Attenuation of the sensing capabilities of PhoQ in transition to obligate insect-bacterial association.
Sodalis glossinidius, a maternally inherited endosymbiont of the tsetse fly, maintains genes encoding homologues of the PhoP-PhoQ two-component regulatory system. This two-component system has been extensively studied in facultative bacterial pathogens and is known to serve as an environmental magnesium sensor and a regulator of key virulence determinants. In the current study, we show that the inactivation of the response regulator, phoP, renders S. glossinidius sensitive to insect derived cationic antimicrobial peptides (AMPs). The resulting mutant strain displays reduced expression of genes involved in the structural modification of lipid A that facilitates resistance to AMPs. In addition, the inactivation of phoP alters the expression of type-III secretion system (TTSS) genes encoded within three distinct chromosomal regions, indicating that PhoP-PhoQ also serves as a master regulator of TTSS gene expression. In the absence of phoP, S. glossinidius is unable to superinfect either its natural tsetse fly host or a closely related hippoboscid louse fly. Furthermore, we show that the S. glossinidius PhoQ sensor kinase has undergone functional adaptations that result in a substantially diminished ability to sense ancestral signals. The loss of PhoQ's sensory capability is predicted to represent a novel adaptation to the static symbiotic lifestyle, allowing S. glossinidius to constitutively express genes that facilitate resistance to host derived AMPs.


Mental Health and Illness.
Circumstances forcing individuals and families to flee set the stage for disruptions in mental health and forge resilience. Individual characteristics and conditions premigration, perimigration, and postmigration influence health, mental health, care-seeking behavior, and stages of well-being and successful resettlement. Primary care providers have strategies to promote mental well-being, including focusing on resilience and social determinants of health. Integrated or collaborative care models are ideal for delivering optimum care for refugee and immigrant communities. Connecting primary and behavioral care promotes a team approach; provides comprehensive, whole-person care; and relies on participation of patients and families.


Gradually layered alternated-substrate synthesis.
Gradually layered alternated-substrate synthesis (GLASS) is an automatic design method for optical coatings, which permits a gradual increase in the layer count of a stack while its optical properties are improved. This method does not require any starting design but only the design target and the list of allowed coating materials. In contrast to the needle technique, in which the coating is optimized between its two real external media, with new layers added inside the coating, the GLASS method adds new layers at the end of the design and uses coating materials as one external medium. This external medium provides new layers and is changed for another coating material each time a new layer is added. At the end, the coating must be matched to the real external medium that was not used during the design procedure.


Collagen IV in Normal Skin and in Pathological Processes.
Type IV collagen is a type of collagen found primarily in the skin within the basement membrane zone. The type IV collagen C4 domain at the C-terminus is not removed in post-translational processing, and the fibers are thus link head-to-head, rather than in a parallel fashion. Also, type IV collagen lacks a glycine in every third amino-acid residue necessary for the tight collagen helix. Thus, the overall collagen-IV conformation is structurally more pliable and kinked, relative to other collagen subtypes. These structural features allow collagen IV to form sheets, which is the primary structural form found in the cutaneous basal lamina. There are six human genes associated with collagen IV, specifically COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6. The aim of this review is to highlight the significance of this protein in normal skin, and in selected diseases. The alpha 3 protein constituent of type IV collagen is thought to be the antigen implicated in Goodpasture's syndrome, wherein the immune system attacks the basement membranes of the renal glomeruli and pulmonary alveoli. In addition, mutations to the genes coding for type IV collagen lead to the Alport syndrome. Furthermore, autoantibodies directed against denatured human type IV collagen have been described in rheumatoid arthritis, scleroderma, and SLE. Structural studies of collagen IV have been utilized to differentiate between subepidermal blistering diseases, including bullous pemphigoid, acquired epidermolysis bullosa, anti-epiligrin cicatricial pemphigoid, and bullous lupus erythematosus. Collagen IV is also of importance in wound healing and in embryogenesis. Pathological studies have demonstrated that minor structural differences in collagen IV can lead to distinct, clinically different diseases.


Successful kidney transplantation normalizes platelet function.
Uraemic platelet dysfunction is not completely understood, in part due to non-physiological platelet function assays. We have developed a physiological flow-based assay that quantifies platelet function in microlitre volumes of blood under arterial shear. The aim of this study was to characterize platelet function before and after kidney transplantation. Ten patients scheduled for living donor kidney transplant surgery and nine healthy controls were analysed using the assay. The motional parameters of platelet behaviour on von Willebrand factor (VWF) were recorded using customized platelet tracking software. The assay was repeated 3-8 weeks post-transplant in the transplant group and at an interval of >3 weeks in normal healthy volunteers. Platelet-VWF interactions were markedly reduced in the 10 pre-transplant patients compared with the healthy controls. In seven patients with immediate graft function, dynamic platelet function returned to normal (despite a small decrease in haemoglobin and haematocrit), but remained markedly abnormal in the three patients with delayed graft function (DGF). Dynamic platelet function returned to normal following transplantation in those with immediate graft function. This early improvement was not observed in those with DGF. There may be important clinical implications, as patients with DGF are more likely to undergo invasive procedures, including transplant biopsies and insertion of central venous catheters.


Ambulatory care databases for managed care organizations.
The uses, advantages, and limitations of ambulatory care databases are discussed, and processes for extracting and using the data are described. Claims databases allow health systems, including managed care organizations, to generate descriptive statistics on patients, providers, and diseases; to conduct comprehensive cost and resource-use analyses; and to build economic models of diseases. The use of health care databases has several advantages over clinical trials, including lower data collection costs, shorter times for analysis, larger numbers of patients, and less inconvenience to patients and providers. These databases allow the effectiveness of a treatment, instead of its efficacy, to be assessed and drug-switching patterns within disease categories to be detected. This information can be used for determining the cost and outcome implications of new treatments and formulary changes, as well as for monitoring disease management programs. Limitations of health care databases include the omission of services not covered by health plans, the risk of coding errors, the absence of indicators of disease severity, and the lack of data that would assist with clinical outcome analysis. Medical and pharmacy claims data do not contain all the information contained in patients' medical records. Despite their limitations, ambulatory care databases are useful for describing patient, provider, and disease characteristics. The databases are also useful for predicting and estimating the implications of a change in the formulary, measuring the effects of treatment guidelines, and monitoring disease management programs.


The effect of sleep deprivation on emotional memory consolidation in participants reporting depressive symptoms.
Sleep has been shown to play a crucial role in the consolidation of emotionally salient memories. However, the influence of sleep, and Sleep Deprivation (SD), on emotional memory consolidation in depressive individuals remains elusive. For this experiment we recruited two groups of healthy students, one reporting mild-to-severe depressive symptoms, and another reporting minimal/no depressive symptoms (assessed using the Beck Depression Inventory; BDI-II). We measured recognition performance for positive, neutral and negative images before and after a 12 h overnight retention interval, during which participants either remained awake in the laboratory or returned home to sleep normally. We found a significant depressive symptomatology group × sleep condition × image valence interaction on memory consolidation across the 12 h retention interval [F(2, 98) = 3.12, p = .049, ηp2 = 0.060]. We also found that depressive participants who slept normally consolidated significantly more negative and neutral images across the 12 h retention interval than depressive participants who were sleep deprived [t(24) = 2.35, p = .028, t(24) = 2.79, p = .010, respectively]. Our preliminary results indicate that SD may impair the consolidation of negative and neutral memories in depressive participants, but not in participants reporting minimal/no depressive symptoms.


Deep sequencing of GDF5 reveals the absence of rare variants at this important osteoarthritis susceptibility locus.
The common single nucleotide polymorphism (SNP) rs143383 in the 5' untranslated region (5'UTR) of growth and differentiation factor 5 (GDF5) is strongly associated with osteoarthritis (OA) and influences GDF5 allelic expression in vitro and in the joint tissues of OA patients. This effect is modulated in cis by another common SNP, also located within the 5'UTR, whilst a common SNP in the 3'UTR influences allelic expression independent of rs143383. DNA variants can be common, rare or extremely rare/unique. To therefore enhance our understanding of the allelic architecture of this very important OA susceptibility locus we sequenced the gene for potentially functional and novel rare variants. Using the Sanger method we sequenced GDF5 in 992 OA patients and 944 controls, with DNA changes identified by sequencing software. We encompassed the protein-coding region of the two GDF5 exons, both untranslated regions and approximately 100 bp of the proximal promoter of the gene. We detected 13 variants. Six were extremely rare with minor allele frequencies (MAFs) of ≤ 0.0006. One is in a predicted transcription factor binding site in the GDF5 promoter whilst two substitute conserved amino acids. The remaining seven variants were common and are previously known variants, with MAFs ranging from 0.025 to 0.39. There was a complete absence of variants with frequencies in-between the extremely rare (n=6) and the common (n=7). This is the first report of the deep sequencing of an OA susceptibility locus. The absence of rare variants informs us that within the regions of the gene that we have sequenced GDF5 does not harbour any novel variants that are able to contribute, at a population level, to the OA association signal mediated by rs143383 nor does it harbour, at a population level, any novel variants that can influence OA susceptibility independent of rs143383.


Endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and timing of surgery.
Carotid endarterectomy reduces the risk of stroke in patients with recently symptomatic stenosis. Benefit depends on the degree of stenosis, and we aimed to see whether it might also depend on other clinical and angiographic characteristics, and on the timing of surgery. We analysed pooled data from the European Carotid Surgery Trial and North American Symptomatic Carotid Endarterectomy Trial. The risk of ipsilateral ischaemic stroke for patients on medical treatment, the perioperative risk of stroke and death, and the overall benefit from surgery were determined in relation to seven predefined and seven post hoc subgroups. 5893 patients with 33000 patient-years of follow-up were analysed. Sex (p=0.003), age (p=0.03), and time from the last symptomatic event to randomisation (p=0.009) modified the effectiveness of surgery. Benefit from surgery was greatest in men, patients aged 75 years or older, and those randomised within 2 weeks after their last ischaemic event, and fell rapidly with increasing delay. For patients with 50% or higher stenosis, the number of patients needed to undergo surgery (ie, number needed to treat) to prevent one ipsilateral stroke in 5 years was nine for men versus 36 for women, five for age 75 years or older versus 18 for younger than 65 years, and five for those randomised within 2 weeks after their last ischaemic event, versus 125 for patients randomised after more than 12 weeks. These results were consistent across the individual trials. Benefit from endarterectomy depends not only on the degree of carotid stenosis, but also on several other clinical characteristics such as delay to surgery after the presenting event. Ideally, the procedure should be done within 2 weeks of the patient's last symptoms.


Task difficulty manipulation reveals multiple demand activity but no frontal lobe hierarchy.
It has been proposed that task control is functionally implemented by a distributed frontoparietal system. It has been argued that one component of this system, the lateral frontal cortex, is functionally organized through a caudal to rostral gradient. Here, we tested 2 competing models, the Information Cascade and Rule Abstraction hypotheses, which suggest different principles underlying the rostrocaudal gradient. We presented participants with 4 vertical lines on a screen and asked them to indicate the position of the shortest line. We manipulated the difficulty of the task in 3 simple ways: By increasing the number of lines, by decreasing the difference between short and normal line length, and by changing the stimulus-response mapping. As expected, these manipulations evoked widespread frontoparietal activation, with activity much more anterior than predicted by Information Cascade and Rule Abstraction models. There were also striking individual differences in the rostrocaudal extent of activity. The results suggest an integrated frontoparietal system, which can be recruited as a whole even by very simple task demands.


Descending optic nerve degeneration in primates.
We cut the optic nerve at the orbital apex in squirrel monkeys to study the descending degeneration of optic nerve axons and their ganglion cell bodies. We could not detect progressive disintegration of the axon from the site of injury back to the cell body. Instead, the entire length of individual axons seemed to degenerate simultaneously as early as 3 weeks and as late as 6 weeks after injury, as judged both by ultrastructural integrity and by continued slow axonal transport, a reflection of local physiologic function. We could not relate the time of degeneration to the distance of the injury from the cell body. Evidently there is a signal of injury to the cell body after axotomy, though the nature of the signal and the mechanism by which it leads to cell death are unknown.


Sir2-independent life span extension by calorie restriction in yeast.
Calorie restriction slows aging and increases life span in many organisms. In yeast, a mechanistic explanation has been proposed whereby calorie restriction slows aging by activating Sir2. Here we report the identification of a Sir2-independent pathway responsible for a majority of the longevity benefit associated with calorie restriction. Deletion of FOB1 and overexpression of SIR2 have been previously found to increase life span by reducing the levels of toxic rDNA circles in aged mother cells. We find that combining calorie restriction with either of these genetic interventions dramatically enhances longevity, resulting in the longest-lived yeast strain reported thus far. Further, calorie restriction results in a greater life span extension in cells lacking both Sir2 and Fob1 than in cells where Sir2 is present. These findings indicate that Sir2 and calorie restriction act in parallel pathways to promote longevity in yeast and, perhaps, higher eukaryotes.


On the Hierarchical Organization of Oscillatory Assemblies: Layered Superimposition and a Global Bioelectric Framework.
Bioelectric oscillations occur throughout the nervous system of nearly all animals, revealed to play an important role in various aspects of cognitive activity such as information processing and feature binding. Modern research into this dynamic and intrinsic bioelectric activity of neural cells continues to raise questions regarding their role in consciousness and cognition. In this theoretical article, we assert a novel interpretation of the hierarchical nature of "brain waves" by identifying that the superposition of multiple oscillations varying in frequency corresponds to the superimposing of the contents of consciousness and cognition. In order to describe this isomorphism, we present a layered model of the global functional oscillations of various frequencies which act as a part of a unified metastable continuum described by the Operational Architectonics theory and suggested to be responsible for the emergence of the phenomenal mind. We detail the purposes, functions, and origins of each layer while proposing our main theory that the superimposition of these oscillatory layers mirrors the superimposition of the components of the integrated phenomenal experience as well as of cognition. In contrast to the traditional view that localizations of high and low-frequency activity are spatially distinct, many authors have suggested a hierarchical nature to oscillations. Our theoretical interpretation is founded in four layers which correlate not only in frequency but in evolutionary development. As other authors have done, we explore how these layers correlate to the phenomenology of human experience. Special importance is placed on the most basal layer of slow oscillations in coordinating and grouping all of the other layers. By detailing the isomorphism between the phenomenal and physiologic aspects of how lower frequency layers provide a foundation for higher frequency layers to be organized upon, we provide a further means to elucidate physiological and cognitive mechanisms of mind and for the well-researched outcomes of certain voluntary breathing patterns and meditative practices which modulate the mind and have therapeutic effects for psychiatric and other disorders.


Disaccharidase activity in the small intestine of gerbils (Meriones unguiculatus) during primary and challenge infections with Giardia lamblia.
The sequence of changes in the activity of six disaccharidases in the small intestine of gerbils during primary and secondary G lamblia infections was examined. The primary G lamblia infection induced a transient reduction in disaccharidase activity which was related to the highest trophozoite burden in the small intestine. During the primary exposure, a 30% to 85% decrease in the activity of enzymes was observed on days 10 and 20 after infection. Secondary exposure of gerbils to G lamblia caused a sharp decrease in disaccharidase activity as early as 24 h after challenge. The reduction in the enzyme activity was not influenced by the size of the challenge inoculum and occurred even when there were no live trophozoites in the small intestine. Disaccharidase deficiency could also be induced by challenge with the soluble extract of the trophozoites. Multiple challenge administrations of G lamblia trophozoites to gerbils induced a persistent disaccharidase deficiency. The results indicate that disaccharidase deficiency associated with the primary G lamblia infection probably represents a direct effect of the parasite on the brush border of the small intestine. On the other hand, the observed disaccharidase deficiency in the secondary G lamblia infection appears to be induced by the local immune responses of the host.


A survey of dioxin-like contaminants in fish from recreational fishing.
The dioxin and dioxin-like compounds are regarded as one of the most toxic group of environmental contaminants. Food for the commercial market is regularly monitored for their dioxin levels and the concentration allowed in food is strictly regulated. Less is known about locally caught fish from recreational fishing, which is often brought home for consumption. This can be fish caught from nearby lakes or streams or fish with marine origin close to industrial areas or harbours that are not regularly monitored for their dioxin levels. In this study, we established collaboration with schools in 13 countries. We received 203 samples of 29 different fish species of which Atlantic cod was the most abundant followed by brown trout and pollock. In general, the majority of samples from the participating countries had low concentrations (between 0.1 and 0.2 pg/g chemical-activated luciferase gene expression toxic equivalency wet weight (CALUX TEQ w.w.)) of dioxins and dioxin-like PCBs. Only 18 samples had concentrations above 1 pg/g CALUX TEQ w.w., and only 2 dab samples had concentration above maximum levels set by the European Commission. The Atlantic cod samples showed a significant reduction in the concentrations of dioxins with increasing latitude indicating less contamination of dioxin and dioxin-like compounds in the north of Norway. The results indicate that a moderate consumption of self-caught fish at presumed non-contaminated sites does not represent a major risk for exposure to dioxins or dioxin-like compounds at concentrations associated with adverse health effects. Recreational fishermen should, however, obtain knowledge about local fish consumption advice.


Epidemiology and clinical manifestations of Lyme borreliosis in childhood. A prospective multicentre study with special regard to neuroborreliosis.
Lyme borreliosis is a tick-borne infection caused by the spirochete Borrelia burgdorferi, whose discovery in 1982 solved an aetiological mystery involving a variety of dermatological and neurological disorders and explained their association with Lyme disease. Lyme borreliosis occurs frequently and is readily treatable with antibiotics. Along with its discovery, however, came the realization that it is difficult to diagnose accurately, especially antibody diagnosis. False-positive antibody results in particular led to gradual widening of the clinical spectrum, and differential diagnosis became increasingly difficult. This prospective, multicentre study presents a systematic description of Lyme borreliosis in childhood, emphasizing epidemiological and clinical issues. Because, predominantly, inpatients were examined, Lyme neuroborreliosis was the focus of the study, with the chief concern being to minimize false-positive results. To this end, we chose to narrow the diagnostic criteria, using the presence of specific antibodies in the cerebrospinal fluid as the determining factor. The epidemiological investigation was focused on the incidence of Lyme neuroborreliosis in childhood in southern Lower Saxony as well as on the prevalence of Lyme neuroborreliosis among acute-inflammatory neurological illnesses in children. The clinical part of the study aimed at establishing criteria for differential diagnosis in addition to the detection of specific antibodies. The detection of specific IgM antibodies using an IgM capture ELISA confirmed the presence of acute Lyme borreliosis. The study examined 208 children with Lyme borreliosis, of whom 169 had Lyme neuroborreliosis, from mid-1986 until the end of 1989. The yearly incidence of Lyme neuroborreliosis in Lower Saxony was 5.8 cases/100,000 children aged 1 to 13. The manifestation index was 0.16, or one case of Lyme neuroborreliosis per 620 infected children, compared with the presence of specific antibodies against B. burgdorferi for children in the same age group and region. Both the seasonal distribution of Lyme borreliosis, which peaked in summer and autumn, as well as the information about when the tick bites took place point to an incubation period of a few weeks. The most frequent manifestation of Lyme neuroborreliosis in childhood was acute peripheral facial palsy, found in 55% of all cases (n = 93). Lyme borreliosis proved to be the most frequently verifiable cause of acute peripheral facial palsy in children, causing every second case of this disorder in summer and autumn.(ABSTRACT TRUNCATED AT 400 WORDS)


The SYGMA programme of phase 3 trials to evaluate the efficacy and safety of budesonide/formoterol given 'as needed' in mild asthma: study protocols for two randomised controlled trials.
In many patients with mild asthma, the low frequency of symptoms and the episodic nature of exacerbations make adherence to regular maintenance treatment difficult. This often leads to over-reliance on short-acting β2-agonist (SABA) reliever medication and under-treatment of the underlying inflammation, with poor control of asthma symptoms and increased risk of exacerbations. The use of budesonide/formoterol 'as needed' in response to symptoms may represent an alternative treatment option for patients with mild asthma. The SYmbicort Given as needed in Mild Asthma (SYGMA) programme consists of two 52-week, double-blind, randomised, multicentre, parallel-group, phase 3 trials of patients aged 12 years and older with a clinical diagnosis of asthma for at least 6 months, who would qualify for treatment with regular inhaled corticosteroids (ICS). SYGMA1 aims to recruit 3750 patients who will be randomised to placebo twice daily (bid) plus as-needed budesonide/formoterol 160/4.5 μg, placebo bid plus as-needed terbutaline 0.4 mg, or budesonide 200 μg bid plus as-needed terbutaline 0.4 mg. The primary objective is to demonstrate the superiority of as-needed budesonide/formoterol over as-needed terbutaline for asthma control, as measured by well-controlled asthma weeks; a secondary objective is to establish the noninferiority of as-needed budesonide/formoterol versus maintenance budesonide plus as-needed terbutaline using the same outcome measure. SYGMA2 aims to recruit 4114 patients who will be randomised to placebo bid plus as-needed budesonide/formoterol 160/4.5 μg, or budesonide 200 μg bid plus as-needed terbutaline 0.4 mg. The primary objective is to demonstrate the noninferiority of as-needed budesonide/formoterol over budesonide bid plus as-needed terbutaline as measured by the annualised severe exacerbation rate. In both studies, use of all blinded study inhalers will be recorded electronically using Turbuhaler® Usage Monitors. Given the known risks of mild asthma, and known poor adherence with regular inhaled corticosteroids, the results of the SYGMA programme will help to determine the efficacy and safety of as-needed budesonide/formoterol therapy in mild asthma. Patient recruitment is complete, and completion of the phase 3 studies is planned in 2017. ClinicalTrials.gov identifiers: NCT02149199 SYGMA1 and NCT02224157 SYGMA2. Registered on 16 May 2014 and 19 August 2014, respectively.


The timing of agricultural production in hazard-prone areas to prevent losses at peak-risk periods: A case of Malawi, Madagascar and Mozambique.
Hazard-prone areas in southern Africa experience many natural hazards, which include cyclones, floods and droughts. The severe climatic conditions of southern Africa have an especially large impact on the agricultural practices of small-scale farmers. These hazards should be mitigated to ensure more resilient communities and food security. This study mainly focuses on the timing of agricultural production in hazard-prone areas to prevent losses at peak-risk periods by adapting the agricultural cycle. This study focuses on the agricultural activities of small-scale farmers in Malawi, Madagascar and Mozambique. A literature review is presented, and a mixed-method research design were followed to determine the timing of production followed by these small-scale farmers and its impact on production and food security. Although this study found that the small-scale farmers generally plant with the first rains, it is recommended by literature that early planting should be practised to ensure optimal production. It is also recommended that small-scale farmers should implement water-management techniques for dry periods, and when farmers practice late planting, the use of residual-moisture retention should be utilised as a mitigation measure. This will in effect ensure that the communities are less vulnerable during peak-risk periods by improving or ensuring food security. Therefore, adapting the planting and production time in these hazard-prone areas at peak-risk periods could limit losses and increase communities' resilience.


The Popeye domain containing genes: essential elements in heart rate control.
The Popeye domain containing (Popdc) gene family displays preferential expression in skeletal muscle and heart. Only recently a significant gain in the understanding of the function of Popdc genes in the heart has been obtained. The Popdc genes encode membrane proteins harboring an evolutionary conserved Popeye domain, which functions as a binding domain for cyclic adenosine monophosphate (cAMP). Popdc proteins interact with the two-pore channel TREK-1 and enhance its current. This protein interaction is modulated by cAMP. Null mutations of members of the Popdc gene family in zebrafish and mouse are associated with severe cardiac arrhythmia phenotypes. While in zebrafish an atrioventricular block was prevalent, in mouse a stress-induced sinus bradycardia was observed, which was due to the presence of sinus pauses. Moreover, the phenotype develops in an age-dependent manner, being absent in the young animal and becoming increasingly severe, as the animals grow older. This phenotype is reminiscent of the sick sinus syndrome (SSS), which affects mostly the elderly and is characterized by the poor ability of the cardiac pacemaker to adapt the heart rate to the physiological demand. While being a prevalent disease, which is responsible for a large fraction of pacemaker implantations in Western countries, SSS is poorly understood at the molecular level. It is therefore expected that the study of the molecular basis of the stress-induced bradycardia in Popdc mice will shed new light on the etiology of pacemaker disease.


Hyperglycemia Enhances Constriction of Retinal Venules via Activation of the Reverse-Mode Sodium-Calcium Exchanger.
Diabetes is associated with hyperglycemia and impairment of retinal microvascular function. However, the impact of hyperglycemia on retinal venular constriction remains unknown. We examined retinal venular responsiveness to endogenous vasoconstrictors and the contribution of the reverse-mode sodium-calcium exchanger (NCX) to these responses during hyperglycemia. Retinal venules were isolated from pigs with streptozocin-induced diabetes (2 weeks, in vivo hyperglycemia) and age-matched control pigs for vasoreactivity and molecular studies. For in vitro hyperglycemia, vessels from euglycemic pigs were exposed to high glucose (25 mmol/L) for 2 h, and 5 mmol/L glucose served as the control. Constrictions of venules from euglycemic pigs to endothelin-1 (ET-1), thromboxane analog U46619, and norepinephrine were mediated by ETA, thromboxane, and α2-adrenergic receptors, respectively, and were insensitive to reverse-mode NCX blockade (KB-R7943). In vivo hyperglycemia enhanced these vasoconstrictions without altering respective receptor mRNA expression. Similarly, in vitro hyperglycemia augmented venular constrictions. Enhanced vasoconstrictions during hyperglycemia were prevented by KB-R7943, while mRNA expression of venular NCX isoforms was unaltered. In vivo hyperglycemia increased vitreous levels of ET-1 but not thromboxane B2 In conclusion, both in vitro and in vivo hyperglycemia enhance retinal venular responses to endogenous vasoconstrictors by activating reverse-mode NCX. Therapies targeting this vascular molecule may alleviate retinal complications during diabetes.


Hospital Management of Severe Hypertriglyceridemia in Children.
Severe Hypertriglyceridemia (HTG), i.e., plasma triglyceride levels exceeding 1000 mg/dL, is one of the established causes of acute pancreatitis and severe abdominal pain. There are no established pediatric guidelines regarding treatment of children and adolescents with severe HTG. To review the pathophysiology and etiology of severe HTG in the pediatric age group, and to discuss management options. Severe HTG is usually due to deficient or absent Lipoprotein Lipase (LPL) activity, which can be due to primary genetic etiology or secondary causes triggering HTG in those with underlying genetic susceptibility. Hospitalization is indicated for patients with severe HTG who are symptomatic with abdominal pain or pancreatitis, in those with uncontrolled diabetes requiring insulin, or, in those with substantial elevations of plasma TG. Fasting followed by fat free diet until plasma TG declines to <1000mg/dL is essential. Subsequently, stringent fat restriction followed by slowly increasing the dietary fat while maintaining the plasma TG concentration at a targeted level is recommended. Insulin infusions are helpful in patients who have some LPL activity, especially in those with diabetes. Plasmapheresis may be considered in those with severe pancreatitis, shock or multi-organ failure. Medications such as fibrates and omega-3 fatty acids are not effective if LPL activity is absent or when plasma TG is >1800 mg/dL. Medications only have an adjunct role in the management. Low fat diet, lifestyle changes, weight loss, control of secondary causes, and patient education form the mainstay of management once the patient is discharged.


Siderophore-mediated iron uptake in Alcaligenes eutrophus CH34 and identification of aleB encoding the ferric iron-alcaligin E receptor.
Siderophore production in response to iron limitation was observed in Alcaligenes eutrophus CH34, and the corresponding siderophore was named alcaligin E. Alcaligin E was characterized as a phenolate-type siderophore containing neither catecholate nor hydroxamate groups. Alcaligin E promoted the growth of siderophore-deficient A. eutrophus mutants under iron-restricted conditions and promoted 59Fe uptake by iron-limited cells. However, the growth of the Sid- mutant AE1152, which was obtained from CH34 by Tn5-Tc mutagenesis, was completely inhibited by the addition of alcaligin E. AE1152 also showed strongly reduced 59Fe uptake in the presence of alcaligin E. This indicates that a gene, designated aleB, which is involved in transport of ferric iron-alcaligin E across the membrane is inactivated. The aleB gene was cloned, and its putative amino acid sequence showed strong similarity to those of ferric iron-siderophore receptor proteins. Both wild-type strain CH34 and aleB mutant AE1152 were able to use the same heterologous siderophores, indicating that AleB is involved only in ferric iron-alcaligin E uptake. Interestingly, no utilization of pyochelin, which is also a phenolate-type siderophore, was observed for A. eutrophus CH34. Genetic studies of different Sid- mutants, obtained after transposon mutagenesis, showed that the genes involved in alcaligin E and ferric iron-alcaligin E receptor biosynthesis are clustered in a 20-kb region on the A. eutrophus CH34 chromosome in the proximity of the cys-232 locus.


Ancient medicine, modern use: Withania somnifera and its potential role in integrative oncology.
Withania somnifera Dunal, commonly known as ashwagandha, has been used for centuries in Ayurvedic medicine to increase longevity and vitality. Western research supports its polypharmaceutical use, confirming antioxidant, anti-inflammatory, immune-modulating, and antistress properties in the whole plant extract and several separate constituents. This article reviews the literature pertaining to Withania somnifera and its botanical constituents as antitumor agents and in conjunction with radiation and chemotherapy treatment. Following a search of MEDLINE and EBSCO databases, it can be concluded that Withania somnifera reduces tumor cell proliferation while increasing overall animal survival time. Furthermore, it has been shown to enhance the effectiveness of radiation therapy while potentially mitigating undesirable side effects. Withania somnifera also reduces the side effects of chemotherapeutic agents cyclophosphamide and paclitaxel without interfering with the tumor-reducing actions of the drugs. These effects have been demonstrated in vitro on human cancer cell lines, and in vivo on animal subjects, but there have been no human trials to date. Given its broad spectrum of cytotoxic and tumor-sensitizing actions, Withania somnifera presents itself as a novel complementary therapy for integrative oncology care.


Learning Support Correlation Filters for Visual Tracking.
For visual tracking methods based on kernel support vector machines (SVMs), data sampling is usually adopted to reduce the computational cost in training. In addition, budgeting of support vectors is required for computational efficiency. Instead of sampling and budgeting, recently the circulant matrix formed by dense sampling of translated image patches has been utilized in kernel correlation filters for fast tracking. In this paper, we derive an equivalent formulation of a SVM model with the circulant matrix expression and present an efficient alternating optimization method for visual tracking. We incorporate the discrete Fourier transform with the proposed alternating optimization process, and pose the tracking problem as an iterative learning of support correlation filters (SCFs). In the fully-supervision setting, our SCF can find the globally optimal solution with real-time performance. For a given circulant data matrix with n2 samples of n ×n pixels, the computational complexity of the proposed algorithm is O(n2 logn) whereas that of the standard SVM-based approaches is at least O(n4). In addition, we extend the SCF-based tracking algorithm with multi-channel features, kernel functions, and scale-adaptive approaches to further improve the tracking performance. Experimental results on a large benchmark dataset show that the proposed SCF-based algorithms perform favorably against the state-of-the-art tracking methods in terms of accuracy and speed.


A randomized clinical trial of auricular point acupressure for chronic low back pain: a feasibility study.
Objectives. This prospective, randomized clinical trial (RCT) was designed to investigate the feasibility and effects of a 4-week auricular point acupressure (APA) for chronic low back pain (CLBP). Methods. Participants were randomized to either true APA (true acupoints with taped seeds on the designated ear points for CLBP) or sham APA (sham acupoints with taped seeds but on different locations than those designated for CLBP). The duration of treatment was four weeks. Participants were assessed before treatment, weekly during treatment, and 1 month following treatment. Results. Participants in the true APA group who completed the 4-week APA treatment had a 70% reduction in worst pain intensity, a 75% reduction in overall pain intensity, and a 42% improvement in disability due to back pain from baseline assessment. The reductions of worst pain and overall pain intensity in the true APA group were statistically greater than participants in the sham group (P < 0.01) at the completion of a 4-week APA and 1 month followup. Discussion. The preliminary findings of this feasibility study showed a reduction in pain intensity and improvement in physical function suggesting that APA may be a promising treatment for patients with CLBP.


Social tagging in the life sciences: characterizing a new metadata resource for bioinformatics.
Academic social tagging systems, such as Connotea and CiteULike, provide researchers with a means to organize personal collections of online references with keywords (tags) and to share these collections with others. One of the side-effects of the operation of these systems is the generation of large, publicly accessible metadata repositories describing the resources in the collections. In light of the well-known expansion of information in the life sciences and the need for metadata to enhance its value, these repositories present a potentially valuable new resource for application developers. Here we characterize the current contents of two scientifically relevant metadata repositories created through social tagging. This investigation helps to establish how such socially constructed metadata might be used as it stands currently and to suggest ways that new social tagging systems might be designed that would yield better aggregate products. We assessed the metadata that users of CiteULike and Connotea associated with citations in PubMed with the following metrics: coverage of the document space, density of metadata (tags) per document, rates of inter-annotator agreement, and rates of agreement with MeSH indexing. CiteULike and Connotea were very similar on all of the measurements. In comparison to PubMed, document coverage and per-document metadata density were much lower for the social tagging systems. Inter-annotator agreement within the social tagging systems and the agreement between the aggregated social tagging metadata and MeSH indexing was low though the latter could be increased through voting. The most promising uses of metadata from current academic social tagging repositories will be those that find ways to utilize the novel relationships between users, tags, and documents exposed through these systems. For more traditional kinds of indexing-based applications (such as keyword-based search) to benefit substantially from socially generated metadata in the life sciences, more documents need to be tagged and more tags are needed for each document. These issues may be addressed both by finding ways to attract more users to current systems and by creating new user interfaces that encourage more collectively useful individual tagging behaviour.


Methods for conceptualising 'visual ability' as a measurable construct in children with cerebral palsy.
Vision influences functioning and disability of children with cerebral palsy, so there is a growing need for psychometrically robust tools to advance assessment of children's vision abilities in clinical practice and research. Vision is a complex construct, and in the absence of clarity about this construct it is challenging to know whether valid, reliable measures exist. This study reports a method for conceptualising 'visual ability' as a measurable construct. Using the items from 19 assessment tools previously identified in a systematic review, this study used a two-phase process: first, deductive content analysis linked items to the International Classification of Functioning, Disability and Health - Child and Youth version (ICF-CY), and second, vision-specific 'Activity'-level items were explored using inductive thematic analysis. The linking and content analysis identified that existing assessment tools are measuring vision across the ICF-CY domains of Body Functions, Activities and Participation, and Environmental and Personal Factors. Items specifically coded to vision at the Activity level were defined as measuring 'how vision is used', and these items form the basis of the conceptualisation that 'visual ability' is measurable as a single construct. The thematic analysis led to the identification of 3 categories containing 13 themes that reflect a child's observable visual behaviours. Seven abilities reflect how a child uses vision: responds or reacts, initiates, maintains or sustains looking, changes or shifts looking, searches, locates or finds, and follows. Four interactions reflect the contexts in which a child uses their vision to purposefully interact: watches and visually interacts with people and faces, objects, over distance, and with hands. Finally, two themes reflect a child's overall use of vision in daily activities: frequency of use, and efficiency of use. This study demonstrates an approach to exploring and explaining a complex topic utilising World Health Organization language and building on existing research. Despite the complexity of vision, the concept of 'how vision is used' can be clearly defined as a measurable construct at the Activity level of the ICF-CY. This study has identified observable visual behaviours that may be developed into items assessing how vision is used in daily activities.


Multimethod study of a large-scale programme to improve patient safety using a harm-free care approach.
We aimed to evaluate whether a large-scale two-phase quality improvement programme achieved its aims and to characterise the influences on achievement. National Health Service (NHS) in England. NHS staff. The programme sought to (1) develop a shared national, regional and locally aligned safety focus for 4 high-cost, high volume harms; (2) establish a new measurement system based on a composite measure of 'harm-free' care and (3) deliver improved outcomes. Phase I involved a quality improvement collaborative intended to involve 100 organisations; phase II used financial incentives for data collection. Multimethod evaluation of the programme. In phase I, analysis of regional plans and of rates of data submission and clinical outcomes reported to the programme. A concurrent process evaluation was conducted of phase I, but only data on submission rates and clinical outcomes were available for phase II. A context of extreme policy-related structural turbulence impacted strongly on phase I. Most regions' plans did not demonstrate full alignment with the national programme; most fell short of recruitment targets and attrition in attendance at the collaborative meetings occurred over time. Though collaborative participants saw the principles underlying the programme as attractive, useful and innovative, they often struggled to convert enthusiasm into change. Developing the measurement system was arduous, yet continued to be met by controversy. Data submission rates remained patchy throughout phase I but improved in reach and consistency in phase II in response to financial incentives. Some evidence of improvement in clinical outcomes over time could be detected but was hard to interpret owing to variability in the denominators. These findings offer important lessons for large-scale improvement programmes, particularly when they seek to develop novel concepts and measures. External contexts may exert far-reaching influence. The challenges of developing measurement systems should not be underestimated.


Synthesis of benzil-o-carboxylate derivatives and isocoumarins through neighboring ester-participating bromocyclizations of o-alkynylbenzoates.
Bromide mediated neighboring ester-participating bromocyclizations of o-alkynylbenzoates are described here for the synthesis of benzil-o-carboxylates. 4-bromoisocoumarins are also synthesized when phenyl o-alkynylbenzoate is used as the substrate. Mechanistic studies suggest that the whole process is composed of an electrophilic bromocyclization and a dibromohydration-based ring-opening, and the neighboring ester group participates in the bromocyclization. Interestingly, the two oxygen atoms of the keto carbonyls in benzil-o-carboxylates are both derived from water. The electrophilic bromo source is in situ generated from the oxidation of bromide.


Nonspherical armoured bubble vibration.
In this paper, we study the dynamics of cylindrical armoured bubbles excited by mechanical vibrations. A step by step transition from cylindrical to spherical shape is reported as the intensity of the vibration is increased, leading to a reduction of the bubble surface and a dissemination of the excess particles. We demonstrate through energy balance that nonspherical armoured bubbles constitute a metastable state. The vibration instills the activation energy necessary for the bubble to return to its least energetic stable state: a spherical armoured bubble. At this point, particle desorption can only be achieved through higher amplitude of excitation required to overcome capillary retention forces. Nonspherical armoured bubbles open perspectives for tailored localized particle dissemination with limited excitation power.


Circadian rhythms in isolated brain regions.
The suprachiasmatic nucleus (SCN) of the mammalian hypothalamus has been referred to as the master circadian pacemaker that drives daily rhythms in behavior and physiology. There is, however, evidence for extra-SCN circadian oscillators. Neural tissues cultured from rats carrying the Per-luciferase transgene were used to monitor the intrinsic Per1 expression patterns in different brain areas and their response to changes in the light cycle. Although many Per-expressing brain areas were arrhythmic in culture, 14 of the 27 areas examined were rhythmic. The pineal and pituitary glands both expressed rhythms that persisted for >3 d in vitro, with peak expression during the subjective night. Nuclei in the olfactory bulb and the ventral hypothalamus expressed rhythmicity with peak expression at night, whereas other brain areas were either weakly rhythmic and peaked at night, or arrhythmic. After a 6 hr advance or delay in the light cycle, the pineal, paraventricular nucleus of the hypothalamus, and arcuate nucleus each adjusted the phase of their rhythmicity with different kinetics. Together, these results indicate that the brain contains multiple, damped circadian oscillators outside the SCN. The phasing of these oscillators to one another may play a critical role in coordinating brain activity and its adjustment to changes in the light cycle.


Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growth.
Malaria, schistosomiasis and leishmaniases are among the most prevalent tropical parasitic diseases and each requires new innovative treatments. Targeting essential parasite pathways, such as those that regulate gene expression and cell cycle progression, is a key strategy for discovering new drug leads. In this study, four clinically approved anti-cancer drugs (Vorinostat, Belinostat, Panobinostat and Romidepsin) that target histone/lysine deacetylase enzymes were examined for in vitro activity against Plasmodium knowlesi, Schistosoma mansoni, Leishmania amazonensis and L. donovani parasites and two for in vivo activity in a mouse malaria model. All four compounds were potent inhibitors of P. knowlesi malaria parasites (IC50 9-370 nM), with belinostat, panobinostat and vorinostat having 8-45 fold selectivity for the parasite over human neonatal foreskin fibroblast (NFF) or human embryonic kidney (HEK 293) cells, while romidepsin was not selective. Each of the HDAC inhibitor drugs caused hyperacetylation of P. knowlesi histone H4. None of the drugs was active against Leishmania amastigote or promastigote parasites (IC50 > 20 μM) or S. mansoni schistosomula (IC50 > 10 μM), however romidepsin inhibited S. mansoni adult worm parings and egg production (IC50 ∼10 μM). Modest in vivo activity was observed in P. berghei infected mice dosed orally with vorinostat or panobinostat (25 mg/kg twice daily for four days), with a significant reduction in parasitemia observed on days 4-7 and 4-10 after infection (P < 0.05), respectively.


Reducing broad-spectrum antibiotic use in intensive care unit between first and second waves of COVID-19 did not adversely affect mortality.
The COVID-19 pandemic increased the use of broad-spectrum antibiotics due to diagnostic uncertainty, particularly in critical care. Multi-professional communication became more difficult, weakening stewardship activities. To determine changes in bacterial co-/secondary infections and antibiotics used in COVID-19 patients in critical care, and mortality rates, between the first and second waves. Prospective audit comparing bacterial co-/secondary infections and their treatment during the first two waves of the pandemic in a single-centre teaching hospital intensive care unit. Data on demographics, daily antibiotic use, clinical outcomes, and culture results in patients diagnosed with COVID-19 infection were collected over 11 months. From March 9th, 2020 to September 2nd, 2020 (Wave 1), there were 156 patients and between September 3rd, 2020 and February 1st, 2021 (Wave 2) there were 235 patients with COVID-19 infection admitted to intensive care. No significant difference was seen in mortality or positive blood culture rates between the two waves. The proportion of patients receiving antimicrobial therapy (93.0% vs 81.7%; P < 0.01) and the duration of meropenem use (median (interquartile range): 5 (2-7) vs 3 (2-5) days; P = 0.01) was lower in Wave 2. However, the number of patients with respiratory isolates of Pseudomonas aeruginosa (4/156 vs 21/235; P < 0.01) and bacteraemia from a respiratory source (3/156 vs 20/235; P < 0.01) increased in Wave 2, associated with an outbreak of infection. There was no significant difference between waves with respect to isolation of other pathogens. Reduced broad-spectrum antimicrobial use in the second wave of COVID-19 compared with the first wave was not associated with significant change in mortality.


Assessment of distortion in a three-dimensional rotational angiography system.
The purpose of this project was to determine the degree of geometrical distortion in a three-dimensional (3D) image volume generated by a digital fluorography system with rotational image acquisition capabilities. 3D imaging is a valuable adjunct in neuroangiography for visualization and measurement of cerebral aneurysms and for determination of the optimum projection for intervention. To enable spatially accurate 3D reconstruction the system must correct for geometrical distortion in the image intensifier television system as well as for deviations in gantry motion. 3D volumes were reconstructed from 100 X-ray projections acquired over a 180 degrees arc over a period of 8 s. A phantom was constructed to assess geometrical distortion in the three dimensions. The phantom consisted of 1 mm diameter ball bearings embedded in Perspex in a cubic lattice configuration. The ball bearings were placed at 20 mm intervals over a 140 mm cubic volume. Distortion was assessed by taking measurements between points of known separation and using a differential distortion measurement. The maximum error in the 3D location of objects was found to be 1.4 mm, while the differential distortion was found to range from -1.0% to +2.3%. The 3D images were found to have negligible visual distortion, enabling subjective assessments to be made with confidence to aid intervention.


[Vitamin D levels in older healthy Chilean adults and their association with functional performance].
People over 60 years old are at risk of Vitamin D deficiency, which can affect functional performance, since this vitamin is involved in muscle function and protein synthesis. To measure 25OH vitamin D levels in healthy older people from Santiago de Chile, and evaluate their relationship with functional performance. Healthy subjects aged 60 years or more and living in the community were invited to participate. People with chronic diseases, cognitive impairment, physical disability, smokers and those consuming more than three medications per day were excluded. Hand grip and gait speed were measured and a blood sample was obtained to measure 25OH vitamin D by radioimmunoanalysis. One hundred and four participants aged 60 to 98 years (55% females) were studied. Mean vitamin D levels were 17.3 ± 6.1 ng/mL. Females had lower levels than males (15.6 ± 5.8 and 19.2 ± 6.0 ng/mL respectively p < 0.01). Eighty three percent of females and 55.3% of males had values below 20 ng/mL (the cutoff point for deficiency). Only 3.5% of females and 8.5% of males had values of 30 ng/ml or higher. There was a significant correlation between vitamin D levels, gait speed and grip strength (r = 0.32 and 0.34 respectively, p < 0.01), especially in women over 74 years. Vitamin D deficiency is almost universal in healthy adults over 60 years living in Santiago de Chile, especially in women. This deficiency is associated with a deranged functional performance and is a potentially modifiable risk factor for disability.


Mechanotransduction by TRP channels: general concepts and specific role in the vasculature.
Transient receptor potential (TRP) ion channel superfamily is involved in sensing and transmission of a broad variety of external or internal stimuli, including but not limited to mechanical stress. Based on homology analysis, genetic and molecular studies have recently identified TRP channels in different tissues, comprising blood vessels. In invertebrates, many TRP channels including five TRPV channels identified in Caenorhabditis elegans and two in Drosophila have been implicated in mechanosensory behaviors as molecular basis of volume regulation, hearing and touch sensitivity. Consistently, in mammals many TRP family members such as TRPC1, TRPC3, TRPC6, TRPM4, TRPM7, TRPN1, TRPA1, TRPY1, TRPP1, TRPP2, and notably, TRPV1, TPRV2 as well as TRPV4 have been reported to be involved in mechanotransduction. This review summarizes recent and at times controversial findings on the role and regulation of TRP channels in mechanotransduction. Specifically, we highlight the relevance of TRPV channels in vascular regulation and focus on TRPV4 in the vascular system of the lung, which is constantly exposed to a unique combination of circumferential and longitudinal strains. In light of our observation in intact pulmonary microvessels that mechanical stress induced Ca(2+) signaling in endothelial cells is closely related to TRPV4 activity, we postulate that TRPV4 plays a critical role in lung vascular mechanotransduction. The progress in this rapidly expanding field may allow for the identification of new molecular targets and the development of new therapeutic approaches in a number of intractable diseases related to mechanical stress.


Core-shell nanoparticles for gas phase detection based on silver nanospheres coated with a thin molecularly imprinted polymer adsorbed on a chemiresistor.
We present a novel gas phase detection prototype based on assembling core-shell nanospheres made of a silver core and coated with a molecularly imprinted polymer (MIP) adsorbed onto an interdigitated array (IDA) electrode chemiresistor (CR). The core-shell nanospheres, AgNP@MIPs, were imprinted with linalool, a volatile terpene alcohol, as a model system. The thickness of the MIP layer was tuned to a few nanometers to enable the facile ingress and egress of the linalool, as well as to enhance the electrical transduction through the Ag core. The AgNP@MIPs were spread onto the IDA-CR modified with various positively charged polymers, by drop casting and dip-coating. The AgNP@MIPs were characterized by various techniques such as extra high-resolution scanning and tunnelling electron microscopy and X-ray diffraction. The MIP recognition event was transduced into a measurable increase in the resistance. The response to linalool exposure and removal was fast and the device was fully recovered and could be reused. Finally, the difference in the resistance change between imprinted and non-imprinted nanospheres was substantial.


Liquisolid technique for dissolution rate enhancement of a high dose water-insoluble drug (carbamazepine).
Different liquisolid formulations of carbamazepine were accomplished by dissolving the drug in the non-toxic hydrophilic liquids, and adsorbing the solution onto the surface of silica. In order to reduce the amounts of carrier and aerosil in liquisolid formulations, some additives namely polyvinylpyrrolidone (PVP), hydroxypropyle methylcellulose (HPMC) and polyethylene glycol (PEG 35000) were added to liquid medication to increase loading factor. The effects of various ratios of carrier to coating material, PVP concentration, effect of aging and type of the carrier on dissolution rate of liquisolid compacts were studied. X-ray crystallography and differential scanning calorimetery (DSC) were used for evaluation of physicochemical properties of carbamazepine in liquisolid formulations. The results showed that the drug loading factor was increased significantly in the presence of additives. Liquisolid formulations containing PVP as additive, exhibited significantly higher drug dissolution rates compared to the compacts prepared by the direct compression technique. It was shown that microcrystalline cellulose had more liquid retention potential in comparison with lactose, and the formulations containing microcrystalline cellulose as carrier, showed higher dissolution rate. By decreasing the ratio of microcrystalline cellulose to silica from 20 to 10, an improvement in dissolution rate was observed. Further decrease in the ratio of microcrystalline cellulose:silica from 10 to 5 resulted in a significant reduction in dissolution rate. Increasing of PVP concentration in liquid medication caused a dramatic increase in dissolution rate at first 30min. The results showed that the dissolution rate of liquisolid tablets was not significantly affected by storing the tablets at 25 degrees C/75% relative humidity for a period of 6 months. The results of DSC and X-ray crystallography did not show any changes in crystallinity of the drug and interaction between carbamazepine and exipients during the process.


Re-evaluating the green versus red signal in eukaryotes with secondary plastid of red algal origin.
The transition from endosymbiont to organelle in eukaryotic cells involves the transfer of significant numbers of genes to the host genomes, a process known as endosymbiotic gene transfer (EGT). In the case of plastid organelles, EGTs have been shown to leave a footprint in the nuclear genome that can be indicative of ancient photosynthetic activity in present-day plastid-lacking organisms, or even hint at the existence of cryptic plastids. Here, we evaluated the impact of EGT on eukaryote genomes by reanalyzing the recently published EST dataset for Chromera velia, an interesting test case of a photosynthetic alga closely related to apicomplexan parasites. Previously, 513 genes were reported to originate from red and green algae in a 1:1 ratio. In contrast, by manually inspecting newly generated trees indicating putative algal ancestry, we recovered only 51 genes congruent with EGT, of which 23 and 9 were of red and green algal origin, respectively, whereas 19 were ambiguous regarding the algal provenance. Our approach also uncovered 109 genes that branched within a monocot angiosperm clade, most likely representing a contamination. We emphasize the lack of congruence and the subjectivity resulting from independent phylogenomic screens for EGT, which appear to call for extreme caution when drawing conclusions for major evolutionary events.


Expression of TLR4-PTGE2 signaling genes in atherosclerotic carotid plaques and peripheral blood.
Toll-like receptor 4 (TLR4)/prostaglandine synthetase 2 (PTGS2) signaling plays a relevant role in atherosclerotic plaque vulnerability. The purpose of this study was to check the gene expression of 6 genes participating to TLR4/PTGS2 signaling (TLR4, PTGS2, ACSL4, PTGER3, PTGER4, and EPRAP) in carotid plaques and blood samples from the same individual and to evaluate these genes as biomarker of plaque progression. We investigated differential gene expression by qRT-PCR in 62 atherosclerotic patients' carotid plaques and corresponding blood sample. A very weak or no correlation was observed in the overall population or analyzing asymptomatic patients. These analyzed genes are most likely not suitable for inclusion in the clinical routine as biomarkers of plaque instability.


Investigation of Stress Level Among Dentistry Students, General Dentists, and Pediatric Dental Specialists During Performing Pediatric Dentistry in Kerman, Iran, in 2017.
Dentists are exposed to stress and tension as they have a close contact with the patients. The increase in stress may affect the dentists' performance and can be a major threat to the physical and mental health of the patients. Pediatric dentistry requires experience, without which the amateur dentists and students feel lack of self-confidence, and consequently be unable to deal with problematic patients. There is no study investigating stress during pediatric dentistry among the dentistry students as well as general and pediatric dentists in Iran. Regarding the importance ofthis subject, we aimed to evaluate the stress level among the aforementioned three dental service providers during pediatric dentistry. This study was conducted on 300 dentistry students, general dentists, and pediatric dental specialists in Kerman, Iran. The data were collected using a questionnaire entailing demographic information and therapeutic practices of pediatric dentistry. After checking the participant's comments, the data were analyzed using SPSS version 16 (IBM, Texas, USA). According to the results, the mean age of the participants was 28±5 years. Out of the 300 participants, 113 (37.7%) and 178 (59.3%) cases were male and female, respectively, and 9 (3%) participants did not fill out this part. Furthermore, 108 (36%), 173 (57.7%), 6 (2%), and 10 (3.3%) subjects were general students, general dentists, residents, and pediatric residents, respectively. Anesthesia injection in the mandible for an anxious child and amalgam restoration in the mandible led to the highest and lowest stress levels in the participants, respectively. Furthermore, the mean stress levels were significantly different between the practices performed in the maxilla and mandible (P<0.001). In addition, the females showed a significantly higher level of stress, compared to the males (P<0.001). The specialists had significantly lower stress than the dentistry students and general dentists (P<0.001). As the findings indicated, anesthetic injection to a nervous infant was the most stressful practice in pediatric dentistry. The results also showed that the pediatric dental specialists had lower stress level, compared to the students and general dentists.


Protective Effect of Green Tea Consumption on Colorectal Cancer Varies by Lifestyle Factors.
The inconsistent findings regarding green tea intake and colorectal cancer (CRC) risk in several epidemiological studies might result from variations in lifestyle factors. Therefore, we examined whether increased green tea intake was associated with a decreased risk of CRC and how the risk of CRC was altered by the protective effect of green tea consumption and five health-related factors. A case-control study including 2742 participants (922 cases and 1820 controls) was conducted in Korea. Green tea consumption was assessed using a semiquantitative food frequency questionnaire. The risk of CRC was approximately 40% less in the participants in the highest green tea intake tertile than in participants in the lowest green tea intake tertile. Of the five lifestyle factors examined, high body mass index and physical inactivity were independent risk factors for CRC. Regarding the interactions between tea consumption and lifestyle factors, high green tea consumption was associated with a decreased risk of CRC, with or without considering lifestyle factors. However, moderate green tea consumption increased the risk of CRC among ever-smokers, ever-drinkers and the high-inflammatory diet group. Increased consumption of green tea might be helpful to reduce the risk of CRC in those with an unhealthy lifestyle.


Detection of deep vein thrombosis: combined flow and blood pool radionuclide venography vs contrast venography.
This study was performed to validate the combined study of flow radionuclide venography (FRV) with subsequent 99mTc-red blood cell(RBC) blood pool radionuclide venography(BRV) for the detection of deep vein thrombosis (DVT). Findings in 32 patients with suspected DVT of lower extremities (n = 52) were compared with those of corresponding contrast venograms (CV) serving as a reference method. FRV was performed by using three separate doses of a large 99mTc04-bolus (10-12 cc) injection. The findings were as follows: concerning the detection of DVT in calf veins, agreement between FRV and CV, FRV+BRV and CV, and BRV and CV were 67%, 73% and 60%, respectively. For femoral veins, agreement between FRV and CV was 96%, while it was 87% between BRV and CV. When FRV and BRV of femoral veins were evaluated in combination, 100% agreement between radionuclide and radiologic method was observed. For iliac veins there was no disagreement in comparison of the methods either singly or in combination. In 7.6% of the extremities, collaterals not demonstrated by CV and BRV were visualized only by FRV. Although the radioactive agent was injected in a relatively large volume, all of the calf veins could not be filled even when they were completely patent. It was concluded that a combined study of FRV with BRV improved the diagnostic value of radionuclide venography for the detection of DVT in calf and femoral veins.


Quantitative analysis of N-glycans from human alfa-acid-glycoprotein using stable isotope labeling and zwitterionic hydrophilic interaction capillary liquid chromatography electrospray mass spectrometry as tool for pancreatic disease diagnosis.
In this work we demonstrate the potential of glycan reductive isotope labeling (GRIL) using [(12)C]- and [(13)C]-coded aniline and zwitterionic hydrophilic interaction capillary liquid chromatography electrospray mass spectrometry (μZIC-HILIC-ESI-MS) for relative quantitation of glycosylation variants in selected glycoproteins present in samples from cancer patients. Human α1-acid-glycoprotein (hAGP) is an acute phase serum glycoprotein whose glycosylation has been described to be altered in cancer and chronic inflammation. However, it is not clear yet whether some particular glycans in hAGP can be used as biomarker for differentiating between these two pathologies. In this work, hAGP was isolated by immunoaffinity chromatography (IAC) from serum samples of healthy individuals and from those suffering chronic pancreatitis and different stages of pancreatic cancer, respectively. After de-N-glycosylation, relative quantitation of the hAGP glycans was carried out using stable isotope labeling and μZIC-HILIC-ESI-MS analysis. First, protein denaturing conditions prior to PNGase F digestion were optimized to achieve quantitative digestion yields, and the reproducibility of the established methodology was evaluated with standard hAGP. Then, the proposed method was applied to the analysis of the clinical samples (control vs. pathological). Pancreatic cancer samples clearly showed an increase in the abundance of fucosylated glycans as the stage of the disease increases and this was unlike to samples from chronic pancreatitis. The results gained here indicate the mentioned glycan in hAGP as a candidate structure worth to be corroborated by an extended study including more clinical cases; especially those with chronic pancreatitis and initial stages of pancreatic cancer. Importantly, the results demonstrate that the presented methodology combining an enrichment of a target protein by IAC with isotope coded relative quantitation of N-glycans can be successfully used for targeted glycomics studies. The methodology is assumed being suitable as well for other such studies aimed at finding novel cancer associated glycoprotein biomarkers.


Handling technology of Mega-Watt millimeter-waves for optimized heating of fusion plasmas.
Millimeter-wave components were re-examined for high power (Mega-Watt) and steady-state (greater than one hour) operation. Some millimeter-wave components, including waveguide joints, vacuum pumping sections, power monitors, sliding waveguides, and injection windows, have been improved for high power CW (Continuous Waves) transmission. To improve transmission efficiency, information about the wave phase and mode content of high power millimeter-waves propagating in corrugated waveguides, which are difficult to measure directly, were obtained by a newly developed method based on retrieved phase information. To optimize the plasma heating efficiency, a proof-of-principle study of the injection polarization feedback control was performed in the low power test stand.


Imbalance in the composition of the duodenal microbiota of children with coeliac disease.
Coeliac disease (CD) is the most common immune-mediated enteropathy characterized by chronic inflammation of the small intestinal mucosa. The ingestion of gluten is responsible for the symptoms of CD, but other environmental factors are also thought to play a role in this disorder. In this study, the composition of the duodenal microbiota of coeliac children with active disease, symptom-free CD patients on a gluten-free diet and control children was determined. Bacteriological analyses of duodenal biopsy specimens were carried out by fluorescent in situ hybridization coupled with flow cytometry. The proportions of total bacteria and Gram-negative bacteria were significantly higher in CD patients with active disease than in symptom-free CD patients and controls. Bacteroides and Escherichia coli groups were significantly more abundant in CD patients with active disease than in controls, whilst these bacterial deviations were normalized in symptom-free CD patients. The ratio of Lactobacillus--Bifidobacterium to Bacteroides--E. coli was significantly reduced in coeliac patients with either active or inactive disease compared with controls. The differences in Atopobium, Eubacterium rectale--Clostridium coccoides, Clostridium histolyticum, Clostridium lituseburense, sulphate-reducing bacteria and Faecalibacterium prausnitzii populations among the three groups of children were less relevant. Overall, the higher incidence of Gram-negative and potentially pro-inflammatory bacteria in the duodenal microbiota of coeliac children was linked to the symptomatic presentation of the disease and could favour the pathological process of the disorder.


Novel analogs and stereoisomers of the marine toxin neodysiherbaine with specificity for kainate receptors.
Antagonists for kainate receptors (KARs), a family of glutamategated ion channels, are efficacious in a number of animal models of neuropathologies, including epilepsy, migraine pain, and anxiety. To produce molecules with novel selectivities for kainate receptors, we generated three sets of analogs related to the natural marine convulsant neodysiherbaine (neoDH), and we characterized their pharmacological profiles. Radioligand displacement assays with recombinant alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and KARs demonstrated that functional groups at two positions on the neoDH molecule are critical pharmacological determinants; only binding to the glutamate receptor (GluR)5-2a subunit was relatively insensitive to structural modifications of the critical functional groups. NeoDH analogs in which the l-glutamate congener was disrupted by epimerization retained low affinity for GluR5-2a and GluR6a KAR subunits. Most of the analogs showed agonist activity in electrophysiological recordings from human embryonic kidney-T/17 cells expressing GluR5-2a KARs, similar to the natural convulsant neoDH. In contrast, 2,4-epi-neoDH inhibited glutamate currents evoked from both GluR5-2a and GluR6a receptor-expressing cells. Therefore, this compound represents the first compound to exhibit functional antagonist activity on GluR5-2a and GluR6a KAR subunits without concurrent activity on AMPA receptor subunits. Finally, binding affinity of the synthetic ligands for the GluR5-2a subunit closely correlated with their seizurogenic potency, strongly supporting a role for receptors containing this subunit in the convulsant reaction to KAR agonists. The analogs described here offer further insight into structural determinants of ligand selectivity for KARs and potentially represent useful pharmacological tools for studying the role of KARs in synaptic physiology and pathology.


Yoga and Mindfulness for Social-Emotional Development and Resilience in 3-5 Year-Old Children: Non-Randomized, Controlled Intervention.
Early childhood is the key life course period for development of social-emotional skills, providing the foundation for school readiness and resilience in later life. Age-appropriate yoga and mindfulness programs may contribute to the development of critical skills in children. Young children from minoritized communities that face structural racism and health disparities may benefit from programs that support social-emotional development and contribute to future academic success. Systematic reviews of yoga interventions for young children have indicated the potential for effectiveness in supporting social-emotional development, executive function, and physical activity. However, studies of yoga and mindfulness with non-White children are sparse and, overall, the evidence base to date for such programs remains limited by non-controlled studies and the variable quality of studies evaluating programs in early childhood settings. The analysis of data from a non-randomized, controlled intervention aimed to assess the effect of exposure to a yoga and mindfulness program for early childhood development of social-emotional skills in a majority Black/African American urban preschool setting in southeastern US. Children in the intervention received group yoga and mindfulness led by a certified children's yoga teacher who also had training and experience as a school teacher. Intervention participants engaged in activities for 20 minutes once per week for 32 weeks, while the control group had no yoga. The final sample included 579 in the historical control group and 122 in the intervention group. Results indicated that children who participated in the yoga and mindfulness program had higher total protective factor (TPF) subscores on the Devereux Early Childhood Assessment over time than children who did not receive yoga and mindfulness programming, and that the difference was statistically significant (P<0.05). Participation in the intervention group significantly predicted increases in initiative score, self-control score, and TPF score, as well as a decrease in the behavioral concerns. School based yoga and mindfulness programming can support social-emotional skills and resilience in young children. Additional studies with larger sample sizes and randomization are needed on use of yoga and mindfulness in young children for social-emotional development, particularly for Black/African American children and others from minoritized communities.


Programmed death ligand-1 expression and memory T-cell generation in Coxiella burnetii infection.
Programmed death ligand-1 (PD-L1) is a co-signaling molecule that regulates T-cell responses in vivo. Its role in bacterial infections, including Q fever, a zoonosis due to Coxiella burnetii infection, is not well understood. We showed by flow cytometry that PD-L1 membrane expression was specifically increased in T-cells from patients with acute Q fever, not from patients with Q fever endocarditis, suggesting that PD-L1 plays a role in the early phases of C. burnetii infection. To assess this hypothesis, we studied the role of PD-L1 in C. burnetii-infected mice. C. burnetii infection resulted in PD-L1 up-regulation in splenocytes. Anti-PD-L1 antibodies injected into the mice did not affect the total number of splenic T-cells but increased the relative number of CD4(+) T-cells compared with CD8(+) T-cells. Additionally, anti-PD-L1 antibodies significantly increased the number of splenic CD4(+) and CD8(+) T cells that expressed low membrane CD62L levels. Our results indicate that the increased expression of PD-L1 by T-cells is associated with a decreased number of memory T-cells during C. burnetii infection, opening new perspectives in the understanding of Q fever pathophysiology.


Factors associated with 1-year mortality after discharge for acute stroke: what matters?
To evaluate factors associated with 1-year mortality after discharge for acute stroke. In this retrospective cohort study, we studied 305 patients with ischemic stroke or intracerebral hemorrhage discharged in 2010/2011. We linked Get With The Guidelines®-Stroke clinical data with New York State administrative data and used multivariate regression models to examine variables related to 1-year all-cause mortality poststroke. The mean age was 68.6 ± 14.8 years and 51.1% were women. A total of 146 (47.9%) were discharged directly home, 96 (31.5%) to inpatient rehabilitation facilities (IRFs), and 63 (20.7%) to skilled nursing facilities (SNFs). Overall, 24 (7.9%) patients died within 1-year post-discharge. Older age (adjusted odds ratio [OR] 1.05, 95% confidence interval [CI] 1.00-1.10), higher National Institutes of Health Stroke Scale (NIHSS) on admission (OR 1.10, 95% CI 1.03-1.17), and discharge destination (IRF vs. home, OR 0.10, 95% CI 0.01-0.94; and SNF vs. home, OR 2.22, 95% CI 0.71-6.95) were factors associated with 1-year all-cause mortality. When ambulation status at discharge was added to the model, ambulation with assistance and non-ambulation were significantly associated with mortality (ambulatory with assistance vs. ambulatory, OR 9.42, 95% CI 1.87-47.61; nonambulatory vs. ambulatory, OR 12.65, 95% CI 1.89-84.89). While age and NIHSS on admission are important predictors of long-term outcomes, factors at discharge - ambulation status at discharge and discharge destination - are associated with 1-year mortality post-discharge for acute stroke and therefore could represent therapeutic targets to improve long-term survival in future studies.


Predicting outcomes for children with neuroblastoma using a multigene-expression signature: a retrospective SIOPEN/COG/GPOH study.
More accurate prognostic assessment of patients with neuroblastoma is required to better inform the choice of risk-related therapy. The aim of this study is to develop and validate a gene-expression signature to improve outcome prediction. 59 genes were selected using an innovative data-mining strategy, and were profiled in the largest neuroblastoma patient series (n=579) to date using real-time quantitative PCR starting from only 20 ng of RNA. A multigene-expression signature was built using 30 training samples, tested on 313 test samples, and subsequently validated in a blind study on an independent set of 236 tumours. The signature has a performance, sensitivity, and specificity of 85.4% (95% CI 77.7-93.2), 84.4% (66.5-94.1), and 86.5% (81.1-90.6), respectively, to predict patient outcome. Multivariate analysis indicates that the signature is a significant independent predictor of overall survival and progression-free survival after controlling for currently used risk factors: patients with high molecular risk have a higher risk of death from disease and higher risk of relapse or progression than patients with low molecular risk (odds ratio 19.32 [95% CI 6.50-57.43] and 3.96 [1.97-7.97] for overall survival and progression-free survival, respectively, both p<0.0001). Patients at an increased risk of an adverse outcome can also be identified in the current treatment groups, showing the potential of this signature for improved clinical management. These results were confirmed in the validation study, in which the signature was also independently statistically significant in a model adjusted for MYCN status, age, International Neuroblastoma Staging System stage, ploidy, International Neuroblastoma Pathology Classification grade of differentiation, and mitosis karyorrhexis index (odds ratios between 4.81 and 10.53 depending on the model for overall survival and 3.68 [95% CI 2.01-6.71] for progression-free survival). The 59-gene expression signature is an accurate predictor of outcome in patients with neuroblastoma. The signature is an independent risk predictor, identifying patients with an increased risk of poor outcome in the current clinical-risk groups. The method and signature is suitable for routine laboratory testing, and should be evaluated in prospective studies. The Belgian Foundation Against Cancer, the Children Cancer Fund Ghent, the Belgian Society of Paediatric Haematology and Oncology, the Belgian Kid's Fund and the Fondation Nuovo-Soldati (JV), the Fund for Scientific Research Flanders (KDP, JH), the Fund for Scientific Research Flanders, the Institute for the Promotion of Innovation by Science and Technology in Flanders, Strategisch basisonderzoek, the Fondation Fournier Majoie pour l'Innovation, the Instituto Carlos III, the Italian Neuroblastoma Foundation, the European Community under the FP6, and the Belgian programme of Interuniversity Poles of Attraction.


Influence of cAMP and calcium on [3H]inositol efflux, inositol phosphate accumulation, and insulin release from isolated rat islets.
The influence of cyclic AMP (cAMP) and extracellular calcium on phosphoinositide (PI) hydrolysis in isolated islets was assessed and related to insulin output. Three stimulants were chosen to activate the beta-cell: sulfated cholecystokinin (CCK-8S, 200 nM), high-level glucose (20 mM), and the sulfonylurea tolbutamide (200 microM). The insulin secretory response to all three agonists was amplified by forskolin (which increases cAMP levels) and reduced by nitrendipine (which decreases calcium influx). All three stimulants increased the hydrolysis of inositol-containing phospholipids, an event monitored by an increase in [3H]inositol efflux from [3H]inositol-prelabeled islets and by the accumulation of labeled inositol phosphates. Forskolin, despite its positive impact on insulin secretion, reduced [3H]inositol efflux and inositol phosphate accumulation in response to all agonists. A similar inhibitory effect on these parameters was noted with nitrendipine; however, nitrendipine abolished secretion in response to all agonists. These findings support the following conclusions: 1) an increase in cellular cAMP levels reduces the quantitative impact of various agonists on these indices of PI hydrolysis; 2) despite this inhibitory effect, cAMP amplifies the insulin secretory response to these agonists; and 3) extracellular calcium is a crucial determinant of both PI hydrolysis and the ensuing insulin secretory response.


Cultural neuroscience of the self: understanding the social grounding of the brain.
Cultural neuroscience is an interdisciplinary field of research that investigates interrelations among culture, mind and the brain. Drawing on both the growing body of scientific evidence on cultural variation in psychological processes and the recent development of social and cognitive neuroscience, this emerging field of research aspires to understand how culture as an amalgam of values, meanings, conventions, and artifacts that constitute daily social realities might interact with the mind and its underlying brain pathways of each individual member of the culture. In this article, following a brief review of studies that demonstrate the surprising degree to which brain processes are malleably shaped by cultural tools and practices, the authors discuss cultural variation in brain processes involved in self-representations, cognition, emotion and motivation. They then propose (i) that primary values of culture such as independence and interdependence are reflected in the compositions of cultural tasks (i.e. daily routines designed to accomplish the cultural values) and further (ii) that active and sustained engagement in these tasks yields culturally patterned neural activities of the brain, thereby laying the ground for the embodied construction of the self and identity. Implications for research on culture and the brain are discussed.


Coriolus versicolor (Yunzhi) extract attenuates growth of human leukemia xenografts and induces apoptosis through the mitochondrial pathway.
Coriolus versicolor (CV), also called Yunzhi, has been demonstrated to exert anti-tumor effects on various types of cancer cells. Our previous studies have demonstrated that a standardized aqueous ethanol extract prepared from CV inhibited the proliferation of human leukemia cells via induction of apoptosis. The present study aimed to evaluate the underlying mechanisms of apoptosis through modulation of Bax, Bcl-2 and cytochrome c protein expressions in a human pro-myelocytic leukemia (HL-60) cell line, as well as the potential of the CV extract as anti-leukemia agent using the athymic mouse xenograft model. Our results demonstrated that the CV extract dose-dependently suppressed the proliferation of HL-60 cells (IC50 = 150.6 microg/ml), with increased nucleosome production from apoptotic cells. Expression of pro-apoptotic protein Bax was significantly up-regulated in HL-60 cells treated with the CV extract, especially after 16 and 24 h. Meanwhile, expression of anti-apoptotic protein Bcl-2 was concomitantly down-regulated, as reflected by the increased Bax/Bcl-2 ratio. The CV extract markedly, but transiently, promoted the release of cytochrome c from mitochondria to cytosol after 24-h incubation. In vivo studies in the athymic nude mouse xenograft model also confirmed the growth-inhibitory activity of the CV extract on human leukemia cells. In conclusion, the CV extract attenuated the human leukemia cell proliferation in vivo, and in vitro possibly by inducing apoptosis through the mitochondrial pathway. The CV extract is likely to be valuable for the treatment of some forms of human leukemia.


Patterns of communication breakdowns resulting in injury to surgical patients.
Communication breakdowns are a common threat to surgical safety, but there are little data to guide initiatives to improve communication. In surgeon-review of 444 surgical malpractice claims from 4 liability insurers, we identified 60 cases involving communication breakdowns resulting in harm to patients. Two surgeon-reviewers analyzed these cases to identify common characteristics and associated factors. Based on identified patterns, potential interventions to prevent communication breakdowns were developed and their potential impact was assessed. The 60 cases involved 81 communication breakdowns, occurring in the preoperative (38%), intraoperative (30%), and postoperative periods (32%). Seventy-two percent of cases involved one communication breakdown. The majority of breakdowns were verbal communications (92%) involving 1 transmitter and 1 receiver (64%). Attending surgeons were the most common team member involved. Status asymmetry (74%) and ambiguity about responsibilities (73%) were commonly associated factors. Forty-three percent of communication breakdowns occurred with handoffs and 39% with transfers in the patient's location. The most common communication breakdowns involved residents failing to notify the attending surgeon of critical events and a failure of attending-to-attending handoffs. Proposed interventions could prevent 45% to 73% of communication breakdowns in this cases series. Serious communication breakdowns occur across the continuum of care, typically result from a failure in verbal communication between a surgical attending and another caregiver, and often involve ambiguity about responsibilities. Interventions to prevent these breakdowns should involve: defined triggers that mandate communication with an attending surgeon; structured handoffs and transfer protocols; and standard use of read-backs.


Drug safety assessment in clinical trials: methodological challenges and opportunities.
Randomized controlled trials are the principal means of establishing the efficacy of drugs. However pre-marketing trials are limited in size and duration and exclude high-risk populations. They have limited statistical power to detect rare but potentially serious adverse events in real-world patients. We summarize the principal methodological challenges in the reporting, analysis and interpretation of safety data in clinical trials using recent examples from systematic reviews. These challenges include the lack of an evidentiary gold standard, the limited statistical power of randomized controlled trials and resulting type 2 error, the lack of adequate ascertainment of adverse events and limited generalizability of trials that exclude high risk patients. We discuss potential solutions to these challenges. Evaluation of drug safety requires careful examination of data from heterogeneous sources. Meta-analyses of drug safety should include appropriate statistical methods and assess the optimal information size to avoid type 2 errors. They should evaluate outcome reporting biases and missing data to ensure reliable and accurate interpretation of findings. Regulatory and academic partnerships should be fostered to provide an independent and transparent evaluation of drug safety.


Redox Flow Batteries, Hydrogen and Distributed Storage.
Social, economic, and political pressures are causing a shift in the global energy mix, with a preference toward renewable energy sources. In order to realize widespread implementation of these resources, large-scale storage of renewable energy is needed. Among the proposed energy storage technologies, redox flow batteries offer many unique advantages. The primary limitation of these systems, however, is their limited energy density which necessitates very large installations. In order to enhance the energy storage capacity of these systems, we have developed a unique dual-circuit architecture which enables two levels of energy storage; first in the conventional electrolyte, and then through the formation of hydrogen. Moreover, we have begun a pilot-scale demonstration project to investigate the scalability and technical readiness of this approach. This combination of conventional energy storage and hydrogen production is well aligned with the current trajectory of modern energy and mobility infrastructure. The combination of these two means of energy storage enables the possibility of an energy economy dominated by renewable resources.


Ebstein Anomaly in Pregnancy.
A 27-year-old primiparous woman with 28 weeks gestational age was admitted to our hospital with worsening shortness of breath. She was diagnosed with Ebstein's anomaly three years ago, but preferred to be left untreated. The patient was not cyanotic and her vital signs were stable. Her ECG showed incomplete RBBB and prolonged PR-interval. Blood tests revealed mild anemia. Observation of two-dimensional echo with color flow Doppler study showed Ebstein's anomaly with PFO as additional defects, EF of 57%, LV and LA dilatation, RV atrialization, severe TR, and moderate PH with RVSP of 44.3 mmHg. The patient then underwent elective sectio caesaria at 30 weeks of gestational age; both the mother and her baby were alive and were in good conditions. there was an increasing breathlessness in this patient so that there was an increasing need to take a decision for her pregnancy.Ebstein's anomaly is a complicated congenital anomaly. Medical treatment may be followed for many years in patients with mild forms of Ebstein's anomaly. Surgery should be considered if there is objective evidence of debasement such as significant enlargement of heart size, reduction of systolic function in echocardiography.


Authority and the Future of Consent in Population-Level Biomedical Research.
Population-level biomedical research has become crucial to the health system's ability to improve the health of the population. This form of research raises a number of well-documented ethical concerns, perhaps the most significant of which is the inability of the researcher to obtain fully informed specific consent from participants. Two proposed technical solutions to this problem of consent in large-scale biomedical research that have become increasingly popular are meta-consent and dynamic consent. We critically examine the ethical and practical credentials of these proposals and find them lacking. We suggest that the consent problem is not solved by adopting a technology driven approach grounded in a notion of 'specific' consent but by taking seriously the role of research governance in combination with broader conceptions of consent. In our view, these approaches misconstrue the rightful location of authority in the way in which population-level biomedical research activities are structured and organized. We conclude by showing how and why the authority for determining the nature and shape of choice making about participation ought not to lie with individual participants, but rather with the researchers and the research governance process, and that this necessarily leads to the endorsement of a fully articulated broad consent approach.


Active learning: learning a motor skill without a coach.
When we learn a new skill (e.g., golf) without a coach, we are "active learners": we have to choose the specific components of the task on which to train (e.g., iron, driver, putter, etc.). What guides our selection of the training sequence? How do choices that people make compare with choices made by machine learning algorithms that attempt to optimize performance? We asked subjects to learn the novel dynamics of a robotic tool while moving it in four directions. They were instructed to choose their practice directions to maximize their performance in subsequent tests. We found that their choices were strongly influenced by motor errors: subjects tended to immediately repeat an action if that action had produced a large error. This strategy was correlated with better performance on test trials. However, even when participants performed perfectly on a movement, they did not avoid repeating that movement. The probability of repeating an action did not drop below chance even when no errors were observed. This behavior led to suboptimal performance. It also violated a strong prediction of current machine learning algorithms, which solve the active learning problem by choosing a training sequence that will maximally reduce the learner's uncertainty about the task. While we show that these algorithms do not provide an adequate description of human behavior, our results suggest ways to improve human motor learning by helping people choose an optimal training sequence.