences as expected in extended bouts of SB and brief bursts of activity, thus providing evidence of construct validity. EVA offers a unique and comprehensive generic method that is able, for the first time, to capture the time pattern (both frequency and intensity) of PA and SB, which can be tailored for both occupational and public health research.


Relationship between unusual hepatic acyl coenzyme A profiles and the pathogenesis of Reye syndrome.
This study examines the relationship between impaired fatty acid oxidation and the pathogenesis of Reye syndrome. We present a hypothesis proposing that many clinical signs of this childhood disease are caused by accumulation of unusual acyl CoA esters, precursors to deacylated metabolites found in the patients' blood and urine. A new method was developed to measure acyl CoA compounds in small human liver biopsy samples, offering several advantages over previous techniques. A major finding was an accumulation in Reye syndrome patients of short- and medium-chain acyl CoA intermediates of fatty acid and branched-chain amino acid oxidation. These metabolites included octanoyl, isovaleryl, butyryl, isobutyryl, propionyl, and methylmalonyl CoA esters. The findings were explained in a model of hepatic fatty acid oxidation involving three interrelated pathways: mitochondrial beta-oxidation, peroxisomal beta-oxidation, and omega-oxidation in the endoplasmic reticulum. The results suggest that pathogenesis in Reye syndrome stems from generalized mitochondrial damage resulting in accumulation of acyl CoA esters. High levels of these compounds lead to inhibition of mitochondrial pathways for ureogenesis, gluconeogenesis, and fatty acid oxidation. The inhibited pathways, in turn, could cause the hyperammonemia, hypoglycemia, and hypoketonemia observed in patients. The model also explains underlying biochemical differences between patients with Reye syndrome and medium-chain acyl CoA dehydrogenase deficiency, another disorder of fatty acid metabolism. Acetyl CoA levels, in the latter disease, were dramatically decreased, compared with both human controls and Reye syndrome patients.


A hybrid neural learning algorithm using evolutionary learning and derivative free local search method.
In this paper we investigate a hybrid model based on the Discrete Gradient method and an evolutionary strategy for determining the weights in a feed forward artificial neural network. Also we discuss different variants for hybrid models using the Discrete Gradient method and an evolutionary strategy for determining the weights in a feed forward artificial neural network. The Discrete Gradient method has the advantage of being able to jump over many local minima and find very deep local minima. However, earlier research has shown that a good starting point for the discrete gradient method can improve the quality of the solution point. Evolutionary algorithms are best suited for global optimisation problems. Nevertheless they are cursed with longer training times and often unsuitable for real world application. For optimisation problems such as weight optimisation for ANNs in real world applications the dimensions are large and time complexity is critical. Hence the idea of a hybrid model can be a suitable option. In this paper we propose different fusion strategies for hybrid models combining the evolutionary strategy with the discrete gradient method to obtain an optimal solution much quicker. Three different fusion strategies are discussed: a linear hybrid model, an iterative hybrid model and a restricted local search hybrid model. Comparative results on a range of standard datasets are provided for different fusion hybrid models.


[Aggression regulation in eating disorders: evidence for a brief body and movement oriented intervention].
Individuals with eating disorders tend to internalise their anger and aggression excessively. However, an evidence-based intervention, targeted on this persistent issue, was missing until now. Therefore, a body and movement oriented intervention was developed, which supports patients to reframe and redirect anger and aggression against the destructive influence of the eating disorder.
 AIM: To study the effectiveness of the aggression regulation intervention.
 METHOD: The intervention was tested in a first randomised controlled trial (RCT) in an outpatient setting and in a two-center RCT in a multidisciplinary day hospital setting. Coping with anger was measured by the Self-Expression and Control Scale (SECS). Eating disorder pathology was measured by the Eating Disorder Examination Questionnaire (EDE-Q).
 RESULTS: Both RCTs delivered first evidence for the brief body and movement oriented intervention to reduce excessive anger internalisation in individuals with eating disorders. Moreover, in the outpatient trial the eating disorder pathology was significantly more reduced in the intervention group compared to the control group.
 CONCLUSION: There is first evidence for the effectiveness of a body and movement oriented approach of reducing excessive anger internalisation in individuals with eating disorders.


HNPCC-Lynch syndrome and idiopathic inflammatory bowel disease. A hypothesis on sharing of genes.
Colon cancer occurring in patients with Lynch Syndrome and in Inflammatory Bowel Disease (IBD) share many features. There is some evidence to support the assumption that multiple genetic factors play an important role in the pathogenesis of idiopathic IBD and Lynch Syndrome. In our previous study, providing detailed medical, genetic and pathologic findings on 202 hereditary non polyposis colorectal cancer (HNPCC) relatives we found in the colonic mucosa features indicating an IBD though all the screened subjects of the family denied symptoms of IBD. Some studies have reported that the rate of undetected IBD ranges from 27 to 38%. Finally, a member of this family, considered not at risk for cancer by genetic analysis results, developed a clinically manifested IBD. The morphological aspects of the disease were not discussed in our previous study. It is possible that many members of this family inherit a major gene giving liability to the disease and are carriers of a subclinical form of IBD with a minimal morphological marker which becomes manifest in some members when other factors intervene. A possible genetic model linking the two diseases can be suggested: IBD needs two major genes for susceptibility (s) and clinical development (D). Both can be present in IBD and Lynch Syndrome, but in the latter a third gene plays a suppressor role on the development gene (D). In conclusion, we hypothesize that the IBD developing gene may be considered as protective against HNPCC, and this condition may result in a selective genetic advantage.


Definition of a population of CD4-8- T cells that express the alpha beta T-cell receptor and respond to interleukins 2, 3, and 4.
Whereas most T cells express surface CD4 or CD8 molecules, a minority lacks both. CD4-8- cells usually express the gamma delta T-cell receptor, but here we describe a population of CD4-8- T cells from the peripheral blood that express the alpha beta heterodimer. These cells have different surface antigens than gamma delta+ T cells, expressing CD5 but lacking CD16, and differ in function from gamma delta+ T cells. CD4-8- alpha beta+ cells lack non-major histocompatibility complex-restricted cytolytic function but can be induced to lyse their target cells after activation of their T-cell receptors. A peculiar characteristic of these cells is their responsiveness to interleukin 3. Since these cells have not altered their phenotype or function over a 12-month period in culture, they appear to be mature T cells. The results indicate that normal human peripheral blood contains two subsets of CD4-8- T cells, expressing either gamma delta or alpha beta receptors, that differ in function, phenotype, and growth control.


BAG3 promotes tumour cell proliferation by regulating EGFR signal transduction pathways in triple negative breast cancer.
Triple-negative breast cancer (TNBC), is a heterogeneous disease characterised by absence of expression of the estrogen receptor (ER), progesterone receptor (PR) and lack of amplification of human epidermal growth factor receptor 2 (HER2). TNBC patients can exhibit poor prognosis and high recurrence stages despite early response to chemotherapy treatment. In this study, we identified a pro-survival signalling protein BCL2- associated athanogene 3 (BAG3) to be highly expressed in a subset of TNBC cell lines and tumour tissues. High mRNA expression of BAG3 in TNBC patient cohorts significantly associated with a lower recurrence free survival. The epidermal growth factor receptor (EGFR) is amplified in TNBC and EGFR signalling dynamics impinge on cancer cell survival and disease recurrence. We found a correlation between BAG3 and EGFR expression in TNBC cell lines and determined that BAG3 can regulate tumour cell proliferation, migration and invasion in EGFR expressing TNBC cells lines. We identified an interaction between BAG3 and components of the EGFR signalling networks using mass spectrometry. Furthermore, BAG3 contributed to regulation of proliferation in TNBC cell lines by reducing the activation of components of the PI3K/AKT and FAK/Src signalling subnetworks. Finally, we found that combined targeting of BAG3 and EGFR was more effective than inhibition of EGFR with Cetuximab alone in TNBC cell lines. This study demonstrates a role for BAG3 in regulation of distinct EGFR modules and highlights the potential of BAG3 as a therapeutic target in TNBC.


Economics and the Transformation of the Mental Health System.
Mental illnesses provide a difficult set of challenges to American health and social institutions. Those challenges have been a continuous concern of David Mechanic's over the course of his career. In this article we trace the development of modern economic and organizational structures that drive the delivery of mental health care in the early part of the twenty-first century. We show how the nature of mental disorders themselves and the treatment for addressing those illnesses pose fundamental difficulties to health care organizational and financing structures. We analyze the factors that have caused the dramatic changes in how American society has addressed mental illnesses over the past fifty years. Specifically, we note the central influence that mainstream health, income support, and disability programs have had in shaping mental health care. We argue that the interaction of the unique features of mental illnesses and changes in mainstream health and social policy led mental health care to evolve so differently from general medical care.


Spontaneous Coronary Artery Dissection: Report of 3 Cases and Literature Review Hormonal, Autoimmune, Morphological Factors.
The number of cases with spontaneous coronary artery dissection (SCAD) is considered to be being underestimated because of a large amount of SCAD leading to sudden death without previous diagnosis. Besides, not only in clinics but also in autopsy practice, correct diagnosis of SCAD is important to prevent forensic malpractice.The article is intended to discuss the pathological findings through the forensic point of view for improving the malpractice expertise in scope of clinicians' timely antemortem diagnosis according to risk factors and in scope of forensic pathologists' the cause of death determination ability according to macroscopical and microscopical findings of the autopsy.In 3 cases reported, the main characteristics were the female sex, pregnancy history and a sudden death without any trauma. However, although there are many women giving birth or using oral contraceptives, only some of them are facing with SCAD. This suggests the possibility of some hereditary factors, whereas hereditary characteristics may be understood in many different ways like hormone-releasing regulating mechanisms as well as immunity, morphology, or any other mechanism. For instance, autoimmunity has been also a hereditary underlying factor for vessel injury considered in presented cases.


Mania and stroke: a systematic review.
Mania is a rare consequence of stroke and according to the sparse published information it is difficult to describe its demographic, clinical and prognostic characteristics. We performed a systematic review of all cases of mania and stroke to describe those characteristics. Studies were identified from comprehensive searches of electronic databases, reference lists of the studies collected and handbooks. Two authors independently assessed abstracts, and collected and extracted data. From 265 abstracts, 139 were potentially relevant. For the first analysis, which tries to answer the clinical question of the relationship between mania and stroke, 49 studies met the inclusion criteria and described 74 cases. For the second analysis, we looked for an explicit temporal and causal relationship between manic symptoms and stroke, and selected 32 studies describing 49 cases. In both analyses, the typical patient was male, without a personal or family history of psychiatric disorder, with at least one vascular risk factor, but without subcortical atrophy and had suffered a right cerebral infarct. The majority of patients (92%) presented elevated mood as the first symptom. The other frequent symptoms were an increased rate or amount of speech (71%), insomnia (69%) and agitation (63%). Post-stroke mania should be considered in any manic patient who presents concomitant neurological focal deficits and is older than expected for the onset of primary mania. The results of a systematic study of mania in acute stroke with subsequent follow-up and data from diffusion MR or perfusion CT in a multicenter study with a central database would be relevant.


Hepatitis C virus re-treatment in the era of direct-acting antivirals: projections in the USA.
The introduction of oral direct-acting antivirals (DAAs) has dramatically changed the landscape of HCV treatment. However, a small percentage of patients fail to achieve sustained virologic response (SVR). Understanding the number of people who fail on DAAs and require re-treatment is important for budget impact and disease burden projections. To quantify the number of HCV patients who fail to achieve SVR on oral DAAs (NS5A vs. non-NS5A) and require re-treatment. We used a mathematical model to simulate clinical management of HCV in the USA, which included the implementation of HCV screening, treatment, and disease progression. We simulated different waves of DAA treatment and used real-world data to extract SVR rates and market shares of available therapies. Our model projected that the number of people living without viraemia (i.e. cured) would increase from 0.70 million in 2014 to 1.78 million by 2020. Between 2014 and 2020, 1.50 million people would receive treatment with DAAs, of whom 124 000 (8.3%) are projected to fail to achieve SVR. Among those treatment failures, 66 600 (53.7%) patients would fail treatment with NS5A inhibitors and 69 600 (56.1%) would have cirrhosis. During the same period, 34 200 people would progress to decompensated cirrhosis and 27 300 would develop hepatocellular carcinoma after failing to achieve SVR. Even in the era of highly effective DAAs, a significant number of patients will fail to achieve SVR and will require re-treatment options. Timely and effective re-treatment is essential to prevent the long-term sequelae of HCV.


Does coffee consumption alter plasma lipoprotein(a) concentrations? A systematic review.
Coffee consumption alters plasma lipid and cholesterol concentrations, however, its effects on lipoprotein(a) (Lp(a)) have received little study. The aim of this PRISMA compliant systematic review was to examine the role of coffee on serum Lp(a). This study was prospectively registered (PROSPERO 2015:CRD42015032335). PubMed, Scopus, Web of Science and Cochrane Central were searched from inception until 9th January 2016 to detect trials and epidemiological studies investigating the impact of coffee on serum Lp(a) concentrations in humans. We identified six relevant publications describing nine experimental trials of various designs. There were a total of 640 participants across all studies and experimental groups. In short-term controlled studies, consumption of coffee, or coffee diterpenes was associated with either a reduction in serum Lp(a) of ≤11 mg/dL (6 trials, 275 participants), or no effect (2 trials, 56 participants). Conversely, one cross-sectional study with 309 participants showed serum Lp(a) was elevated in chronic consumers of boiled coffee who had a median Lp(a) of 13.0 mg/dL (range 0-130) compared with consumers of filtered coffee who had median Lp(a) 7.9 mg/dL (range 0-144). The effect of coffee on Lp(a) is complex and may follow a biphasic time-course. The type of coffee and the method of preparation appear to be important to determining the effect on Lp(a).


Cyclosporine use in miscellaneous clinical settings other than organ transplantations: is there any evidence for target levels?
Cyclosporine, once a corner stone in organ transplantation for decades, its use is expanded to treat several autoimmune conditions despite lacking profound evidence for its advantages. The aim of the retrospective study was to evaluate differences in trough blood levels of cyclosporine in some clinical indications other than transplantation. Blood cyclosporine trough levels determined by fluorescent polarization immunoassay (FPIA) TDx Abbott Diagnostics for TDM purpose in one year period was pooled from laboratory data-base. Total of 304 levels from 45 patients (26 males: 19 females) aged 2-62 years, who were on oral cyclosporine daily maintenance dose for conditions like systemic lupus erythematosus (SLE), atopic dermatitis (ADS), idiopathic thrombocytopenic purpura (ITP), dermatopolymyositis (DMS), and cardiomyopathy (CMP) were included. Cyclosporine trough was undetectable in 27 occasions, with maximum1213 microg/L, mode 74 ug/L, median 91 ug/L, mean 104.4+/-119.5 ug/L SD, and SE 6.85 respectively. Despite poorly de fi ned target, most clinicians desired trough concentrations not exceeding 100 microg/L, aiming to reduce toxicity. In this respect, nearly 35% were above this point, whereas 8% were below the detection limit of the method. There were no significant differences in concentrations within diagnostic groups except for ADS versus ITP (p<0.0039). Extended use of cyclosporine in several autoimmune diseases is promising. However, no evidence-based target levels in miscellaneous indications. Studies are needed to demonstrate overall benefits of CSA in relation to trough level and dynamic indicators (biomarkers) like expression of IL-2 and its receptor as targeted cell products in the future.


GODIVA2: interactive visualization of environmental data on the Web.
GODIVA2 is a dynamic website that provides visual access to several terabytes of physically distributed, four-dimensional environmental data. It allows users to explore large datasets interactively without the need to install new software or download and understand complex data. Through the use of open international standards, GODIVA2 maintains a high level of interoperability with third-party systems, allowing diverse datasets to be mutually compared. Scientists can use the system to search for features in large datasets and to diagnose the output from numerical simulations and data processing algorithms. Data providers around Europe have adopted GODIVA2 as an INSPIRE-compliant dynamic quick-view system for providing visual access to their data.


Perfusion MRI indexes variability in the functional brain effects of theta-burst transcranial magnetic stimulation.
Transcranial Magnetic Stimulation (TMS) is an important tool for testing causal relationships in cognitive neuroscience research. However, the efficacy of TMS can be variable across individuals and difficult to measure. This variability is especially a challenge when TMS is applied to regions without well-characterized behavioral effects, such as in studies using TMS on multi-modal areas in intrinsic networks. Here, we examined whether perfusion fMRI recordings of Cerebral Blood Flow (CBF), a quantitative measure sensitive to slow functional changes, reliably index variability in the effects of stimulation. Twenty-seven participants each completed four combined TMS-fMRI sessions during which both resting state Blood Oxygen Level Dependent (BOLD) and perfusion Arterial Spin Labeling (ASL) scans were recorded. In each session after the first baseline day, continuous theta-burst TMS (TBS) was applied to one of three locations: left dorsolateral prefrontal cortex (L dlPFC), left anterior insula/frontal operculum (L aI/fO), or left primary somatosensory cortex (L S1). The two frontal targets are components of intrinsic networks and L S1 was used as an experimental control. CBF changes were measured both before and after TMS on each day from a series of interleaved resting state and perfusion scans. Although TBS led to weak selective increases under the coil in CBF measurements across the group, individual subjects showed wide variability in their responses. TBS-induced changes in rCBF were related to TBS-induced changes in functional connectivity of the relevant intrinsic networks measured during separate resting-state BOLD scans. This relationship was selective: CBF and functional connectivity of these networks were not related before TBS or after TBS to the experimental control region (S1). Furthermore, subject groups with different directions of CBF change after TBS showed distinct modulations in the functional interactions of targeted networks. These results suggest that CBF is a marker of individual differences in the effects of TBS.


Control of the chewing louse Bovicola (Werneckiella) ocellatus in donkeys, using essential oils.
Infestations by lice can be a significant clinical and welfare issue in the management of large animals. The limited range of commercial pediculicides available and the development of resistance have led to the need to explore alternative louse management approaches. The results of in vitro and in vivo trials undertaken to control populations of the donkey chewing louse, Bovicola ocellatus (Piaget) (Phthiraptera: Trichodectidae) using the essential oils of tea tree (Melaleuca alternifolia) and lavender (Lavandula angustifolia) are reported here. Results of contact and vapour bioassays showed that 5% (v/v) tea tree and lavender oils resulted in > 80% louse mortality after 2 h of exposure. On farms, separate groups of 10 donkeys sprayed with 5% (v/v) tea tree and lavender oil as part of their usual grooming regime showed significant reductions in louse numbers compared with a control group (0.2% polysorbate 80 in water). These findings indicate that tea tree and lavender essential oils can provide clinically useful levels of control of B. ocellatus when used as part of a grooming routine and suggest that with further development could form the basis of an easy to apply and valuable component of a louse management programme for donkeys.


Resistance-promoting effects of ependymoma treatment revealed through genomic analysis of multiple recurrences in a single patient.
As in other brain tumors, multiple recurrences after complete resection and irradiation of supratentorial ependymoma are common and frequently result in patient death. This standard-of-care treatment was established in the pregenomic era without the ability to evaluate the effect that mutagenic therapies may exert on tumor evolution and in promoting resistance, recurrence, and death. We seized a rare opportunity to characterize treatment effects and the evolution of a single patient's ependymoma across four recurrences after different therapies. A combination of high-depth whole-genome and exome-based DNA sequencing of germline and tumor specimens, RNA sequencing of tumor specimens, and advanced computational analyses were used. Treatment with radiation and chemotherapies resulted in a substantial increase in mutational burden and diversification of the tumor subclonal architecture without eradication of the founding clone. Notable somatic alterations included a MEN1 driver, several epigenetic modifiers, and therapy-induced mutations that impacted multiple other cancer-relevant pathways and altered the neoantigen landscape. These genomic data provided new mechanistic insights into the genesis of ependymoma and pathways of resistance. They also revealed that radiation and chemotherapy were significant forces in shaping the increased subclonal complexity of each tumor recurrence while also failing to eradicate the founding clone. This raises the question of whether standard-of-care treatments have similar consequences in other patients with ependymoma and other types of brain tumors. If so, the perspective obtained by real-time genomic characterization of a tumor may be essential for making effective patient-specific and adaptive clinical decisions.


Persistent Encopresis, Enuresis, and Anxiety in a 7-Year-Old Girl.
Sonia is a 7-year-old old girl who was referred to the Developmental-Behavioral Pediatrics Clinic by the Pediatric Urology Clinic because of persistent wetting and soiling behaviors. Since age 3 years, she has had a history of encopresis (and wetting) for which she has seen gastroenterology and urology specialists. The mother reports that Sonia has accidents almost daily, and she is not upset when sitting in her urine or feces. She dislikes going into the bathroom or sitting on the toilet by herself. She participated in a behavior modification program associated with the pediatric urology clinic, which helps children learn healthy voiding habits and achieve continence.Sonia also has anxious behaviors. She bites her nails and chews on her hair or shirt. She is afraid of small spaces such as those between the bed and the wall and needs to have stuffed animals cover them. Other instances that trigger her anxious behaviors include loud noises, having a substitute teacher, being separated from her mother, and going to certain bathrooms or new places. She also has severe tantrums, which involve throwing and breaking objects, kicking, and hitting her head against doors.A cognitive behavioral therapy program was recommended to target anxiety symptoms, in addition to timed toileting after meals and polyethylene glycol. At a clinic visit several months later, symptoms of anxiety, encopresis, and enuresis persisted. Cognitive behavior therapy was continued and sertraline 25 mg was prescribed for anxiety. In addition, she was referred to a pediatrician who specializes in relaxation techniques and hypnotherapy.Sonia showed modest improvement with these interventions. There were fewer episodes of angry outbursts and a decrease in soiling and wetting, but at times, but she continued to have intermittent periods of wetting and soiling and fear of going to the bathroom by herself persisted.(This Challenging Case extends observations reviewed in a previous Challenging Case: J Dev Behav Pediatr 2010;531:513-515; DOI: 10.1097/DBP.0b013e3181e5a464.).


Human immunodeficiency virus type 1 viral protein R (Vpr) arrests cells in the G2 phase of the cell cycle by inhibiting p34cdc2 activity.
The Vpr accessory gene product of human immunodeficiency virus types 1 and 2 and simian immunodeficiency virus is believed to play a role in permitting entry of the viral core into the nucleus of nondividing cells. A second role for Vpr was recently suggested by Rogel et al. (M. E. Rogel, L. I. Wu, and M. Emerman, J. Virol. 69:882-888, 1995), who showed that Vpr prevents the establishment in vitro of chronically infected HIV producer cell lines, apparently by causing infected cells to arrest in the G2/M phase of the cell cycle. In cycling cells, progression from G2 to M phase is driven by activation of the p34cdc2/cyclin B complex, an event caused, in part, by dephosphorylation of two regulatory amino acids of p34cdc2 (Thr-14 and Tyr-15). We show here that Vpr arrests the cell cycle in G2 by preventing the activation of the p34cdc2/cyclin B complex. Vpr expression in cells caused p34cdc2 to remain in the phosphorylated, inactive state, p34cdc2/cyclin B complexes immunoprecipitated from cells expressing Vpr were almost completely inactive in a histone H1 kinase assay. Coexpression of a constitutively active mutant p34cdc2 molecule with Vpr relieved the G2 arrest. These findings strongly suggest that Vpr arrests cells in G2 by preventing the activation of the p34cdc2/cyclin B complex that is required for entry into M phase. In vivo, Vpr might, by preventing p34cdc2 activation, delay or prevent apoptosis of infected cells. This would increase the amount of virus each infected cell produced.


Analysis of SiO2 nanoparticles binding proteins in rat blood and brain homogenate.
A multitude of nanoparticles, such as titanium oxide (TiO2), zinc oxide, aluminum oxide, gold oxide, silver oxide, iron oxide, and silica oxide, are found in many chemical, cosmetic, pharmaceutical, and electronic products. Recently, SiO2 nanoparticles were shown to have an inert toxicity profile and no association with an irreversible toxicological change in animal models. Hence, exposure to SiO2 nanoparticles is on the increase. SiO2 nanoparticles are routinely used in numerous materials, from strengthening filler for concrete and other construction composites, to nontoxic platforms for biomedical application, such as drug delivery and theragnostics. On the other hand, recent in vitro experiments indicated that SiO2 nanoparticles were cytotoxic. Therefore, we investigated these nanoparticles to identify potentially toxic pathways by analyzing the adsorbed protein corona on the surface of SiO2 nanoparticles in the blood and brain of the rat. Four types of SiO2 nanoparticles were chosen for investigation, and the protein corona of each type was analyzed using liquid chromatography-tandem mass spectrometry technology. In total, 115 and 48 plasma proteins from the rat were identified as being bound to negatively charged 20 nm and 100 nm SiO2 nanoparticles, respectively, and 50 and 36 proteins were found for 20 nm and 100 nm arginine-coated SiO2 nanoparticles, respectively. Higher numbers of proteins were adsorbed onto the 20 nm sized SiO2 nanoparticles than onto the 100 nm sized nanoparticles regardless of charge. When proteins were compared between the two charges, higher numbers of proteins were found for arginine-coated positively charged SiO2 nanoparticles than for the negatively charged nanoparticles. The proteins identified as bound in the corona from SiO2 nanoparticles were further analyzed with ClueGO, a Cytoscape plugin used in protein ontology and for identifying biological interaction pathways. Proteins bound on the surface of nanoparticles may affect functional and conformational properties and distributions in complicated biological processes.


How does casualty load affect trauma care in urban bombing incidents? A quantitative analysis.
The aim of this modeling study was to examine how casualty load affects the level of trauma care in multiple casualty incidents and to define the surge capacity of the hospital trauma assets. The disaster plan of a U.S. Level I trauma center was translated into a computer model and challenged with simulated casualties based on 223 patients from 22 bombing incidents treated at an Israeli hospital. The model assigns providers and facilities to casualties and computes the level of care for each critical casualty from six variables that reflect the composition of the trauma team and access to facilities. The model predicts a sigmoid-shaped relationship between casualty load and the level of care, with the upper flat portion of the curve corresponding to the surge capacity of the trauma assets of the hospital. This capacity is 4.6 critical patients per hour using immediately available assets. A fully deployed disaster plan shifts the curve to the right, increasing the surge capacity to 7.1. Overtriage rates of 50% and 75% shift the curve to the left, decreasing the surge capacity to 3.8 and 2.7, respectively. This model defines the quantitative relationship between an increasing casualty load and gradual degradation of the level of trauma care in multiple casualty incidents, and defines the surge capacity of the hospital trauma assets as a rate of casualty arrival rather than a number of beds. The study demonstrates the value of dynamic computer modeling as an important tool in disaster planning.


Double knockouts reveal that protein tyrosine phosphatase 1B is a physiological target of calpain-1 in platelets.
Calpains are ubiquitous calcium-regulated cysteine proteases that have been implicated in cytoskeletal organization, cell proliferation, apoptosis, cell motility, and hemostasis. Gene targeting was used to evaluate the physiological function of mouse calpain-1 and establish that its inactivation results in reduced platelet aggregation and clot retraction potentially by causing dephosphorylation of platelet proteins. Here, we report that calpain-1 null (Capn1-/-) platelets accumulate protein tyrosine phosphatase 1B (PTP1B), which correlates with enhanced tyrosine phosphatase activity and dephosphorylation of multiple substrates. Treatment of Capn1-/- platelets with bis(N,N-dimethylhydroxamido)hydroxooxovanadate, an inhibitor of tyrosine phosphatases, corrected the aggregation defect and recovered impaired clot retraction. More importantly, platelet aggregation, clot retraction, and tyrosine dephosphorylation defects were rescued in the double knockout mice lacking both calpain-1 and PTP1B. Further evaluation of mutant mice by the ferric chloride-induced arterial injury model suggests that the Capn1-/- mice are relatively resistant to thrombosis in vivo. Together, our results demonstrate that PTP1B is a physiological target of calpain-1 and suggest that a similar mechanism may regulate calpain-1-mediated tyrosine dephosphorylation in other cells.


Sprint Assessment Using Machine Learning and a Wearable Accelerometer.
Field-based sprint performance assessments rely on metrics derived from a simple model of sprinting dynamics parameterized by 2 constants, v0 and τ, which indicate a sprinter's maximal theoretical velocity and the time it takes to approach v0, respectively. This study aims to automate sprint assessment by estimating v0 and τ using machine learning and accelerometer data. To this end, photocells recorded 10-m split times of 28 subjects for three 40-m sprints while wearing an accelerometer around the waist. Features extracted from the accelerometer data were used to train a classifier to identify the sprint start and regression models to estimate the sprint model parameters. Estimates of v0, τ, and 30-m sprint time (t30) were compared between the proposed method and a photocell method using root mean square error and Bland-Altman analysis. The root mean square error of the sprint start estimate was .22 seconds and ranged from .52 to .93 m/s for v0, .14 to .17 seconds for τ, and .23 to .34 seconds for t30. Model-derived sprint performance metrics from most regression models were significantly (P < .01) correlated with t30. Comparison of the proposed method and a physics-based method suggests pursuit of a combined approach because their strengths appear to complement each other.


Evidence of a reduced and modified mitochondrial protein import apparatus in microsporidian mitosomes.
Microsporidia are a group of highly adapted obligate intracellular parasites that are now recognized as close relatives of fungi. Their adaptation to parasitism has resulted in broad and severe reduction at (i) a genomic level by extensive gene loss, gene compaction, and gene shortening; (ii) a biochemical level with the loss of much basic metabolism; and (iii) a cellular level, resulting in lost or cryptic organelles. Consistent with this trend, the mitochondrion is severely reduced, lacking ATP synthesis and other typical functions and apparently containing only a fraction of the proteins of canonical mitochondria. We have investigated the mitochondrial protein import apparatus of this reduced organelle in the microsporidian Encephalitozoon cuniculi and find evidence of reduced and modified machinery. Notably, a putative outer membrane receptor, Tom70, is reduced in length but maintains a conserved structure chiefly consisting of tetratricopeptide repeats. When expressed in Saccharomyces cerevisiae, EcTom70 inserts with the correct topology into the outer membrane of mitochondria but is unable to complement the growth defects of Tom70-deficient yeast. We have scanned genomic data using hidden Markov models for other homologues of import machinery proteins and find evidence of severe reduction of this system.


MDMA does not alter responses to the Trier Social Stress Test in humans.
±3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a stimulant-psychedelic drug with unique social effects. It may dampen reactivity to negative social stimuli such as social threat and rejection. Perhaps because of these effects, MDMA has shown promise as a treatment for post-traumatic stress disorder (PTSD). However, the effect of single doses of MDMA on responses to an acute psychosocial stressor has not been tested. In this study, we sought to test the effects of MDMA on responses to stress in healthy adults using a public speaking task. We hypothesized that the drug would reduce responses to the stressful task. Volunteers (N = 39) were randomly assigned to receive placebo (N = 13), 0.5 mg/kg MDMA (N = 13), or 1.0 mg/kg MDMA (N = 13) during a stress and a no-stress session. Dependent measures included subjective reports of drug effects and emotional responses to the task, as well as salivary cortisol, heart rate, and blood pressure. The stress task produced its expected increase in physiological responses (cortisol, heart rate) and subjective ratings of stress in all three groups, and MDMA produced its expected subjective and physiological effects. MDMA alone increased ratings of subjective stress, heart rate, and saliva cortisol concentrations, but contrary to our hypothesis, it did not moderate responses to the Trier Social Stress Test. Despite its efficacy in PTSD and anxiety, MDMA did not reduce either the subjective or objective responses to stress in this controlled study. The conditions under which MDMA relieves responses to negative events or memories remain to be determined.


Lungworm disease in cats: ABCD guidelines on prevention and management.
Cardiopulmonary nematodes are emerging parasites of cats in Europe. A number of helminth parasites may be involved. The most prevalent lungworm in domestic cats is Aelurostrongylus abstrusus. Oslerus rostratus and Troglostrongylus species are found mainly in wild cats. The trichurid Capillaria aerophila has a low host specificity and is not uncommon in cats. Additionally the lung flukes Paragonimus species are reported in many species outside of Europe, including cats. Lungworm infections may be asymptomatic, or cause mild to severe respiratory signs, dependent on the worm species and burden; mixed infections are observed. Kittens can be vertically infected and may develop a more severe disease. Affected cats show a productive cough, mucopurulent nasal discharge, tachypnoea, dyspnoea and, in severe cases, respiratory failure and death. Early diagnosis and treatment greatly improves the prognosis. First-stage larvae can be easily detected in fresh faecal samples; the Baermann migration method is the enrichment technique of choice, but takes 24 h. Lungworm larvae can be found in tracheal swabs and bronchoalveolar lavage fluid, but with less sensitivity than in faeces. Molecular methods have been developed that exhibit high specificity and sensitivity, and allow diagnosis in the prepatent phase. Treatment options include fenbendazole paste, milbemycin oxime/praziquantel and various spot-on formulations. Severe cases should receive prompt medical care in an intensive care unit. Avoiding predation is at present the only preventive measure for pulmonary worms with indirect life cycles. C aerophila has zoonotic potential, causing severe pulmonary disease in humans. Some Paragonimus species are also of zoonotic concern.


Pocket tape measure for waist circumference: training medical students and residents on a simple assessment of body composition.
Metabolic syndrome, the clustering of hyperglycemia, hypertension and dyslipidemia, increases the risk of coronary heart disease. Abdominal obesity is an important cue for the clinician to consider metabolic syndrome. Measurement of waist circumference is a simple means of identifying abdominal obesity. The development and distribution of pocket tape measures to medical students, residents and attending physicians were initiated to enhance identification and treatment of metabolic syndrome. Distribution of the tape measures was added to a cardiovascular nutrition component in a 4th-y medical school curriculum. The nutrition component continued to include computer-based cases and pocket reference cards. Limited data suggest that the addition of pocket tape measures to the nutrition component of an ambulatory care clerkship may increase the percentage of medical students who use waist circumference to identify patients at risk for metabolic syndrome. It is anticipated that student use will increase with role modeling by residents and attending physicians.


The Shape of Things to Come in Speech Production: A Functional Magnetic Resonance Imaging Study of Visual Form Interference during Lexical Access.
Studies of context effects in speech production have shown that semantic feature overlap produces interference in naming of categorically related objects. In neuroimaging studies, this semantic interference effect is consistently associated with involvement of left superior and middle temporal gyri. However, at least part of this effect has recently been shown to be attributable to visual form similarity, as categorically related objects typically share visual features. This fMRI study examined interference produced by visual form overlap in the absence of a category relation in a picture-word interference paradigm. Both visually similar and visually dissimilar distractors led to increased BOLD responses in the left inferior frontal gyrus compared with the congruent condition. Naming pictures in context with a distractor word denoting an object visually similar in form slowed RTs compared with unrelated words and was associated with reduced activity in the left posterior middle temporal gyrus. This area is reliably observed in lexical level processing during language production tasks. No significant differential activity was observed in areas typically engaged by early perceptual or conceptual feature level processing or in areas proposed to be engaged by postlexical language processes, suggesting that visual form interference does not arise from uncertainty or confusion during perceptual or conceptual identification or after lexical processing. We conclude that visual form interference has a lexical locus, consistent with the predictions of competitive lexical selection models.


Comparison of nonintensified and intensified CCD detectors for laser-induced breakdown spectroscopy.
The performance and sensitivity of an intensified CCD array system and a nonintensified CCD array detector system are compared for laser-induced breakdown spectroscopy (LIBS). LIBS measurements were recorded in a calcium-based aerosol-seeded gas stream at ambient pressure. The signal-to-noise ratio based on the 393.37-nm calcium emission line was calculated as a function of detector delay with respect to the plasma-initiating laser pulse. Both ensemble-averaging and single-shot spectral analyses were performed. For all conditions, the intensified CCD system provided an enhanced signal-to-noise ratio compared with the nonintensified CCD system.


The role of fecundity and reproductive effort in defining life-history strategies of North American freshwater mussels.
Selection is expected to optimize reproductive investment resulting in characteristic trade-offs among traits such as brood size, offspring size, somatic maintenance, and lifespan; relative patterns of energy allocation to these functions are important in defining life-history strategies. Freshwater mussels are a diverse and imperiled component of aquatic ecosystems, but little is known about their life-history strategies, particularly patterns of fecundity and reproductive effort. Because mussels have an unusual life cycle in which larvae (glochidia) are obligate parasites on fishes, differences in host relationships are expected to influence patterns of reproductive output among species. I investigated fecundity and reproductive effort (RE) and their relationships to other life-history traits for a taxonomically broad cross section of North American mussel diversity. Annual fecundity of North American mussel species spans nearly four orders of magnitude, ranging from < 2000 to 10 million, but most species have considerably lower fecundity than previous generalizations, which portrayed the group as having uniformly high fecundity (e.g. > 200000). Estimates of RE also were highly variable, ranging among species from 0.06 to 25.4%. Median fecundity and RE differed among phylogenetic groups, but patterns for these two traits differed in several ways. For example, the tribe Anodontini had relatively low median fecundity but had the highest RE of any group. Within and among species, body size was a strong predictor of fecundity and explained a high percentage of variation in fecundity among species. Fecundity showed little relationship to other life-history traits including glochidial size, lifespan, brooding strategies, or host strategies. The only apparent trade-off evident among these traits was the extraordinarily high fecundity of Leptodea, Margaritifera, and Truncilla, which may come at a cost of greatly reduced glochidial size; there was no relationship between fecundity and glochidial size for the remaining 61 species in the dataset. In contrast to fecundity, RE showed evidence of a strong trade-off with lifespan, which was negatively related to RE. The raw number of glochidia produced may be determined primarily by physical and energetic constraints rather than selection for optimal output based on differences in host strategies or other traits. By integrating traits such as body size, glochidial size, and fecundity, RE appears more useful in defining mussel life-history strategies. Combined with trade-offs between other traits such as growth, lifespan, and age at maturity, differences in RE among species depict a broad continuum of divergent strategies ranging from strongly r-selected species (e.g. tribe Anodontini and some Lampsilini) to K-selected species (e.g. tribes Pleurobemini and Quadrulini; family Margaritiferidae). Future studies of reproductive effort in an environmental and life-history context will be useful for understanding the explosive radiation of this group of animals in North America and will aid in the development of effective conservation strategies.


Measuring use of positive thinking skills: psychometric testing of a new scale.
Positive thinking interventions improve adaptive functioning and quality of life in many populations. However, no direct measure of positive thinking skills taught during intervention exists. This psychometric study of a convenience sample of 109 autism spectrum disorder (ASD) caregivers examined a new eight-item Positive Thinking Skills Scale (PTSS), which measures the frequency of use of positive thinking skills. The PTSS was found to be internally consistent (α = .90). Construct validity was supported by significant correlations (p < .01) with positive cognitions (r = .53), resourcefulness (r = .63), depression (r = -.45), and general well-being (r = .40). The findings support use of the PTSS as a potential indicator of intervention fidelity among ASD caregivers. However, because it is not specific for ASD caregivers, the PTSS has the potential for wider usage in other populations for whom the identification of specific positive thinking skills could provide direction for future intervention.


Male circumcision as a measure to control HIV infection and other sexually transmitted diseases.
There is growing epidemiological evidence from sub-Saharan Africa that male circumcision reduces the risk of HIV acquisition. We review the recent evidence of the protective effect on HIV and other sexually transmitted diseases, including discussion of possible biological mechanisms and highlighting the limitations of the observational studies on which these findings are based. We conclude by discussing the public health implications of these findings, including issues such as safety, acceptability, feasibility and cost-effectiveness of promoting male circumcision in African populations.


Delivery of the HIV-1 Tat protein to dendritic cells by the CyaA vector induces specific Th1 responses and high affinity neutralizing antibodies in non human primates.
The human immunodeficiency virus type 1 (HIV-1) Tat is a key protein playing a major role in the infectivity of the virus. Thus, HIV-Tat based vaccines have been proposed as an attractive option to treat AIDS. Recently, we have shown that the recombinant detoxified adenylate cyclase (CyaA) from Bordetella pertussis carrying HIV-Tat (CyaA-E5-Tat), targets dendritic cells (DCs) and induces specific Th1 polarized and neutralizing antibody responses in mice. To further explore the potentialities of this prototype vaccine for human use, we analyzed the CyaA-E5-Tat induced antibody responses in non-human primates and established the biological characteristics of these antibodies. African Green Monkeys (AGM) were immunized with CyaA-E5-Tat in the presence or in the absence of alum adjuvant. First, we showed that the anti-CyaA antibodies induced by such immunization does not interfere with the binding of CyaA-E5-Tat to its receptor at the DC surface, the alphaMbeta2 integrin. Monkeys immunized with CyaA-E5-Tat, with or without alum, produced anti-Tat antibodies that mainly recognized the N-terminal domain of the Tat protein. Importantly, all sera obtained after three immunizations displayed the capacity to bind to Tat and neutralize its transactivating function in vitro. Finally, in the absence of alum, CyaA-E5-Tat, induced Th1 Tat specific T cell responses. These findings reveal that CyaA-E5-Tat is efficiently delivered in non-human primates and had a significant impact on the generation of neutralizing anti-Tat antibodies. These observations are, thus, encouraging for the use of the CyaA vector in human and also suggest that CyaA-E5-Tat might be a useful tool to decipher the biological characteristic of such antibodies.


Changes in glucose and cholesterol levels in patients with schizophrenia treated with typical or atypical antipsychotics.
The association of hyperglycemia and hypercholesterolemia with use of atypical antipsychotics has been documented in case reports and uncontrolled studies. The authors' goal was to assess the effects of clozapine, olanzapine, risperidone, and haloperidol on glucose and cholesterol levels in hospitalized patients with schizophrenia or schizoaffective disorder during a randomized double-blind 14-week trial. One hundred fifty-seven patients with schizophrenia or schizoaffective disorder who were inpatients at four hospitals were originally included in the study. The 14-week trial consisted of an 8-week fixed-dose period and a 6-week variable-dose period. Planned assessments included fasting glucose and cholesterol, which were collected at baseline and at the end of the 8-week period and the following 6-week period. One hundred eight of the 157 patients provided blood samples at baseline and at least at one point after random assignment to clozapine, olanzapine, risperidone, or haloperidol during the treatment trial. Seven of these patients had diabetes; their glucose levels were >125 mg/dl at baseline. Data from 101 patients were used for statistical analyses. During the initial 8-week period there was an overall significant increase in mean glucose levels. There were significant increases in glucose levels at the end of the 8-week fixed-dose period for patients given clozapine (N=27) and those given haloperidol (N=25). The olanzapine group showed a significant increase of glucose levels at the end of the 6-week variable-dose period (N=22). Fourteen of the 101 patients developed abnormal glucose levels (>125 mg/dl) during the trial (six with clozapine, four with olanzapine, three with risperidone, and one with haloperidol). Cholesterol levels were increased at the end of the 8-week fixed-dose period for the patients given clozapine (N=27) and those given olanzapine (N=26); cholesterol levels were also increased at the end of the 6-week variable-dose period for patients given olanzapine (N=22). In this prospective randomized trial, clozapine, olanzapine, and haloperidol were associated with an increase of plasma glucose level, and clozapine and olanzapine were associated with an increase in cholesterol levels. The mean changes in glucose and cholesterol levels remained within clinically normal ranges, but approximately 14% of the patients developed abnormally high glucose levels during the course of their participation in the study.


Community health workers to improve adherence to anti-seizure medication in rural South Africa: Is it cost-effective?
Epilepsy is a common, chronic neurological disorder that disproportionately affects individuals living in low- and middle-income countries (LMICs), where the treatment gap remains high and adherence to medication remains low. Community health workers (CHWs) have been shown to be effective at improving adherence to chronic medications, yet no study assessing the costs of CHWs in epilepsy management has been reported. Using a Markov model with age- and sex-varying transition probabilities, we determined whether deploying CHWs to improve epilepsy treatment adherence in rural South Africa would be cost-effective. Data were derived using published studies from rural South Africa. Official statistics and international disability weights provided cost and health state values, respectively, and health gains were measured using quality adjusted life years (QALYs). The intervention was estimated at International Dollars ($) 123 250 per annum per sub-district community and cost $1494 and $1857 per QALY gained for males and females, respectively. Assuming a costlier intervention and lower effectiveness, cost per QALY was still less than South Africa's Gross Domestic Product per capita of $13 215, the cost-effectiveness threshold applied. CHWs would be cost-effective and the intervention dominated even when costs and effects of the intervention were unfavorably varied. Health system re-engineering currently underway in South Africa identifies CHWs as vital links in primary health care, thereby ensuring sustainability of the intervention. Further research on understanding local health state utility values and cost-effectiveness thresholds could further inform the current model, and undertaking the proposed intervention would provide better estimates of its efficacy on reducing the epilepsy treatment gap in rural South Africa.


Global guideline for the diagnosis and management of rare yeast infections: an initiative of the ECMM in cooperation with ISHAM and ASM.
Uncommon, or rare, yeast infections are on the rise given increasing numbers of patients who are immunocompromised or seriously ill. The major pathogens include those of the genera Geotrichum, Saprochaete, Magnusiomyces, and Trichosporon (ie, basidiomycetes) and Kodamaea, Malassezia, Pseudozyma (ie, now Moesziomyces or Dirkmeia), Rhodotorula, Saccharomyces, and Sporobolomyces (ie, ascomycetes). A considered approach to the complex, multidisciplinary management of infections that are caused by these pathogens is essential to optimising patient outcomes; however, management guidelines are either region-specific or require updating. In alignment with the One World-One Guideline initiative to incorporate regional differences, experts from diverse geographical regions analysed publications describing the epidemiology and management of the previously mentioned rare yeasts. This guideline summarises the consensus recommendations with regards to the diagnostic and therapeutic options for patients with these rare yeast infections, with the intent of providing practical assistance in clinical decision making. Because there is less clinical experience of patients with rare yeast infections and studies on these patients were not randomised, nor were groups compared, most recommendations are not robust in their validation but represent insights by use of expert opinions and in-vitro susceptibility results. In this Review, we report the key features of the epidemiology, diagnosis, antifungal susceptibility, and treatment outcomes of patients with Geotrichum, Saprochaete, Magnusiomyces, and Trichosporon spp infections.


Association of diastolic blood pressure with cardiovascular events in older people varies upon cardiovascular history.
In older age, a low DBP has been associated with increased risk of cardiovascular events, especially in frail older people. We tested the hypothesis that low DBP is associated with a high risk of cardiovascular events in people with a previous history of cardiovascular disease, as a proxy of vascular impairment. We included 5804 participants (mean age 75 years) from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) who as part of the trial were intensively monitored for an average period of 3.2 years. DBP was categorized in low (<70 mmHg), normal (70-90 mmHg) or high (>90 mmHg). Cox proportional hazards analyses were used to estimate hazard ratio with 95% confidence intervals (CI); analyses were stratified for cardiovascular history. Participants with low DBP had a 1.24-fold (1.04; 1.49) increased risk of cardiovascular events compared with those with normal DBP. After further adjusting for cardiovascular factors, this association attenuated to 1.05 (0.86; 1.28). A previous history of cardiovascular disease significantly modified the relation between DBP and risk of cardiovascular events (P-interaction 0.042). In participants without a history of cardiovascular disease, DBP was marginally significantly associated with an increased event risk (hazard ratio (95% CI) per 10 mmHg increase in DBP 1.08 (0.99; 1.18), P value = 0.07), whereas in participants with a history of cardiovascular disease, higher DBP was associated with a decreased risk of cardiovascular events (hazard ratio (95% CI) per 10 mmHg increase in DBP 0.92 (0.85; 0.99, P value = 0.018). These risk estimates were independent of potential confounders, including classical cardiovascular risk factors. The association of DBP with cardiovascular events in older people varies upon their previous history, showing that in participants with preexisting cardiovascular diseases, a higher DBP associates with a decreased risk of future cardiovascular events.


The safety of intrauterine devices among young women: a systematic review.
The objective was to determine the association between use of intrauterine devices (IUDs) by young women and risk of adverse outcomes. We searched Pubmed, CINAHL, Embase, Popline and the Cochrane Library for articles from inception of database through December 2015. For outcomes specific to IUD use (IUD expulsion and perforation), we examined effect measures for IUD users generally aged 25 years or younger compared with older IUD users. For outcomes of pregnancy, infection, pelvic inflammatory disease (PID), and heavy bleeding or anemia, we examined young IUD users compared with young users of other contraceptive methods or no method. We identified 3169 articles of which 16 articles from 14 studies met our inclusion criteria. Six studies (Level II-2, good to poor) reported increased risk of expulsion among younger age groups compared with older age groups using copper-bearing (Cu-) IUDs. Two studies (Level II-2, fair) examined risks of expulsion among younger compared with older women using levonorgestrel-releasing (LNG-) IUDs; one reported no difference in expulsion, while the other reported increased odds for younger women. Four studies (Level II-2, good to poor) examined risk of expulsion among Cu- and LNG-IUD users combined and reported no significant differences between younger and older women. For perforation, four studies (Level II-2, fair to poor) found very low perforation rates (range, 0%-0.1%), with no significant differences between younger and older women. Pregnancies were generally rare among young IUD users in nine studies (Level I to II-2, fair to poor), and no differences were reported for young IUD users compared with young combined oral contraceptive (COC) or etonogestrel (ENG) implant users. PID was rare among young IUD users; one study reported no cases among COC or IUD users, and one reported no difference in PID among LNG-IUD users compared with ENG implant users from nationwide insurance claims data (Level I to II-2, fair). One study reported decreased odds of bleeding with LNG-IUD compared with COC use among young women, while one study of young women reported decreased odds of removal for bleeding with LNG-IUD compared with ENG implant (Level I to II-2, fair). Overall evidence suggests that the risk of adverse outcomes related to pregnancy, perforation, infection, heavy bleeding or removals for bleeding among young IUD users is low and may not be clinically meaningful. However, the risk of expulsion, especially for Cu-IUDs, is higher for younger women compared with older women. If IUD expulsion occurs, a young woman is exposed to an increased risk of unintended pregnancy if replacement contraception is not initiated. IUDs are safe for young women and provide highly effective reversible contraception.


Ultrasound and shockwave therapy for acute fractures in adults.
The morbidity and socioeconomic costs of fractures are considerable. The length of time to healing is an important factor in determining a patient's recovery after a fracture. Ultrasound may have a therapeutic role in reducing the time to union after fracture. To assess the effects of low intensity ultrasound (LIPUS), high intensity focused ultrasound (HIFUS) and extracorporeal shockwave therapies (ECSW) as part of the treatment of acute fractures in adults. We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (December 2011), the Cochrane Central Register of Controlled Trials (in The Cochrane Library 2011, Issue 4), MEDLINE (1950 to November Week 3 2011), EMBASE (1980 to 2011 Week 49), trial registers and reference lists of articles. Randomised controlled trials evaluating ultrasound treatment in the management of acute fractures in adults. Studies including participants over 18 years of age with acute fractures, reporting functional outcomes, time to union, non-union, secondary procedures such as for fixation or delayed or non-union, adverse effects, pain, costs or patient adherence were included. Two authors independently extracted data from the included studies. Treatment effects were assessed using mean differences or risk ratios and, where there was substantial heterogeneity, pooled using a random-effects model. Results from 'worst case' analyses, which gave more conservative estimates of treatment effects for time to fracture union, are reported in preference to those from 'as reported' analyses. Twelve studies, involving 622 participants with 648 fractures, were included. Eight studies were randomised placebo-controlled trials, two studies were randomised controlled trials without placebo controls, one study was a quasi-randomised placebo controlled trial and the remaining study was a quasi-randomised controlled trial without placebo control. Eleven trials tested LIPUS and one trial tested ECSW. Four trials included participants with conservatively treated upper limb complete fractures and six trials included participants with lower limb complete fractures; these were surgically fixed in four trials. The remaining two trials reported results for conservatively treated tibial stress fractures.Very limited data from two complete fracture studies showed no difference between ultrasound and placebo control in functional outcome. Pooled estimates from two studies found LIPUS did not significantly affect the time to return to training or duty in soldiers or midshipmen with stress fractures (mean difference -8.55 days, 95% CI -22.71 to 5.61).Based on a 'worst case' analysis, which adjusted for incomplete data, pooled results from eight heterogeneous studies showed no statistically significant reduction in time to union of complete fractures treated with LIPUS (standardised mean difference -0.47, 95% CI -1.14 to 0.20). This result could include a clinically important benefit or harm, and should be seen in the context of the highly significant statistical heterogeneity (I² = 90%). This heterogeneity was not explained by the a priori subgroup analyses (upper limb versus lower limb fracture, smoking status). An additional subgroup analysis comparing conservatively and operatively treated fractures raised the possibility that LIPUS may be effective in reducing healing time in conservatively managed fractures, but the test for subgroup differences did not confirm a significant difference between the subgroups.Pooled results from eight trials reporting proportion of delayed union or non-union showed no significant difference between LIPUS and control. Adverse effects directly associated with LIPUS and associated devices were found to be few and minor, and compliance with treatment was generally good. One study reporting on pain scores found no difference between groups at eight weeks.One quasi-randomised study (59 fractures) found no significant difference between ECSW and no-placebo control groups in non-union at 12 months (risk ratio 0.56, 95% CI 0.15 to 2.01). There was a clinically small but statistically significant difference in the visual analogue scores for pain in favour of ECSW at three month follow-up. The only reported complication was infection, with no significant difference between the two groups. While a potential benefit of ultrasound for the treatment of acute fractures in adults cannot be ruled out, the currently available evidence from a set of clinically heterogeneous trials is insufficient to support the routine use of this intervention in clinical practice. Future trials should record functional outcomes and follow-up all trial participants.


Inhibitory effect of Curcuma purpurascens BI. rhizome on HT-29 colon cancer cells through mitochondrial-dependent apoptosis pathway.
Curcuma purpurascens BI. (Zingiberaceae) commonly known as 'Koneng Tinggang' and 'Temu Tis' is a Javanese medicinal plant which has been used for numerous ailments and diseases in rural Javanese communities. In the present study, the apoptogenic activity of dichloromethane extract of Curcuma purpurascens BI. rhizome (DECPR) was investigated against HT-29 human colon cancer cells. Acute toxicity study of DECPR was performed in Sprague-Dawley rats. Compounds of DECPR were analyzed by the gas chromatography-mass spectrometry-time of flight (GC-MS-TOF) analysis. Cytotoxic effect of DECPR on HT-29 cells was analyzed by MTT and lactate dehydrogenase (LDH) assays. Effects of DECPR on reactive oxygen species (ROS) formation and mitochondrial-initiated events were investigated using a high content screening system. The activities of the caspases were also measured using a fluorometric assay. The quantitative PCR analysis was carried out to examine the gene expression of Bax, Bcl-2 and Bcl-xl proteins. The in vivo acute toxicity study of DECPR on rats showed the safety of this extract at the highest dose of 5 g/kg. The GC-MS-TOF analysis of DECPR detected turmerone as the major compound in dichloromethane extract. IC50 value of DECPR towards HT-29 cells after 24 h treatment was found to be 7.79 ± 0.54 μg/mL. In addition, DECPR induced LDH release and ROS generation in HT-29 cells through a mechanism involving nuclear fragmentation and cytoskeletal rearrangement. The mitochondrial-initiated events, including collapse in mitochondrial membrane potential and cytochrome c leakage was also triggered by DECPR treatment. Initiator caspase-9 and executioner caspase-3 was dose-dependently activated by DECPR. The quantitative PCR analysis on the mRNA expression of Bcl-2 family of proteins showed a significant up-regulation of Bax associated with down-regulation in Bcl-2 and Bcl-xl mRNA expression. The findings presented in the current study showed that DECP suppressed the proliferation of HT-29 colon cancer cells and triggered the induction of apoptosis through mitochondrial-dependent pathway.


Trichomonas vaginalis is dependent on uptake and degradation of human low density lipoproteins.
Human plasma low density lipoprotein uptake by the urogenital pathogen, Trichomonas vaginalis, was examined. Rapid binding and internalization of 125I-labeled low density lipoproteins by live T. vaginalis was observed at 37 degrees C. Data showing parasite degradation of the internalized apoproteins and lipid accumulation following low density lipoprotein uptake was obtained. Acquisition of low density lipoproteins was by a trichomonad surface protein that possessed a molecular weight of greater than 250,000. The receptor is specific for apolipoprotein CIII, a component of high, low, and very low density lipoprotein subfractions. Low density lipoproteins in a semi-defined medium of trypticase, nucleic acid precursors, vitamins, and maltose promoted T. vaginalis growth and multiplication at rates and levels equal to the yeast extract-trypticase-serum complex medium routinely used for culture of trichomonads. HeLa cell membranes as a source of lipids were unable to sustain T. vaginalis organisms. These data demonstrate host lipoprotein internalization by T. vaginalis via a specific uptake mechanism.


Flexible/Bendable Acoustofluidics Based on Thin-Film Surface Acoustic Waves on Thin Aluminum Sheets.
In this paper, we explore the acoustofluidic performance of zinc oxide (ZnO) thin-film surface acoustic wave (SAW) devices fabricated on flexible and bendable thin aluminum (Al) foils/sheets with thicknesses from 50 to 1500 μm. Directional transport of fluids along these flexible/bendable surfaces offers potential applications for the next generation of microfluidic systems, wearable biosensors and soft robotic control. Theoretical calculations indicate that bending under strain levels up to 3000 με causes a small frequency shift and amplitude change (<0.3%) without degrading the acoustofluidic performance. Through systematic investigation of the effects of the Al sheet thickness on the microfluidic actuation performance for the bent devices, we identify the optimum thickness range to both maintain efficient microfluidic actuation and enable significant deformation of the substrate, providing a guide to design such devices. Finally, we demonstrate efficient liquid transportation across a wide range of substrate geometries including inclined, curved, vertical, inverted, and lateral positioned surfaces using a 200 μm thick Al sheet SAW device.


Baseline and follow-up laboratory monitoring of cardiovascular medications.
Laboratory monitoring of medications is typically used to establish safety prior to drug initiation and to detect drug-related injury following initiation. It is unclear whether black box warnings (BBWs) as well as evidence- and consensus-based clinical guidelines increase the likelihood of appropriate monitoring. To determine the proportion of patients newly initiated on selected cardiovascular medications with baseline assessment and follow-up laboratory monitoring and compare the prevalence of laboratory testing for drugs with and without BBWs and guidelines. This cross-sectional study included patients aged 18 years or older from a large multispecialty group practice who were prescribed a cardiovascular medication (angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, amiodarone, digoxin, lipid-lowering agents, diuretics, and potassium supplements) between January 1 and July 31, 2008. The primary outcome measure was laboratory test ordering for baseline assessment and follow-up monitoring of newly initiated cardiovascular medications. The number of new users of each study drug ranged from 49 to 1757 during the study period. Baseline laboratory test ordering across study drugs ranged from 37.4% to 94.8%, and follow-up laboratory test ordering ranged from 20.0% to 77.2%. Laboratory tests for drugs with baseline laboratory assessment recommendations in BBWs were more commonly ordered than for drugs without BBWs (86.4% vs 78.0%, p < 0.001). Drugs with follow-up monitoring recommendations in clinical guidelines had a lower prevalence of monitoring (33.1% vs 50.7%, p < 0.001). Baseline assessment of cardiovascular medication monitoring is variable. Quality measurement of adherence to BBW recommendations may improve monitoring.


Extracellular Uridine Triphosphate and Adenosine Triphosphate Attenuate Endothelial Inflammation through miR-22-Mediated ICAM-1 Inhibition.
Adenosine and uridine triphosphate (ATP and UTP) can act as extracellular signalling molecules, playing important roles in vascular biology and disease. ATP and UTP acting via the P2Y2-receptor have, for example, been shown to regulate endothelial dilatation, inflammation and angiogenesis. MicroRNAs (miRNAs), a class of regulatory, short, non-coding RNAs, have been shown to be important regulators of these biological processes. In this study, we used RNA deep-sequencing to explore changes in miRNA expression in the human microvascular endothelial cell line HMEC-1 upon UTP treatment. The expression of miR-22, which we have previously shown to target ICAM-1 mRNA in HMEC-1, increased significantly after stimulation. Up-regulation of miR-22 and down-regulation of cell surface ICAM-1 were confirmed with qRT-PCR and flow cytometry, respectively. siRNA-mediated knockdown of the P2Y2-receptor abolished the effect of UTP on miR-22 transcription. Leukocyte adhesion was significantly inhibited in HMEC-1 following miR-22 overexpression and treatment with UTP/ATP. In conclusion, extracellular UTP and ATP can attenuate ICAM-1 expression and leukocyte adhesion in endothelial cells through miR-22.


A model for play-based intervention for children with ADHD.
The importance of play in the social development of children is undisputed. Even though children with attention-deficit hyperactivity disorder (ADHD) experience serious social problems, there is limited research on their play. By integrating literature on ADHD with literature on play, we can postulate how play is influenced by the characteristics of ADHD. These postulations enabled us to propose a theoretical model (proposed model) to depict the interactive process between the characteristics of ADHD and factors that promote play. This paper presents the revised model and principles for intervention based on the results of a study investigating the play of children with ADHD (reported elsewhere). We tested the proposed model in a study comparing two groups of children (n = 350) between the ages of 5 and 11 years. One group consisted of children diagnosed with ADHD (n = 112) paired with playmates (n = 112) who were typically developing; the control group consisted of typically developing children paired with typically developing playmates (n = 126). The Test of Playfulness was administered, and the model was revised in line with the findings. The findings suggest difficulties in the social play and lack of interpersonal empathy in the play of children with ADHD. We draw on the revised model to propose preliminary principles for play-based interventions for children with ADHD. The principles emphasise the importance of capturing the motivation of children with ADHD, counteracting the effects of lack of interpersonal empathy, and considerations for including playmates in the intervention process.


Structural and mutational analysis of functional differentiation between synaptotagmins-1 and -7.
Synaptotagmins are known to mediate diverse forms of Ca2+-triggered exocytosis through their C2 domains, but the principles underlying functional differentiation among them are unclear. Synaptotagmin-1 functions as a Ca2+ sensor in neurotransmitter release at central nervous system synapses, but synaptotagmin-7 does not, and yet both isoforms act as Ca2+ sensors in chromaffin cells. To shed light into this apparent paradox, we have performed rescue experiments in neurons from synaptotagmin-1 knockout mice using a chimera that contains the synaptotagmin-1 sequence with its C2B domain replaced by the synaptotagmin-7 C2B domain (Syt1/7). Rescue was not achieved either with the WT Syt1/7 chimera or with nine mutants where residues that are distinct in synaptotagmin-7 were restored to those present in synaptotagmin-1. To investigate whether these results arise because of unique conformational features of the synaptotagmin-7 C2B domain, we determined its crystal structure at 1.44 A resolution. The synaptotagmin-7 C2B domain structure is very similar to that of the synaptotagmin-1 C2B domain and contains three Ca2+-binding sites. Two of the Ca2+-binding sites of the synaptotagmin-7 C2B domain are also present in the synaptotagmin-1 C2B domain and have analogous ligands to those determined for the latter by NMR spectroscopy, suggesting that a discrepancy observed in a crystal structure of the synaptotagmin-1 C2B domain arose from crystal contacts. Overall, our results suggest that functional differentiation in synaptotagmins arises in part from subtle sequence changes that yield dramatic functional differences.


Continuous renal replacement therapy versus intermittent hemodialysis in intensive care patients: impact on mortality and renal recovery.
The best renal replacement therapy (RRT) modality remains controversial. We compared mortality and short- and long-term renal recovery between patients treated with continuous RRT and intermittent hemodialysis. Patients of the prospective observational multicenter cohort database OUTCOMEREA™ were included if they underwent at least one RRT session between 2004 and 2014. Differences in patients' baseline and daily characteristics between treatment groups were taken into account by using a marginal structural Cox model, allowing one to substantially reduce the bias resulting from confounding factors in observational longitudinal data analysis. The composite primary endpoint was 30-day mortality and dialysis dependency. Among 1360 included patients with RRT, 544 (40.0 %) and 816 (60.0 %) were initially treated by continuous RRT and intermittent hemodialysis, respectively. At day 30, 39.6 % patients were dead. Among survivors, 23.8 % still required RRT. There was no difference between groups for the primary endpoint in global population (HR 1.00, 95 % CI 0.77-1.29; p = 0.97). In patients with higher weight gain at RRT initiation, mortality and dialysis dependency were significantly lower with continuous RRT (HR 0.54, 95 % CI 0.29-0.99; p = 0.05). Conversely, this technique appeared to be deleterious in patients without shock (HR 2.24, 95 % CI 1.24-4.04; p = 0.01). Six-month mortality and persistent renal dysfunction were not influenced by the RRT modality in patients with dialysis dependence at ICU discharge. Continuous RRT did not appear to improve 30-day and 6-month patient outcomes. It seems beneficial for patients with fluid overload, but might be deleterious in the absence of hemodynamic failure.


A stepwise approach toward closed-loop blood glucose control for intensive care unit patients: results from a feasibility study in type 1 diabetic subjects using vascular microdialysis with infrared spectrometry and a model predictive control algorithm.
Glycemic control can reduce the mortality and morbidity of intensive care patients. The CLINICIP (closed-loop insulin infusion for critically ill patients) project aimed to develop a closed-loop control system for this patient group. Following a stepwise approach, we combined three independently tested subparts to form a semiautomatic closed-loop system and evaluated it with respect to safety and performance aspects by testing it in subjects with type 1 diabetes mellitus (T1DM) in a first feasibility trial. Vascular microdialysis, a multianalyte infrared spectroscopic glucose sensor, and a standard insulin infusion pump controlled by an adaptive model predictive control (MPC) algorithm were combined to form a closed-loop device, which was evaluated in four T1DM subjects during 30-hour feasibility studies. The aim was to maintain blood glucose concentration in the target range between 80 and 110 mg/dl. Mean plasma glucose concentration was 110.5 ± 29.7 mg/dl. The MPC managed to establish normoglycemia within 105 ± 78 minutes after trial start and managed to maintain glucose concentration within the target range for 47% of the time. The hyperglycemic index averaged to 11.9 ± 5.3 mg/dl. Data of the feasibility trial illustrate the device being effective in controlling glycemia in T1DM subjects. However, the monitoring part of the loop must be improved with respect to accuracy and precision before testing the system in the target population.


High-resolution genomic and expression analyses of copy number alterations in HER2-amplified breast cancer.
HER2 gene amplification and protein overexpression (HER2+) define a clinically challenging subgroup of breast cancer with variable prognosis and response to therapy. Although gene expression profiling has identified an ERBB2 molecular subtype of breast cancer, it is clear that HER2+ tumors reside in all molecular subtypes and represent a genomically and biologically heterogeneous group, needed to be further characterized in large sample sets. Genome-wide DNA copy number profiling, using bacterial artificial chromosome (BAC) array comparative genomic hybridization (aCGH), and global gene expression profiling were performed on 200 and 87 HER2+ tumors, respectively. Genomic Identification of Significant Targets in Cancer (GISTIC) was used to identify significant copy number alterations (CNAs) in HER2+ tumors, which were related to a set of 554 non-HER2 amplified (HER2-) breast tumors. High-resolution oligonucleotide aCGH was used to delineate the 17q12-q21 region in high detail. The HER2-amplicon was narrowed to an 85.92 kbp region including the TCAP, PNMT, PERLD1, HER2, C17orf37 and GRB7 genes, and higher HER2 copy numbers indicated worse prognosis. In 31% of HER2+ tumors the amplicon extended to TOP2A, defining a subgroup of HER2+ breast cancer associated with estrogen receptor-positive status and with a trend of better survival than HER2+ breast cancers with deleted (18%) or neutral TOP2A (51%). HER2+ tumors were clearly distinguished from HER2- tumors by the presence of recurrent high-level amplifications and firestorm patterns on chromosome 17q. While there was no significant difference between HER2+ and HER2- tumors regarding the incidence of other recurrent high-level amplifications, differences in the co-amplification pattern were observed, as shown by the almost mutually exclusive occurrence of 8p12, 11q13 and 20q13 amplification in HER2+ tumors. GISTIC analysis identified 117 significant CNAs across all autosomes. Supervised analyses revealed: (1) significant CNAs separating HER2+ tumors stratified by clinical variables, and (2) CNAs separating HER2+ from HER2- tumors. We have performed a comprehensive survey of CNAs in HER2+ breast tumors, pinpointing significant genomic alterations including both known and potentially novel therapeutic targets. Our analysis sheds further light on the genomically complex and heterogeneous nature of HER2+ tumors in relation to other subgroups of breast cancer.


Endocytosis of environmental and engineered micro- and nanosized particles.
There are many studies with cells to find out how particles interact with them. In contrast to micronsized particles, which are actively taken up by phagocytosis or macropinocytosis, nanosized particles may be taken up by cells through different endocytic pathways or by another, yet to be defined mechanism. There is increasing evidence that it is the nanosized particles, which are a particular risk because of their high content of organic chemicals and their pro-oxidative potential due to the high surface-to-volume ratio of the particles as compared to the bulk material. It is the goal of this article to create an understanding for the interaction of particles with biological systems, with particular consideration of the interaction of nanoparticles (NPs) with lung cells. One is attempting to understand, how NPs interact with cellular membranes, as it is hardly known, how they are taken up by cells, how they are trafficking in cells, and how they interact with subcellular compartments, such as with mitochondria or with the nucleus. Cells tend to defend themselves against any foreign material, which is taken up. In general, they try to eliminate particulate intruders and this is what they usually manage with micronsized particles. However, with NPs it is different. NPs may not be eliminated easily, and, hence may stimulate the cells to react in an unfavorable way. What we can learn is that NPs behave differently than microparticles.


Piezo-Electrochemical Energy Harvesting with Lithium-Intercalating Carbon Fibers.
The mechanical and electrochemical properties are coupled through a piezo-electrochemical effect in Li-intercalated carbon fibers. It is demonstrated that this piezo-electrochemical effect makes it possible to harvest electrical energy from mechanical work. Continuous polyacrylonitrile-based carbon fibers that can work both as electrodes for Li-ion batteries and structural reinforcement for composites materials are used in this study. Applying a tensile force to carbon fiber bundles used as Li-intercalating electrodes results in a response of the electrode potential of a few millivolts which allows, at low current densities, lithiation at higher electrode potential than delithiation. More electrical energy is thereby released from the cell at discharge than provided at charge, harvesting energy from the mechanical work of the applied force. The measured harvested specific electrical power is in the order of 1 μW/g for current densities in the order of 1 mA/g, but this has a potential of being increased significantly.


Catastrophic health expenditure among households with members with special diseases: A case study in Kurdistan.
Background: One of the main goals of health systems is to protect people against financial risks associated with diseases that can be catastrophic for patients. In 2014, Health Sector Evolution Plan (HSEP) was implemented in Iran; one of the objectives of HSEP was to reduce out-of-pocket payments and provide more financial protection for people. Therefore, the present study aimed at exploring the likelihood of facing catastrophic health expenditures (CHE) among households with members suffering from dialysis, kidney transplant, or multiple sclerosis (MS) after the implementation of HSEP. Methods: A total number of 385 households were selected using stratified random sampling and were asked to complete the World Health Survey questionnaire through telephone conversations. As outlined by the World Health Organization (WHO), when household out-of-pocket expense for health services is ≥40% of its capacity to pay, then that household is considered to be facing CHE. Furthermore, determinants of CHE were identified using logistic regression. Results: The percentage of facing catastrophic health care expenditures for households with a MS, dialysis, and kidney transplant patient was 20.6%, 18.7%, and 13.8%, respectively. Results of logistic regression analysis revealed that patient's economic status, level of education, supplementary insurance status, type of disease, multiple members with special diseases in the household, rural residence, use of inpatient, dental, and rehabilitation services were effective factors for determining the likelihood of facing CHE. Conclusion: Despite the implementation of HSEP, the percentage of CHE is still high for households that have members who suffer from special diseases. However, basic health insurance packages should be amended and more cost-sharing exemptions should be granted to provide more financial protection for the vulnerable households.


Higher participation in physical activity is associated with less use of inpatient mental health services: A cross-sectional study.
There is a stark disparity in the physical health of people with mental illness compared to those without mental illness, resulting in shorter life expectancy and increased rates of preventable deaths. Physical activity has previously been shown to have a positive impact on various markers of mental health and has been linked with a reduction in hospital admissions for those with chronic physical illness. The purpose of this study was to investigate whether there is a relationship between physical activity and the number of days spent admitted to acute inpatient mental health wards in people with enduring mental illness. Eighty participants from four acute mental health wards in Oxfordshire, UK were included. Subjective and objective measurements of physical activity levels were collected alongside the amount of days spent admitted on acute mental health wards over the year previous. Participants who recorded higher levels of physical activity, both subjectively and objectively, were found to have spent less time admitted to acute mental health services. With a significant negative correlation found, future research should aim to investigate any causative link between physical activity and mental health admission.


Remodeling of networks of interstitial cells of Cajal in a murine model of diabetic gastroparesis.
Patients with long-standing diabetes commonly suffer from gastric neuromuscular dysfunction (gastropathy) causing symptoms ranging from postprandial bloating to recurrent vomiting. Autonomic neuropathy is generally believed to be responsible for diabetic gastropathy and the underlying impairments in gastric emptying (gastroparesis) and receptive relaxation, but the specific mechanisms have not been elucidated. Recently, it has been recognized that interstitial cells of Cajal generate electrical pacemaker activity and mediate motor neurotransmission in the stomach. Loss or defects in interstitial cells could contribute to the development of diabetic gastroparesis. Gastric motility was characterized in spontaneously diabetic NOD/LtJ mice by measuring gastric emptying and by monitoring spontaneous and induced electrical activity in circular smooth muscle cells. Interstitial cells of Cajal were studied by Kit immunofluorescence and transmission electron microscopy. Diabetic mice developed delayed gastric emptying, impaired electrical pacemaking, and reduced motor neurotransmission. Interstitial cells of Cajal were greatly reduced in the distal stomach, and the normally close associations between these cells and enteric nerve terminals were infrequent. Our observations suggest that damage to interstitial cells of Cajal may play a key role in the pathogenesis of diabetic gastropathy.