The intersection of violence, substance use, depression, and STDs: testing of a syndemic pattern among patients attending an urban STD clinic.
High rates of psychosocial and health problems have been identified among patients attending sexually transmitted disease (STD) clinics, who are disproportionately urban, have low income, and are racial/ethnic minorities. This study sought to determine whether these problems co-occurred and whether they indicated the presence of a syndemic. Patients (N = 1557, 46% female, 64% African American) attending an urban STD clinic completed a computerized survey assessing childhood sexual abuse (CSA), depressive symptoms, binge drinking, marijuana use, intimate partner violence (IPV), and sexual risk behavior. Medical records were reviewed to determine incident STD diagnosis. The psychosocial and health problems were interrelated. Endorsing more psychosocial problems was associated with a greater likelihood of having multiple sexual partners and STD diagnosis. Interactions between CSA and marijuana use and between CSA and IPV predicted STD diagnosis. Numerous psychosocial and health problems co-occur among urban STD clinic patients. There was some evidence of a syngergistic relationship (i.e., a syndemic) between these conditions, resulting in worsened sexual health outcomes. Health care needs to be multidisciplinary to address the multiple psychosocial and health problems faced by STD clinic patients. Research needs to identify factors that may underlie these comorbid conditions.


Serotonin in aging, late-life depression, and Alzheimer's disease: the emerging role of functional imaging.
Serotonin (5-HT) neuron and neurotransmitter loss in normal aging and neuropsychiatric diseases of late life may contribute to behavioral changes commonly observed in the elderly population. Extensive evidence implicates a deficit in serotonergic neurotransmission in the development of major depression. It has been further suggested that the age-related changes in 5-HT neurons may predispose the elderly to develop depression. There is also increasing evidence that a combination of disturbances in cholinergic and serotonergic function may play a role in cognitive impairment in Alzheimer's disease (AD), with serotonergic dysfunction potentially responsible for a significant portion of the behavioral aspects of the disease. This implication of the 5-HT system in aging and age-related cognitive and mood disorders rests in large part on post mortem studies and animal models, which are limited in their capacity to predict dynamic human biochemical-behavior relationships or to accurately model the living human brain. Initial applications of functional brain imaging with positron emission tomography (PET) in the in vivo study of the brain in aging depression, and dementia focused on characterizing alterations in physiological measurements of cerebral metabolism and perfusion. However, recent advances in PET radiochemistry, instrumentation, and image processing have paved the way for noninvasive means to test specific hypotheses regarding the direct involvement of 5-HT neurons in the behavioral features of aging and to define and monitor therapeutic regimens for neuropsychiatric conditions of late life. Coupling of clinical trials in well-characterized subject populations with PET imaging using ligands specific for 5-HT receptor subtypes and transporter proteins promises to increase our understanding of the role of the 5-HT system in affective and cognitive aspects of treatment response. Longitudinal studies in aging, late-life depression, and AD are also needed to evaluate the complex interplay between neurodegenerative processes and serotonergic neurotransmission.


Identification of Patients Expected to Benefit from Electronic Alerts for Acute Kidney Injury.
Electronic alerts for heterogenous conditions such as AKI may not provide benefit for all eligible patients and can lead to alert fatigue, suggesting that personalized alert targeting may be useful. Uplift-based alert targeting may be superior to purely prognostic-targeting of interventions because uplift models assess marginal treatment effect rather than likelihood of outcome. This is a secondary analysis of a clinical trial of 2278 adult patients with AKI randomized to an automated, electronic alert system versus usual care. We used three uplift algorithms and one purely prognostic algorithm, trained in 70% of the data, and evaluated the effect of targeting alerts to patients with higher scores in the held-out 30% of the data. The performance of the targeting strategy was assessed as the interaction between the model prediction of likelihood to benefit from alerts and randomization status. The outcome of interest was maximum relative change in creatinine from the time of randomization to 3 days after randomization. The three uplift score algorithms all gave rise to a significant interaction term, suggesting that a strategy of targeting individuals with higher uplift scores would lead to a beneficial effect of AKI alerting, in contrast to the null effect seen in the overall study. The prognostic model did not successfully stratify patients with regards to benefit of the intervention. Among individuals in the high uplift group, alerting was associated with a median reduction in change in creatinine of -5.3% (P=0.03). In the low uplift group, alerting was associated with a median increase in change in creatinine of +5.3% (P=0.005). Older individuals, women, and those with a lower randomization creatinine were more likely to receive high uplift scores, suggesting that alerts may benefit those with more slowly developing AKI. Uplift modeling, which accounts for treatment effect, can successfully target electronic alerts for AKI to those most likely to benefit, whereas purely prognostic targeting cannot.


Comparison of incorporation and extension of nucleotides in vitro opposite 8-hydroxyguanine (7,8-dihydro-8-oxoguanine) in hot spots of the c-Ha-ras gene.
DNA templates with 8-hydroxyguanine (7,8-dihydro-8-oxoguanine, oh8Gua) at a site corresponding to the first or second position of codon 12 of the c-Ha-ras gene were prepared, and the nucleotides inserted opposite the modified base were compared. The Klenow fragment (KF) of Escherichia coli DNA polymerase I inserted C opposite oh8Gua at both positions. Taq DNA polymerase incorporated C and A opposite oh8Gua, and the ratio of C to A was higher at the first position than at the second position. DNA polymerase alpha (pol alpha) inserted A and C at the first position, and A at the second position of codon 12, indicating that the ratio of C to A was higher at the first position. Moreover, we studied the extensions of bases paired with oh8Gua by DNA polymerases with or without 3'-5' exonuclease activity. G and T opposite oh8Gua were removed, and subsequently C was inserted by KF. We found that an oh8Gua:A pair was recognized by the exonuclease activity of the enzyme and that A was partially substituted by C. On the other hand, pol alpha extended only C and A opposite oh8Gua. No difference was observed with oh8Gua at the two positions. These results indicate that the ratio of nucleotides incorporated opposite oh8Gua depends on the sequence context, while there is no particular difference in the extension of base pairs involving oh8Gua by DNA polymerases.


Automatic single cell segmentation on highly multiplexed tissue images.
The combination of mass cytometry and immunohistochemistry (IHC) enables new histopathological imaging methods in which dozens of proteins and protein modifications can be visualized simultaneously in a single tissue section. The power of multiplexing combined with spatial information and quantification was recently illustrated on breast cancer tissue and was described as next-generation IHC. Robust, accurate, and high-throughput cell segmentation is crucial for the analysis of this new generation of IHC data. To this end, we propose a watershed-based cell segmentation, which uses a nuclear marker and multiple membrane markers, the latter automatically selected based on their correlation. In comparison with the state-of-the-art segmentation pipelines, which are only using a single marker for object detection, we could show that the use of multiple markers can significantly increase the segmentation power, and thus, multiplexed information should be used and not ignored during the segmentation. Furthermore, we provide a novel, user-friendly open-source toolbox for the automatic segmentation of multiplexed histopathological images.


Information Topics of Greatest Interest for Return of Genome Sequencing Results among Women Diagnosed with Breast Cancer at a Young Age.
We investigated what information women diagnosed with breast cancer at a young age would want to learn when genome sequencing results are returned. We conducted 60 semi-structured interviews with women diagnosed with breast cancer at age 40 or younger. We examined what specific information participants would want to learn across result types and for each type of result, as well as how much information they would want. Genome sequencing was not offered to participants as part of the study. Two coders independently coded interview transcripts; analysis was conducted using NVivo10. Across result types, participants wanted to learn about health implications, risk and prevalence in quantitative terms, causes of variants, and causes of diseases. Participants wanted to learn actionable information for variants affecting risk of preventable or treatable disease, medication response, and carrier status. The amount of desired information differed for variants affecting risk of unpreventable or untreatable disease, with uncertain significance, and not health-related. Women diagnosed with breast cancer at a young age recognize the value of genome sequencing results in identifying potential causes and effective treatments and expressed interest in using the information to help relatives and to further understand their other health risks. Our findings can inform the development of effective feedback strategies for genome sequencing that meet patients' information needs and preferences.


Multivariate protein signatures of pre-clinical Alzheimer's disease in the Alzheimer's disease neuroimaging initiative (ADNI) plasma proteome dataset.
Recent Alzheimer's disease (AD) research has focused on finding biomarkers to identify disease at the pre-clinical stage of mild cognitive impairment (MCI), allowing treatment to be initiated before irreversible damage occurs. Many studies have examined brain imaging or cerebrospinal fluid but there is also growing interest in blood biomarkers. The Alzheimer's Disease Neuroimaging Initiative (ADNI) has generated data on 190 plasma analytes in 566 individuals with MCI, AD or normal cognition. We conducted independent analyses of this dataset to identify plasma protein signatures predicting pre-clinical AD. We focused on identifying signatures that discriminate cognitively normal controls (n = 54) from individuals with MCI who subsequently progress to AD (n = 163). Based on p value, apolipoprotein E (APOE) showed the strongest difference between these groups (p = 2.3 × 10(-13)). We applied a multivariate approach based on combinatorial optimization ((α,β)-k Feature Set Selection), which retains information about individual participants and maintains the context of interrelationships between different analytes, to identify the optimal set of analytes (signature) to discriminate these two groups. We identified 11-analyte signatures achieving values of sensitivity and specificity between 65% and 86% for both MCI and AD groups, depending on whether APOE was included and other factors. Classification accuracy was improved by considering "meta-features," representing the difference in relative abundance of two analytes, with an 8-meta-feature signature consistently achieving sensitivity and specificity both over 85%. Generating signatures based on longitudinal rather than cross-sectional data further improved classification accuracy, returning sensitivities and specificities of approximately 90%. Applying these novel analysis approaches to the powerful and well-characterized ADNI dataset has identified sets of plasma biomarkers for pre-clinical AD. While studies of independent test sets are required to validate the signatures, these analyses provide a starting point for developing a cost-effective and minimally invasive test capable of diagnosing AD in its pre-clinical stages.


Effects of stimulated Brillouin scattering on the performance of polarization-maintaining all-fiber ring resonators.
Low-loss, polarization-maintaining, all-fiber ring resonators can exhibit nonlinear propagation effects occurring at relatively low input powers. Observations have been made of stimulated Brillouin scattering with input powers of 65 microW that lead to significant nonlinear variations in the measured value of finesse owing to depletion of the power through the stimulated-Brillouin-scattering process. Variations of measured finesse from 320 to 210 have been observed for a variation in input power of 155 microW. The nature of this variation in resonator finesse with input power has been studied and is shown to depend on the level of the input power when the resonator response is optimized.


INT reduction is a valid proxy for eukaryotic plankton respiration despite the inherent toxicity of INT and differences in cell wall structure.
The reduction of 2-para (iodophenyl)-3(nitrophenyl)-5(phenyl) tetrazolium chloride (INT) is increasingly being used as an indirect method to measure plankton respiration. Its greater sensitivity and shorter incubation time compared to the standard method of measuring the decrease in dissolved oxygen concentration, allows the determination of total and size-fractionated plankton respiration with higher precision and temporal resolution. However, there are still concerns as to the method's applicability due to the toxicity of INT and the potential differential effect of plankton cell wall composition on the diffusion of INT into the cell, and therefore on the rate of INT reduction. Working with cultures of 5 marine plankton (Thalassiosira pseudonana CCMP1080/5, Emiliania huxleyi RCC1217, Pleurochrysis carterae PLY-406, Scrippsiella sp. RCC1720 and Oxyrrhis marina CCMP1133/5) which have different cell wall compositions (silica frustule, presence/absence of calcite and cellulose plates), we demonstrate that INT does not have a toxic effect on oxygen consumption at short incubation times. There was no difference in the oxygen consumption of a culture to which INT had been added and that of a replicate culture without INT, for periods of time ranging from 1 to 7 hours. For four of the cultures (T. pseudonana CCMP1080/5, P. carterae PLY-406, E. huxleyi RCC1217, and O. marina CCMP1133/5) the log of the rates of dissolved oxygen consumption were linearly related to the log of the rates of INT reduction, and there was no significant difference between the regression lines for each culture (ANCOVA test, F = 1.696, df = 3, p = 0.18). Thus, INT reduction is not affected by the structure of the plankton cell wall and a single INT reduction to oxygen consumption conversion equation is appropriate for this range of eukaryotic plankton. These results further support the use of the INT technique as a valid proxy for marine plankton respiration.


Direct ribosome isolation from soil to extract bacterial rRNA for community analysis.
A simple method that combines an adapted ribosome isolation method and a common RNA extraction step has been developed for selective recovery of intact rRNA from natural microbial communities in soil. After mechanical cell lysis, ribosomes are separated by centrifugation steps, avoiding massive humic acid contamination and RNA degradation. The protocol accommodates the complex composition of soils by blocking adsorbing surfaces and humic acids with polyvinylpyrrolidone and bovine serum albumin. A usual RNA extraction step yields rRNA accessible for hybridization or reverse transcription-PCR. Hybridization with specific oligonucleotide probes was used for group-specific yield comparison. By using a probe hybridizing to the 16S rRNA of the bacterial kingdom, total bacterial rRNA yield was estimated to be in the range of 0.2 microgram per g for different soils. Group-specific probes did not indicate a selectivity of the isolation procedure and differentiated the compositions of different soil microbial communities. The sequence diversity of the isolated RNA population was also revealed by temperature gradient gel electrophoresis of reverse transcription-PCR amplification products by using a region of the 16S rRNA as a target. The pattern obtained by this analysis differed from a similar one resulting from the separation of amplification products of community DNA preparations. This different view of the community composition is attributable to the correlation of ribosome numbers to the metabolic activity of bacteria in the habitat under observation.


Krüppel-like factor 10 upregulates the expression of cyclooxygenase 1 and further modulates angiogenesis in endothelial cell and platelet aggregation in gene-deficient mice.
Krüppel-like family is a group of zinc-finger transcription factors which play key regulatory roles in cellular growth, development, differentiation and vascularization. Recent studies have shown that one of the members, KLF10, is specifically involved in the process of angiogenesis by acting as a key transcriptional regulator of TGF-β1 in pro-angiogenic cells differentiation and function. KLF10(-/-) mice also displayed impaired blood flow recovery after hindlimb ischemia. However, the mechanism of KLF10 induced angiogenesis is still not well understood. From ChIP-chip, which have been adopt to elucidate the novel target genes and signaling cascades of KLF10, COX-1 (also named as PTGS1) is one of the target genes that may be regulated by Klf10 through promoter binding. In order to investigate the function of KLF10/COX-1 axis, promoter activity, EMSA, ChIP-PCR and tube formation assays were serially performed. Our results demonstrated that KLF10 acts as a transcriptional activator on COX-1 promoter where overexpression of KLF10 induces COX-1 protein expression and mRNA expression in endothelial cells. It has been known that COX-1 is the key enzyme in prostaglandin biosynthesis which regulated angiogenesis in endothelial cells. Using tube formation assay, we further demonstrated that KLF10 overexpressed endothelial cells formed better organized three-dimensional tube structure in contrast to the control group did. To specifically investigate the role for KLF10 in angiogenesis, the its deficient mice exhibited decreased light transmission which represents the extend of platelet aggregation slowing down. Taken together, our results indicate an important role for KLF10 in angiogenesis through the activation of COX-1.


Differential occurrence of reluctant openings in G-protein-inhibited N- and P/Q-type calcium channels.
Voltage-dependent inhibition of N- and P/Q-type calcium channels by G proteins is crucial for presynaptic inhibition of neurotransmitter release, and may contribute importantly to short-term synaptic plasticity. Such calcium-channel modulation could thereby impact significantly the neuro-computational repertoire of neural networks. The differential modulation of N and P/Q channels could even further enrich their impact upon synaptic tuning. Here, we performed in-depth comparison of the G-protein inhibition of recombinant N and P/Q channels, expressed in HEK 293 cells with the m2 muscarinic receptor. While both channel types display classic features of G-protein modulation (kinetic slowing of activation, prepulse facilitation, and voltage dependence of inhibition), we confirmed previously reported quantitative differences, with N channels displaying stronger inhibition and greater relief of inhibition by prepulses. A more fundamental, qualitative difference in the modulation of these two channels was revealed by a modified tail-activation paradigm, as well as by a novel "slope" analysis method comparing time courses of slow activation and prepulse facilitation. The stark contrast in modulatory behavior can be understood within the context of the "willing-reluctant" model, in which binding of G-protein betagamma subunits to channels induces a reluctant mode of gating, where stronger depolarization is required for opening. Our experiments suggest that only N channels could be opened in the reluctant mode, at voltages normally spanned by neuronal action potentials. By contrast, P/Q channels appear to remain closed, especially over these physiological voltages. Further, the differential occurrence of reluctant openings is not explained by differences in the rate of G-protein unbinding from the two channels. These two scenarios predict very different effects of G-protein inhibition on the waveform of Ca(2+) entry during action potentials, with potentially important consequences for the timing and efficacy of synaptic transmission.


Geographic variation in alcohol, drug, and mental health services utilization: what are the sources of the variation?
Studies have documented geographic variation in health services utilization over a range of medical, surgical, and psychiatric conditions. These geographic differences are of concern to policy makers, as they may represent either excessive levels of unnecessary care or inappropriately low utilization of necessary services. However, the sources of geographic variation are not well understood, and variation may not represent a quality problem, to the extent that geographic variation is due to sampling variability or variation in case-mix across sites. Our aim was to determine the extent to which geographic variation in assessment and treatment rates for alcohol, drug, and mental disorders (ADM) was due to variation in case-mix across sites and to quantify the amount of geographic variation after case-mix adjustment. We analyzed data from Healthcare for Communities, a nationally representative telephone survey of ADM disorders and treatment. We utilized fixed effects and random intercept models to analyze whether individuals received a brief primary care ADM assessment, any primary care ADM treatment, any specialty ADM treatment, or any ADM treatment. Using the coefficient of variation and intra-class correlation (ICC) as summaries, we simulated reference distributions for the amount of variability in ADM assessment and treatment rates expected due to variation in case mix across 60 geographic areas. We compared this with the actual variation among our 60 sites, and the variation that remained after adjusting for ADM disorders, physical health, and socioeconomic characteristics. The amount of the variation in assessment and treatment rates explained by geographic area in unadjusted fixed effects and random intercepts models was statistically significant with R2 statistics ranging from 1% to 2% in fixed effects models and ICC's ranging from 0.009 to 0.043. Considerably more variation was explained in analyses that included individual level characteristics such as ADM disorders, physical health, and socioeconomic status, with R2 statistics from 10% to 19%. In random intercept models the ICC's were decreased 20 to 100% in models that adjusted for ADM disorders, physical health, and socioeconomic status. We found significant variation in ADM assessment and treatment rates across geographic sites. However, the magnitude of geographic variation was relatively modest, with 0.9 to 4.3% of the total variation in ADM assessment and treatment occurring at the geographic level. Further, it appears that a moderate amount of this geographic variation may be due to differences in case mix across sites. Although geographic variation in assessment and treatment rates can signal variable quality, there may be only modest potential for improving quality by reducing geographic variation. Further, the success of efforts to decrease geographic variation by focusing on provider behavior may be limited by the extent to which systematic variation is explained by individual characteristics. Future work on geographic differences in mental health care as well as in health services more generally should pay particular attention to adjusting for individual differences in morbidity, which strongly predict treatment utilization.


Metabolomic, behavioral, and reproductive effects of the synthetic estrogen 17 α-ethinylestradiol on the unionid mussel Lampsilis fasciola.
The endocrine disrupting effects of estrogenic compounds in surface waters on fish, such as feminization of males and altered sex ratios, may also occur in aquatic invertebrates. However, the underlying mechanisms of action and toxicity, especially in native freshwater mussels (Order Unionoida), remain undefined. This study evaluated the effects of a 12-day exposure of 17 α-ethinylestradiol (EE2), a synthetic estrogen in oral contraceptives commonly found in surface waters, on the behavior, condition, metabolism, and reproductive status of Lampsilis fasciola. Adult mussels of both sexes were exposed to a control and two concentrations of EE2 (0 ng/L, 5 ng/L considered to be environmentally relevant, and 1,000 ng/L designed to provide a positive metabolic response), and samples of gill tissue were taken on days 4 and 12; gills were used because of the variety of critical processes they mediate, such as feeding, ion exchange, and siphoning. Observations of mussel behavior (mantle display, siphoning, and foot movement) were made daily, and condition of conglutinates (packets of eggs and/or glochidia) released by females was examined. No significant effects of EE2 on glochidia mortality, conglutinate condition, female marsupial gill condition, or mussel foot extension were observed. However, exposure to both concentrations of EE2 significantly reduced male siphoning and mantle display behavior of females. Metabolomics analyses identified 207 known biochemicals in mussel gill tissue and showed that environmentally relevant EE2 concentrations led to decreases in glycogen metabolism end products, glucose, and several essential fatty acids in females after 12 days, indicating reductions in energy reserves that could otherwise be used for growth or reproduction. Moreover, males and females showed significant alterations in metabolites involved in signal transduction, immune response, and neuromodulation. Most of these changes were apparent at 1,000 ng/L EE2, but similar metabolites and pathways were also affected at 5 ng/L EE2. Components of the extracellular matrix of gill tissue were also altered. These results demonstrate the utility of metabolomics when used in conjunction with traditional physiological and behavioral toxicity test endpoints and establish the usefulness of this approach in determining possible underlying toxicological mechanisms of EE2 in exposed freshwater mussels.


Short bowel syndrome: a review of management options.
Extensive resection of the intestinal tract frequently results in inadequate digestion and/or absorption of nutrients, a condition known as short bowel syndrome (SBS). This challenging condition demands a dedicated multidisciplinary team effort to overcome the morbidity and mortality in these patients. With advances in critical care management, more and more patients survive the immediate morbidity of massive intestinal resection to present with SBS. Several therapies, including parenteral nutrition (PN), bowel rehabilitation and surgical procedures to reconstruct bowel have been used in these patients. Novel dietary approaches, pharmacotherapy and timely surgical interventions have all added to the improved outcome in these patients. However, these treatments only partially correct the underlying problem of reduced bowel function and have limited success resulting in 30% to 50% mortality rates. However, increasing experience and encouraging results of intestinal transplantation has added a new dimension to the management of SBS. Literature available on SBS is exhaustive but inconclusive. We conducted a review of scientific literature and electronic media with search terms 'short bowel syndrome, advances in SBS and SBS' and attempted to give a comprehensive account on this topic with emphasis on the recent advances in its management.


Neither respiration nor cytochrome c oxidase affects mitochondrial morphology in Saccharomyces cerevisiae.
Previous studies have reported that mitochondrial morphology and volume in yeast cells are linked to cellular respiratory capacity. These studies revealed that mitochondrial morphology in glucose-repressed or anaerobically grown cells, which lack or have reduced levels of respiration, is different from that in fully respiring cells. Although both oxygen deprivation and glucose repression decrease the levels of respiratory chain proteins, they decrease the expression of many non-mitochondrial proteins as well, making it difficult to determine whether it is a defect in respiration or something else that effects mitochondrial morphology. To determine whether mitochondrial morphology is dependent on respiration per se, we used a strain with a null mutation in PET100, a nuclear gene that is specifically required for the assembly of cytochrome c oxidase. Although this strain lacks respiration, the mitochondrial morphology and volumes are both comparable to those found in its respiration-proficient parent. These findings indicate that respiration is not involved in the establishment or maintenance of yeast mitochondrial morphology, and that the previously observed effects of oxygen availability and glucose repression on mitochondrial morphology are not exerted through the respiratory chain. By applying the principle of symmorphosis to these findings, we conclude that the shape and size of the mitochondrial reticulum found in respiring yeast cells is maintained for reasons other than respiration.


Teaching across the generation gap: a consensus from the Council of Emergency Medicine Residency Directors 2009 academic assembly.
Four distinct generations of physicians currently coexist within the emergency medicine (EM) workforce, each with its own unique life experience, perspective, attitude, and expectation of work and education. To the best of our knowledge, no investigations or consensus statements exist that specifically address the effect of intergenerational differences on undergraduate and graduate medical education in EM. To review the existing literature on generational differences as they pertain to workforce expectations, educational philosophy, and learning styles and to create a consensus statement based on the shared insights of experienced educators in EM, with specific recommendations to improve the effectiveness of EM residency training programs. A group of approximately one hundred EM program directors (PDs), assistant PDs, and other academic faculty attending an annual conference of emergency physician (EP) educators gathered at a breakout session and working group to examine the literature on intergenerational differences, to share insights and discuss interventions tailored to address these stylistic differences, and to formulate consensus recommendations. A set of specific recommendations, including effective educational techniques, was created based on literature from other professions and medical disciplines, as well as the contributions of a diverse group of EP educators. Recommendations included early establishment of clear expectations and consequences, emphasis on timely feedback and individualized guidance during training, explicit reinforcement of a patient-centered care model, use of peer modeling and support, and emphasis on more interactive and small-group learning techniques.


Nanostructured pseudocapacitive materials decorated 3D graphene foam electrodes for next generation supercapacitors.
Nowadays, advancement in performance of proficient multifarious electrode materials lies conclusively at the core of research concerning energy storage devices. To accomplish superior capacitance performance the requirements of high capacity, better cyclic stability and good rate capability can be expected from integration of electrochemical double layer capacitor based carbonaceous materials (high power density) and pseudocapacitive based metal hydroxides/oxides or conducting polymers (high energy density). The envisioned three dimensional (3D) graphene foams are predominantly advantageous to extend potential applicability by offering a large active surface area and a highly conductive continuous porous network for fast charge transfer with decoration of nanosized pseudocapacitive materials. In this article, we review the latest methodologies and performance evaluation for several 3D graphene based metal oxides/hydroxides and conducting polymer electrodes with improved electrochemical properties for next-generation supercapacitors. The most recent research advancements of our and other groups in the field of 3D graphene based electrode materials for supercapacitors are discussed. To assess the studied materials fully, a careful interpretation and rigorous scrutiny of their electrochemical characteristics is essential. Auspiciously, both nano-structuration as well as confinement of metal hydroxides/oxides and conducting polymers onto a conducting porous 3D graphene matrix play a great role in improving the performance of electrodes mainly due to: (i) active material access over large surface area with fast charge transportation; (ii) synergetic effect of electric double layer and pseudocapacitive based charge storing.


Association between Internet Gaming Disorder or Pathological Video-Game Use and Comorbid Psychopathology: A Comprehensive Review.
The addictive use of video games is recognized as a problem with clinical relevance and is included in international diagnostic manuals and classifications of diseases. The association between "Internet addiction" and mental health has been well documented across a range of investigations. However, a major drawback of these studies is that no controls have been placed on the type of Internet use investigated. The aim of this study is to review systematically the current literature in order to explore the association between Internet Gaming Disorder (IGD) and psychopathology. An electronic literature search was conducted using PubMed, PsychINFO, ScienceDirect, Web of Science and Google Scholar (r.n. CRD42018082398). The effect sizes for the observed correlations were identified or computed. Twenty-four articles met the eligibility criteria. The studies included comprised 21 cross-sectional and three prospective designs. Most of the research was conducted in Europe. The significant correlations reported comprised: 92% between IGD and anxiety, 89% with depression, 85% with symptoms of attention deficit hyperactivity disorder (ADHD), and 75% with social phobia/anxiety and obsessive-compulsive symptoms. Most of the studies reported higher rates of IGD in males. The lack of longitudinal studies and the contradictory results obtained prevent detection of the directionality of the associations and, furthermore, show the complex relationship between both phenomena.


Sexual Inactivity in Methadone Maintenance Treatment Patients.
Sexual dysfunction has been extensively studied in methadone maintenance treatment (MMT) patients. However, little data is available regarding sexual inactivity in the MMT patient population. The objectives of this study were to determine the prevalence and putative risk factors for sexual inactivity in the MMT patient population. This cross-sectional study involved 25-71 year old MMT patients recruited from six methadone clinics. Two hundred and seventy-one patients were interviewed for demographic characteristics, comorbidities, concurrent medications used, and sexual activity. The prevalence of sexual inactivity in the MMT population was found to be 47.6%. Increasing age (p < 0.01) and being single/divorced (p < 0.01) were significantly associated with sexual inactivity. In subgroup analysis, increasing age was significantly associated with sexual inactivity in both single/divorced (p < 0.05) and married (p < 0.05) subgroups, while unemployment (p < 0.05) was only significantly associated with sexual inactivity in the earlier subgroup. Our results suggest that sexual inactivity is common in the MMT patient population. The putative risk factors are related to biological and sociocultural factors. Having specific comorbidities or being on certain medications were not correlated with sexual inactivity in the MMT population. Routine assessment of sexual problems is essential, and proper management should be performed for MMT patients.


Radiologic findings of idiopathic granulomatous mastitis.
To describe the radiological findings of idiopathic granulomatous mastitis (IGM). Radiologic findings of 30 women with histopathological diagnosis of IGM were retrospectively evaluated. All had breast feeding history. All the patients had ultrasonography (US), with 12 of them having additional Doppler US. Of 30 patients, 11 had mammography (MG) and 5 MRI. US showed multiple irregular hypoechoic masses and collection areas with tubular connections in 25 of 30. The collection area with low-level internal echoes but without tubular connections, suggesting an abscess were seen in 2 of 30 (6.6%); a hypoechoic mass with an indistinct border in 2 of 30 (6.6%); multiple milimetric hypoechoic nodular masses in 1 of 30 (3.3%). On MG, normal findings were noted in 5 (45.4%); focal asymmetric density in 4 (36.4%), parenchymal distortion in 1 (9%) and diffuse asymmetric opacity with trabecular thickening in 1 (9%) of 30 patients. On MRI, segmental T2 hyperintensity with contrast-enhancement on T1 were seen in 4 of 5 (80%). An enhancing T2 hypointense mass with irregular margin was present in 1 of 5 (20%). Time-signal intensity curve of lesions showed slow enhancement in 1 and moderate in 4 of 5 patients. In IGM, MG findings were nonspecific. In US, multiple irregular hypoechoic masses and collections with tubular connections with fingerlike aspects, and fistulae formation to the skin in patients with breastfeeding history suggested IGM rather than carcinoma. Due to the limited number of patients, no conclusion was reached regarding MRI of IGM.


The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations.
Mitochondrial dysfunction is an early sign of many neurodegenerative diseases. Very recently, two Parkinson disease (PD) associated genes, PINK1 and Parkin, were shown to mediate the degradation of damaged mitochondria via selective autophagy (mitophagy). PINK1 kinase activity is needed for prompt and efficient Parkin recruitment to impaired mitochondria. PD-associated Parkin mutations interfere with the process of mitophagy at distinct steps. Here we show that whole mitochondria are turned over via macroautophagy. Moreover, disease-associated PINK1 mutations also compromise the selective degradation of depolarized mitochondria. This may be due to the decreased physical binding activity of PD-linked PINK1 mutations to Parkin. Thus, PINK1 mutations abrogate autophagy of impaired mitochondria upstream of Parkin. In addition to compromised PINK1 kinase activity, reduced binding of PINK1 to Parkin leads to failure in Parkin mitochondrial translocation, resulting in the accumulation of damaged mitochondria, which may contribute to disease pathogenesis.


Televised medical talk shows--what they recommend and the evidence to support their recommendations: a prospective observational study.
To determine the quality of health recommendations and claims made on popular medical talk shows. Prospective observational study. Mainstream television media. Internationally syndicated medical television talk shows that air daily (The Dr Oz Show and The Doctors). Investigators randomly selected 40 episodes of each of The Dr Oz Show and The Doctors from early 2013 and identified and evaluated all recommendations made on each program. A group of experienced evidence reviewers independently searched for, and evaluated as a team, evidence to support 80 randomly selected recommendations from each show. Percentage of recommendations that are supported by evidence as determined by a team of experienced evidence reviewers. Secondary outcomes included topics discussed, the number of recommendations made on the shows, and the types and details of recommendations that were made. We could find at least a case study or better evidence to support 54% (95% confidence interval 47% to 62%) of the 160 recommendations (80 from each show). For recommendations in The Dr Oz Show, evidence supported 46%, contradicted 15%, and was not found for 39%. For recommendations in The Doctors, evidence supported 63%, contradicted 14%, and was not found for 24%. Believable or somewhat believable evidence supported 33% of the recommendations on The Dr Oz Show and 53% on The Doctors. On average, The Dr Oz Show had 12 recommendations per episode and The Doctors 11. The most common recommendation category on The Dr Oz Show was dietary advice (39%) and on The Doctors was to consult a healthcare provider (18%). A specific benefit was described for 43% and 41% of the recommendations made on the shows respectively. The magnitude of benefit was described for 17% of the recommendations on The Dr Oz Show and 11% on The Doctors. Disclosure of potential conflicts of interest accompanied 0.4% of recommendations. Recommendations made on medical talk shows often lack adequate information on specific benefits or the magnitude of the effects of these benefits. Approximately half of the recommendations have either no evidence or are contradicted by the best available evidence. Potential conflicts of interest are rarely addressed. The public should be skeptical about recommendations made on medical talk shows. Additional details of methods used and changes made to study protocol.


Neutralization of porcine endogenous retrovirus by antibodies against the membrane-proximal external region of the transmembrane envelope protein.
Immunization of different species including goats, rats, hamsters and guinea pigs with the recombinant ectodomain of the transmembrane envelope (TM) protein p15E of porcine endogenous retrovirus (PERV) has been shown to result in the production of virus-neutralizing antibodies. The sera recognize two groups of epitopes, one located in the fusion peptide-proximal region (FPPR) and the second in the membrane-proximal external region (MPER) of p15E. Most interestingly, the epitopes in the MPER are similar to epitopes in the TM protein gp41 of human immunodeficiency virus type 1 (HIV-1) recognized by mAbs 2F5 and 4E10, which broadly neutralize HIV-1. To study which epitope and which antibody population are involved in the process of neutralization of PERV, this study generated a new antiserum in a goat using an elongated ectodomain of p15E. The immune serum neutralized PERV at a higher titre and recognized broader epitopes in the FPPR and MPER of p15E. For the first time, antibody subpopulations were isolated from this serum using affinity chromatography with immobilized proteins and peptides corresponding to the FPPR and MPER of p15E. Only the affinity-purified antibodies specifically binding the MPER neutralized PERV, indicating that, as in the case of HIV-1, the MPER is an important target of neutralizing activity.


Mild renal insufficiency is associated with increased left ventricular mass in men, but not in women: an arterial stiffness-related phenomenon--the Hoorn Study.
Mild renal insufficiency has recently been recognized as an important risk factor for cardiovascular disease (CVD). The mechanisms underlying this association are incompletely understood. Increased left ventricular mass (LVM) is an independent risk factor for CVD, which is particularly common in end-stage renal disease (ESRD) and which has been shown to be associated with mild renal insufficiency. Increased arterial stiffness has also been shown to be an independent risk factor for CVD in ESRD and has also been associated with mild renal insufficiency. We hypothesized that the association between mild renal insufficiency and increased LVM could be mediated through increased arterial stiffness, and that this may be one of the pathways linking mild renal insufficiency to CVD. We therefore investigated, in a cross-sectional population-based study, the influence of increased arterial stiffness on the association between renal function and LVM. The study population consisted of 742 elderly individuals (373 men and 369 women). Renal function was estimated by the serum creatinine level in micromol/L; by the Cockcroft-Gault formula in mL/min and by the Modification of Diet in Renal Disease (MDRD) formula. LVM was obtained by echocardiography. The mean estimates of renal function in men and women were, respectively, 103.7 (SD 17.0) and 86.8 (SD 11.2) micromol/L for the serum creatinine level; 63.4 (SD 12.9) and 61.4 (SD 11.0) mL/min/1.73 m(2) for the Cockcroft-Gault formula; and 59.7 (SD 10.8) and 60.9 (SD 10.5) mL/min per 1.73 m(2) for the MDRD formula. LVM was 93.1 (SD 26.4) g/m(2) in men and 86.7 (SD 22.3) g/m(2) in women. In men, impaired renal function, as estimated by the Cockcroft-Gault and the MDRD formula, was significantly associated with greater LVM after adjustment for age, glucose tolerance, hypertension, and prior CVD [regression coefficient beta (95% CI), 1.28 (0.22 to 2.33) g/m(2) and 1.63 (0.41 to 2.86) g/m(2) per 5 mL/min/1.73 m(2) decrease, respectively]. However, the association between impaired renal function and increased LVM was not statistically significant after adjustment for arterial stiffness estimates [regression coefficient beta (95% CI), 0.02 (-1.60 to 1.64) g/m(2) and 0.54 (-1.25 to 2.33) g/m(2) per 5 mL/min/1.73 m(2) decrease, respectively]. In women, impaired renal function was not significantly associated with greater LVM. Our study shows that in a general elderly population, even mild impairment of renal function is associated with adverse changes in left ventricular structure. In men, but not in women, this leads to greater LVM, a process that may be related to increases in arterial stiffness. Importantly, these novel findings suggest that such changes occur early in the process of renal functional deterioration, which may explain, in part, the increase in cardiovascular risk in men with mildly impaired renal function.


Neural tube defects: recent advances, unsolved questions, and controversies.
Neural tube defects are severe congenital malformations affecting around one in every 1000 pregnancies. An innovation in clinical management has come from the finding that closure of open spina bifida lesions in utero can diminish neurological dysfunction in children. Primary prevention with folic acid has been enhanced through introduction of mandatory food fortification in some countries, although not yet in the UK. Genetic predisposition accounts for most of the risk of neural tube defects, and genes that regulate folate one-carbon metabolism and planar cell polarity have been strongly implicated. The sequence of human neural tube closure events remains controversial, but studies of mouse models of neural tube defects show that anencephaly, open spina bifida, and craniorachischisis result from failure of primary neurulation, whereas skin-covered spinal dysraphism results from defective secondary neurulation. Other malformations, such as encephalocele, are likely to be postneurulation disorders.


An RNA polymerase mutant with reduced accuracy of chain elongation.
A new Escherichia coli RNA polymerase mutant was isolated which exhibited reduced accuracy of chain elongation in vivo and in vitro. The novel isolation procedure consisted of simultaneous selection for rifampicin resistance and screening for increased leakiness of an early, strongly polar nonsense mutation of lacZ, one of a special class of mutations whose leakiness reflects mainly transcriptional rather than translational errors. The spontaneous mutant thus isolated displayed a 3-4-fold increase in the leakiness of two different lacZ mutations of this class. Transduction analysis indicated that a single mutation, mapping in or very near the rpoB gene for the beta subunit of RNA polymerase, conferred both rifampicin resistance and increased nonsense leakiness. In an in vitro fidelity assay, homogeneous RNA polymerases from the mutant and parent strains exhibited error rates of 1/0.90 X 10(5) and 1/2.0 X 10(5), respectively, for the poly[d(A-T)] X poly[d(A-T)]-directed misincorporation of noncomplementary GMP. These error rates were verified by product analyses which further revealed that GMP was misincorporated in place of AMP in the synthesis of poly[r(A-U)]. The error rate of wild-type K12 RNA polymerase from a different source was 1/2.0 X 10(5), while that of a hybrid RNA polymerase, containing mutant core enzyme and wild-type sigma subunit, was 1/0.64 X 10(5). These error rates confirmed the selection of a transcriptional accuracy mutant. The error frequencies observed are much lower than those reported in other in vitro assays. The safeguards used to avoid artifactually enhanced misincorporation, and to thereby quantitate lower error rates, are discussed.


Monocyclic Quinone Structure-Activity Patterns: Synthesis of Catalytic Inhibitors of Topoisomerase II with Potent Antiproliferative Activity.
The monocyclic 1,4-benzoquinone, HU-331, the direct oxidation product of cannabidiol, inhibits the catalytic activity of topoisomerase II but without inducing DNA strand breaks or generating free radicals, and unlike many fused-ring quinones exhibits minimal cardiotoxicity. Thus, monocyclic quinones have potential as anticancer agents, and investigation of the structural origins of their biological activity is warranted. New syntheses of cannabidiol and (±)-HU-331 are here reported. Integrated synthetic protocols afforded a wide range of polysubstituted resorcinol derivatives; many of the corresponding novel 2-hydroxy-1,4-benzoquinone derivatives are potent inhibitors of the catalytic activity of topoisomerase II, some more so than HU-331, whose monoterpene unit replaced by a 3-cycloalkyl unit conferred increased antiproliferative properties in cell lines with IC50 values extending below 1 mM, and greater stability in solution than HU-331. The principal pharmacophore of quinones related to HU-331 was identified. Selected monocyclic quinones show potential for the development of new anticancer agents.


A multifunctional multimaterial system for on-demand protein release.
In order to provide best control of the regeneration process for each individual patient, the release of protein drugs administered during surgery may need to be timely adapted and/or delayed according to the progress of healing/regeneration. This study aims to establish a multifunctional implant system for a local on-demand release, which is applicable for various types of proteins. It was hypothesized that a tubular multimaterial container kit, which hosts the protein of interest as a solution or gel formulation, would enable on-demand release if equipped with the capacity of diameter reduction upon external stimulation. Using devices from poly(ɛ-caprolactone) networks, it could be demonstrated that a shape-memory effect activated by heat or NIR light enabled on-demand tube shrinkage. The decrease of diameter of these shape-memory tubes (SMT) allowed expelling the payload as demonstrated for several proteins including SDF-1α, a therapeutically relevant chemotactic protein, to achieve e.g. continuous release with a triggered add-on dosing (open tube) or an on-demand onset of bolus or sustained release (sealed tube). Considering the clinical relevance of protein factors in (stem) cell attraction to lesions and the progress in monitoring biomarkers in body fluids, such on-demand release systems may be further explored e.g. in heart, nerve, or bone regeneration in the future.


Adenovirus precursor pVII protein stability is regulated by its propeptide sequence.
Adenovirus encodes for the pVII protein, which interacts and modulates virus DNA structure in the infected cells. The pVII protein is synthesized as the precursor protein and undergoes proteolytic processing by viral proteinase Avp, leading to release of a propeptide sequence and accumulation of the mature VII protein. Here we elucidate the molecular functions of the propeptide sequence present in the precursor pVII protein. The results show that the propeptide is the destabilizing element targeting the precursor pVII protein for proteasomal degradation. Our data further indicate that the propeptide sequence and the lysine residues K26 and K27 regulate the precursor pVII protein stability in a co-dependent manner. We also provide evidence that the Cullin-3 E3 ubiquitin ligase complex alters the precursor pVII protein stability by association with the propeptide sequence. In addition, we show that inactivation of the Cullin-3 protein activity reduces adenovirus E1A gene expression during early phase of virus infection. Collectively, our results indicate a novel function of the adenovirus propeptide sequence and involvement of Cullin-3 in adenovirus gene expression.


Pricing a Protest: Forecasting the Dynamics of Civil Unrest Activity in Social Media.
Online social media activity can often be a precursor to disruptive events such as protests, strikes, and "occupy" movements. We have observed that such civil unrest can galvanize supporters through social networks and help recruit activists to their cause. Understanding the dynamics of social network cascades and extrapolating their future growth will enable an analyst to detect or forecast major societal events. Existing work has primarily used structural and temporal properties of cascades to predict their future behavior. But factors like societal pressure, alignment of individual interests with broader causes, and perception of expected benefits also affect protest participation in social media. Here we develop an analysis framework using a differential game theoretic approach to characterize the cost of participating in a cascade, and demonstrate how we can combine such cost features with classical properties to forecast the future behavior of cascades. Using data from Twitter, we illustrate the effectiveness of our models on the "Brazilian Spring" and Venezuelan protests that occurred in June 2013 and November 2013, respectively. We demonstrate how our framework captures both qualitative and quantitative aspects of how these uprisings manifest through the lens of tweet volume on Twitter social media.


Enhancement of Cortical Network Activity in vitro and Promotion of GABAergic Neurogenesis by Stimulation with an Electromagnetic Field with a 150 MHz Carrier Wave Pulsed with an Alternating 10 and 16 Hz Modulation.
In recent years, various stimuli were identified capable of enhancing neurogenesis, a process which is dysfunctional in the senescent brain and in neurodegenerative and certain neuropsychiatric diseases. Applications of electromagnetic fields to brain tissue have been shown to affect cellular properties and their importance for therapies in medicine is recognized. In this study, differentiating murine cortical networks on multiwell microelectrode arrays were repeatedly exposed to an extremely low-electromagnetic field (ELEMF) with alternating 10 and 16 Hz frequencies piggy backed onto a 150 MHz carrier frequency. The ELEMF exposure stimulated the electrical network activity and intensified the structure of bursts. Further, the exposure to electromagnetic fields within the first 28 days in vitro of the differentiation of the network activity induced also reorganization within the burst structure. This effect was already most pronounced at 14 days in vitro after 10 days of exposure. Overall, the development of cortical activity under these conditions was accelerated. These functional electrophysiological changes were accompanied by morphological ones. The percentage of neurons in the neuron glia co-culture was increased without affecting the total number of cells, indicating an enhancement of neurogenesis. The ELEMF exposure selectively promoted the proliferation of a particular population of neurons, evidenced by the increased proportion of GABAergic neurons. The results support the initial hypothesis that this kind of ELEMF stimulation could be a treatment option for specific indications with promising potential for CNS applications, especially for degenerative diseases, such as Alzheimer's disease and other dementias.


Turbulent mixing: A perspective.
Mixing of initially distinct substances plays an important role in our daily lives as well as in ecological and technological worlds. From the continuum point of view, which we adopt here, mixing is complete when the substances come together across smallest flow scales determined in part by molecular mechanisms, but important stages of the process occur via the advection of substances by an underlying flow. We know how smooth flows enable mixing but less well the manner in which a turbulent flow influences it; but the latter is the more common occurrence on Earth and in the universe. We focus here on turbulent mixing, with more attention paid to the postmixing state than to the transient process of initiation. In particular, we examine turbulent mixing when the substance is a scalar (i.e., characterized only by the scalar property of its concentration), and the mixing process does not influence the flow itself (i.e., the scalar is "passive"). This is the simplest paradigm of turbulent mixing. Within this paradigm, we discuss how a turbulently mixed state depends on the flow Reynolds number and the Schmidt number of the scalar (the ratio of fluid viscosity to the scalar diffusivity), point out some fundamental aspects of turbulent mixing that render it difficult to be addressed quantitatively, and summarize a set of ideas that help us appreciate its physics in diverse circumstances. We consider the so-called universal and anomalous features and summarize a few model studies that help us understand them both.


Runx family genes in a cartilaginous fish, the elephant shark (Callorhinchus milii).
The Runx family genes encode transcription factors that play key roles in hematopoiesis, skeletogenesis and neurogenesis and are often implicated in diseases. We describe here the cloning and characterization of Runx1, Runx2, Runx3 and Runxb genes in the elephant shark (Callorhinchus milii), a member of Chondrichthyes, the oldest living group of jawed vertebrates. Through the use of alternative promoters and/or alternative splicing, each of the elephant shark Runx genes expresses multiple isoforms similar to their orthologs in human and other bony vertebrates. The expression profiles of elephant shark Runx genes are similar to those of mammalian Runx genes. The syntenic blocks of genes at the elephant shark Runx gene loci are highly conserved in human, but represented by shorter conserved blocks in zebrafish indicating a higher degree of rearrangements in this teleost fish. Analysis of promoter regions revealed conservation of binding sites for transcription factors, including two tandem binding sites for Runx that are totally conserved in the distal promoter regions of elephant shark Runx1-3. Several conserved noncoding elements (CNEs), which are putative cis-regulatory elements, and miRNA binding sites were identified in the elephant shark and human Runx gene loci. Some of these CNEs and miRNA binding sites are absent in teleost fishes such as zebrafish and fugu. In summary, our analysis reveals that the genomic organization and expression profiles of Runx genes were already complex in the common ancestor of jawed vertebrates.


Lyssavirus detection and typing using pyrosequencing.
Rabies is a fatal zoonosis caused by a nonsegmented negative-strand RNA virus, namely, rabies virus (RABV). Apart from RABV, at least 10 additional species are known as rabies-related lyssaviruses (RRVs), and some of them are responsible for occasional spillovers into humans. More lyssaviruses have also been detected recently in different bat ecosystems, thanks to the application of molecular diagnostic methods. Due to the variety of the members of the genus Lyssavirus, there is the necessity to develop a reliable molecular assay for rabies diagnosis able to detect and differentiate among the existing rabies and rabies-related viruses. In the present study, a pyrosequencing protocol targeting the 3' terminus of the nucleoprotein (N) gene was applied for the rapid characterization of lyssaviruses. Correct identification of species was achieved for each sample tested. Results from the pyrosequencing assay were also confirmed by those obtained using the Sanger sequencing method. A pan-lyssavirus one-step reverse transcription (RT)-PCR was developed within the framework of the pyrosequencing procedure. The sensitivity (Se) of the one-step RT-PCR assay was determined by using in vitro-transcribed RNA and serial dilutions of titrated viruses. The assay demonstrated high analytical and relative specificity (Sp) (98.94%) and sensitivity (99.71%). To date, this is the first case in which pyrosequencing has been applied for lyssavirus identification using a cheaper diagnostic approach than the one for all the other protocols for rapid typing that we are acquainted with. Results from this study indicate that this procedure is suitable for lyssavirus detection in samples of both human and animal origin.


Differences in affinity of monoclonal and naturally acquired polyclonal antibodies against Plasmodium falciparum merozoite antigens.
Malaria is a major global cause of deaths and a vaccine is urgently needed. We have employed the P. falciparum merozoite antigens MSP2-3D7/FC27 and AMA1, used them in ELISA, and coupled them in different ways using surface plasmon resonance (SPR) and estimated affinity (measured as kd) of monoclonal as well as naturally-acquired polyclonal antibodies in human plasma. There were major differences in kd depending on how the antigens were immobilized and where the His-tag was placed. For AMA1 we could see correlations with invasion inhibition. Using different immobilizations of proteins in SPR, we could see only moderate correlations with levels of antibodies in ELISA, indicating that in ELISA the proteins were not uniformly bound and that antibodies with many specificities exist in natural immunisation. The correlations between ELISA and SPR were enhanced when only parasite positive samples were included, which may indicate that high affinity antibodies are difficult to maintain over long periods of time. We found higher kd values for MSP2 (indicating lower affinity) compared to AMA1, which might be partly explained by MSP2 being an intrinsically disordered protein, while AMA1 is globular. For future vaccine studies and for understanding immunity, it is important to consider how to present proteins to the immune system to achieve highest antibody affinities.


Ketamine for the treatment of addiction: Evidence and potential mechanisms.
Ketamine is a dissociative anaesthetic drug which acts on the central nervous system chiefly through antagonism of the n-methyl-d-aspartate (NMDA) receptor. Recently, ketamine has attracted attention as a rapid-acting anti-depressant but other studies have also reported its efficacy in reducing problematic alcohol and drug use. This review explores the preclinical and clinical research into ketamine's ability to treat addiction. Despite methodological limitations and the relative infancy of the field, results thus far are promising. Ketamine has been shown to effectively prolong abstinence from alcohol and heroin in detoxified alcoholics and heroin dependent individuals, respectively. Moreover, ketamine reduced craving for and self-administration of cocaine in non-treatment seeking cocaine users. However, further randomised controlled trials are urgently needed to confirm ketamine's efficacy. Possible mechanisms by which ketamine may work within addiction include: enhancement of neuroplasticity and neurogenesis, disruption of relevant functional neural networks, treating depressive symptoms, blocking reconsolidation of drug-related memories, provoking mystical experiences and enhancing psychological therapy efficacy. Identifying the mechanisms by which ketamine exerts its therapeutic effects in addiction, from the many possible candidates, is crucial for advancing this treatment and may have broader implications understanding other psychedelic therapies. In conclusion, ketamine shows great promise as a treatment for various addictions, but well-controlled research is urgently needed. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.


Role of opioid antagonists in the treatment of women with glucoregulation abnormalities.
Beta-endorphin were detected in the endocrine pancreas and seem able to influence insulin and glucagon release. Hence, endogenous opioids could have a role in glucoregulation and in the pathogenesis of obesity beyond the previously detected effects on appetite. Metabolic abnormalities, such as hyperinsulinemia, insulin-resistance and obesity, are common features of polycystic ovary syndrome (PCOS), and seem to have a pathogenetic role in this disorder. A link between opioids and PCOS-related hyperinsulinism is suggested by the finding of altered central opioid tone and elevated beta-endorphins levels, directly correlated with body weight, in these patients. Furthermore, naloxone and naltrexone significantly reduce the insulin response to glucose load only in hyperinsulinemic PCOS patients. This effect is obtained chiefly through an improvement of insulin clearance. Naltrexone is also able to ameliorate the abnormal gonadotrophins secretion and to improve the ovarian responsiveness in obese PCOS women undergoing ovulation induction with exogenous GnRH. Such effects are believed to be obtained through an amelioration of hyperinsulinemia. Gonadal steroids modulate the opioid system both centrally and in peripheral districts. Nevertheless, the decline of ovarian function does not abolish the opioidergic control of glucoregulation. Post-menopausal period is characterised by a high prevalence of hyperinsulinemia and insulin-resistance. In particular, an association between hyperinsulinemia and increased opioid activity was found in postmenopausal women showing a central body fat distribution. Both naloxone and naltrexone ameliorate the metabolic imbalance also when it appears in the climacteric period, and mainly by increasing insulin clearance. The benefits of naltrexone may represent in the future a useful tool for the treatment of women with hyperinsulinism in the clinical practice.


A novel measure of poverty and its association with elevated sexual risk behavior among young Black MSM.
This study determined whether a novel (single-item) measure of poverty is associated with elevated sexual risk among young Black men who have sex with men who reside in a US city with high HIV seroprevalence. A convenience sample of 600 Black men who have sex with men (ages 16-29) completed a computer-assisted self-interview. The questionnaire included an item asking men, 'In the past 12 months have you missed meals because you did not have enough money to eat?' Selected measures of sexual risk and prevalence of chlamydia, gonorrhea, and HIV were assessed as outcomes of this novel measure of poverty. About 22% had missed meals due to lack of money. In age-adjusted analyses, these men were more likely to report: (1) having concurrent sex partners ( P = .03), (2) having sex with partners who were generally five or more years older ( P = .02), (3) not using condoms the first time they had sex with their most recent new partner ( P = .015), (4) having sex with persons not known by name ( P = .02), (5) depending on sex partners for food, money, and shelter ( P < .0001), and (6) testing positive for Chlamydia at study enrollment ( P < .02). Of interest, an association in frequency of recent condomless anal sex as top ( P = .04) was observed; however, the association for recent condomless sex as bottom ( P = .37) was not significant. For young Black men who have sex with men, a novel method of assessing poverty may be predictive of many sexual risk behaviors. Clinicians may benefit this population by including this question as part of their patient interview and prioritizing services when indicated.


The E3 ligase TTC3 facilitates ubiquitination and degradation of phosphorylated Akt.
The serine threonine kinase Akt is a core survival factor that underlies a variety of human diseases. Although regulatory phosphorylation and dephosphorylation have been well documented, the other posttranslational mechanisms that modulate Akt activity remain unclear. We show here that tetratricopeptide repeat domain 3 (TTC3) is an E3 ligase that interacts with Akt. TTC3 contains a canonical RING finger motif, a pair of tetratricopeptide motifs, a putative Akt phosphorylation site, and nuclear localization signals, and is encoded by a gene within the Down syndrome (DS) critical region on chromosome 21. TTC3 is an Akt-specific E3 ligase that binds to phosphorylated Akt and facilitates its ubiquitination and degradation within the nucleus. Moreover, DS cells exhibit elevated TTC3 expression, reduced phosphorylated Akt, and accumulation in the G(2)M phase, which can be reversed by TTC3 siRNA or Myr-Akt. Thus, interaction between TTC3 and Akt may contribute to the clinical symptoms of DS.


Breastfeeding modifies the effects of environment tobacco smoke exposure on respiratory diseases and symptoms in Chinese children: the Seven Northeast Cities Study.
To evaluate the potential effect of interaction between breastfeeding and environmental tobacco smoke (ETS) exposure on respiratory health, we studied 31 049 children (aged 2-14 years) from 25 districts of seven cities in northeast China. Parents of the children completed standardized questionnaires that characterized the children's histories of respiratory symptoms and illness, feeding methods, ETS exposure, and other associated risk factors. Breastfeeding was defined as having been mainly breastfed for 3 months or more. The results showed that the association of ETS exposure with childhood respiratory conditions/diseases was modified by breastfeeding, and the association for nonbreastfed children was stronger than that for breastfed children. In particular, for nonbreastfed children, the odds ratios (ORs) for the effect of current ETS exposure asthma was 1.71 (95% CI: 1.43-2.05); however, the OR for breastfed children was 1.33 (95% CI: 1.20-1.48), indicating that the interactions between breastfeeding and current ETS exposure on asthma were statistically significant (P = 0.019). When stratified by school (kindergarten vs. elementary school), breastfeeding was more protective for asthma-related symptoms among children from kindergarten. In conclusion, this study shows that breastfeeding is associated with smaller associations between ETS exposure and respiratory conditions in children, suggesting that breastfeeding reduces susceptibility to the respiratory effects of ETS.


Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial.
Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents. SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of study treatment were included for safety analysis (ClinicalTrials.gov identifier: NCT02606461). Two hundred eighty-five patients were enrolled (selinexor, n = 188; placebo, n = 97). PFS was significantly longer with selinexor versus placebo: hazard ratio (HR) 0.70 (95% CI, 0.52 to 0.95; one-sided P = .011; medians 2.8 v 2.1 months), as was time to next treatment: HR 0.50 (95% CI, 0.37 to 0.66; one-sided P < .0001; medians 5.8 v 3.2 months). With crossover, no difference was observed in overall survival. The most common treatment-emergent adverse events of any grade versus grade 3 or 4 with selinexor were nausea (151 [80.7%] v 11 [5.9]), decreased appetite (113 [60.4%] v 14 [7.5%]), and fatigue (96 [51.3%] v 12 [6.4%]). Four (2.1%) and three (3.1%) patients died in the selinexor and placebo arms, respectively. Exploratory RNA sequencing analysis identified that the absence of CALB1 expression was associated with longer PFS with selinexor compared with placebo (median 6.9 v 2.2 months; HR, 0.19; P = .001). Patients with advanced, refractory DD-LPS showed improved PFS and time to next treatment with selinexor compared with placebo. Supportive care and dose reductions mitigated side effects of selinexor. Prospective validation of CALB1 expression as a predictive biomarker for selinexor in DD-LPS is warranted.


Infection of class II-deficient mice by the DA strain of Theiler's virus.
The DA strain of Theiler's virus causes, in susceptible strains of mice, a persistent infection of the white matter of the spinal cord accompanied by chronic inflammation and primary demyelination. In resistant strains, including all H-2b strains, mice clear the infection after 1 to 2 weeks. We inoculated RHAbetao/o mice, an H-2b strain which does not express class II molecules. We found that they are susceptible to persistent infection and that they develop foci of chronic inflammation with demyelination. However, these foci are smaller and contain fewer demyelinated axons than those observed in susceptible SJL/J or beta2m-/- mice.


Broad host range plasmids can invade an unexpectedly diverse fraction of a soil bacterial community.
Conjugal plasmids can provide microbes with full complements of new genes and constitute potent vehicles for horizontal gene transfer. Conjugal plasmid transfer is deemed responsible for the rapid spread of antibiotic resistance among microbes. While broad host range plasmids are known to transfer to diverse hosts in pure culture, the extent of their ability to transfer in the complex bacterial communities present in most habitats has not been comprehensively studied. Here, we isolated and characterized transconjugants with a degree of sensitivity not previously realized to investigate the transfer range of IncP- and IncPromA-type broad host range plasmids from three proteobacterial donors to a soil bacterial community. We identified transfer to many different recipients belonging to 11 different bacterial phyla. The prevalence of transconjugants belonging to diverse Gram-positive Firmicutes and Actinobacteria suggests that inter-Gram plasmid transfer of IncP-1 and IncPromA-type plasmids is a frequent phenomenon. While the plasmid receiving fractions of the community were both plasmid- and donor- dependent, we identified a core super-permissive fraction that could take up different plasmids from diverse donor strains. This fraction, comprising 80% of the identified transconjugants, thus has the potential to dominate IncP- and IncPromA-type plasmid transfer in soil. Our results demonstrate that these broad host range plasmids have a hitherto unrecognized potential to transfer readily to very diverse bacteria and can, therefore, directly connect large proportions of the soil bacterial gene pool. This finding reinforces the evolutionary and medical significances of these plasmids.


Apples to apples: can differences in out-of-hospital cardiac arrest incidence and outcomes between Sweden and Ireland be explained by core Utstein variables?
Variation in reported incidence and outcome based on aggregated data is a persistent feature of out-of-hospital cardiac arrest (OHCA) epidemiology. To investigate the extent to which patient-level analysis using core 'Utstein' variables explains inter-country variation between Sweden and the Republic of Ireland. A retrospective cross-sectional comparative study was performed, including all Swedish and Irish OHCA cases attended by Emergency Medical Services (EMS-attended OHCA) where resuscitation was attempted from 1st January 2012 to 31st December 2014. Incidence rates per 100,000 population were adjusted for age and gender. Two subgroups were extracted: (1) Utstein - adult patients, bystander-witnessed collapse, presumed medical aetiology, initial shockable rhythm and (2) Emergency Medical Service (EMS)-witnessed events. Multivariable logistic regression analysis was used to identify predictors of survival following multiple imputations of data. Five thousand eight hundred eighty six Irish and 15,303 Swedish patients were included. Swedish patients were older than Irish patients (median age 71 vs. 66 years respectively). Adjusted incidence was significantly higher in Sweden compared to the Republic of Ireland (52.9 vs. 43.1 per 100,000 population per year). Proportionate survival in Sweden was greater for both subgroups and all age categories. Regression analysis of the Utstein subgroup predicted approximately 17% of variation in outcome, but there was a large unexplained 'country effect' for survival in favour of Sweden (OR 4.40 (95% CI 2.55-7.56)). Using patient level data, a proportion of inter-country variation was explained, but substantial variation was not explained by the core Utstein variables. Researchers and policy makers should be aware of the potential for unmeasured differences when comparing OHCA incidence and outcomes between countries.


A randomized trial of planned cesarean or vaginal delivery for twin pregnancy.
Twin birth is associated with a higher risk of adverse perinatal outcomes than singleton birth. It is unclear whether planned cesarean section results in a lower risk of adverse outcomes than planned vaginal delivery in twin pregnancy. We randomly assigned women between 32 weeks 0 days and 38 weeks 6 days of gestation with twin pregnancy and with the first twin in the cephalic presentation to planned cesarean section or planned vaginal delivery with cesarean only if indicated. Elective delivery was planned between 37 weeks 5 days and 38 weeks 6 days of gestation. The primary outcome was a composite of fetal or neonatal death or serious neonatal morbidity, with the fetus or infant as the unit of analysis for the statistical comparison. A total of 1398 women (2795 fetuses) were randomly assigned to planned cesarean delivery and 1406 women (2812 fetuses) to planned vaginal delivery. The rate of cesarean delivery was 90.7% in the planned-cesarean-delivery group and 43.8% in the planned-vaginal-delivery group. Women in the planned-cesarean-delivery group delivered earlier than did those in the planned-vaginal-delivery group (mean number of days from randomization to delivery, 12.4 vs. 13.3; P=0.04). There was no significant difference in the composite primary outcome between the planned-cesarean-delivery group and the planned-vaginal-delivery group (2.2% and 1.9%, respectively; odds ratio with planned cesarean delivery, 1.16; 95% confidence interval, 0.77 to 1.74; P=0.49). In twin pregnancy between 32 weeks 0 days and 38 weeks 6 days of gestation, with the first twin in the cephalic presentation, planned cesarean delivery did not significantly decrease or increase the risk of fetal or neonatal death or serious neonatal morbidity, as compared with planned vaginal delivery. (Funded by the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00187369; Current Controlled Trials number, ISRCTN74420086.).


Pediatric nonalcoholic fatty liver disease, metabolic syndrome and cardiovascular risk.
Nonalcoholic fatty liver disease (NAFLD) encompasses a range of liver histology severity and outcomes in the absence of chronic alcohol use. The mildest form is simple steatosis in which triglycerides accumulate within hepatocytes. A more advanced form of NAFLD, non-alcoholic steatohepatitis, includes inflammation and liver cell injury, progressive to cryptogenic cirrhosis. NAFLD has become the most common cause of chronic liver disease in children and adolescents. The recent rise in the prevalence rates of overweight and obesity likely explains the NAFLD epidemic worldwide. NAFLD is strongly associated with abdominal obesity, type 2 diabetes, and dyslipidemia, and most patients have evidence of insulin resistance. Thus, NAFLD shares many features of the metabolic syndrome (MetS), a highly atherogenic condition, and this has stimulated interest in the possible role of NAFLD in the development of atherosclerosis. Accumulating evidence suggests that NAFLD is associated with a significantly greater overall mortality than in the general population, as well as with increased prevalence of cardiovascular disease (CVD), independently of classical atherosclerotic risk factors. Yet, several studies including the pediatric population have reported independent associations between NAFLD and impaired flow-mediated vasodilatation and increased carotid artery intimal medial thickness-two reliable markers of subclinical atherosclerosis-after adjusting for cardiovascular risk factors and MetS. Therefore, the rising prevalence of obesity-related MetS and NAFLD in childhood may lead to a parallel increase in adverse cardiovascular outcomes. In children, the cardiovascular system remains plastic and damage-reversible if early and appropriate interventions are established effectively. Therapeutic goals for NAFLD should address nutrition, physical activity, and avoidance of smoking to prevent not only end-stage liver disease but also CVD.


Osteopontin is highly susceptible to cleavage in bovine milk and the proteolytic fragments bind the αVβ₃-integrin receptor.
Site-specific and partial proteolysis of milk proteins can both alter and increase their biological activity. The milk protein osteopontin (OPN) is a highly phosphorylated integrin-binding molecule present in most tissues and body fluids. Osteopontin is a biological substrate for matrix metalloproteinases, thrombin, plasmin, and cathepsin D. These proteases cleave OPN at several positions near the integrin-binding sequence Arg-Gly-Asp(138). This cleavage can either increase or reduce the ability of OPN to bind integrins and illustrates that small differences in the cleavage pattern can have a substantial effect on the functionality of OPN. Bovine milk OPN (bOPN) exists in both intact full-length and cleaved forms, and in this study, 6 N-terminal bOPN fragments originating from proteolytic cleavage were purified and characterized by mass spectrometry. These fragments were generated by cleavage at the Lys(145)-Ser(146), Arg(147)-Ser(148), Lys(149)-Lys(150), Phe(151)-Arg(152), Arg(152)-Arg(153), and Arg(153)-Ser(154) peptide bonds. The principal protease in milk, plasmin, appeared to cleave 3 of these sites. However, the major cleavage site was observed to be at the Phe(151)-Arg(152) bond, which does not match the specificity of plasmin. The bOPN fragments were shown to interact with the integrin receptor αVβ₃ as efficiently as the well-characterized and highly active OPN fragment Ile(1)-Arg(152), generated by thrombin cleavage of human milk OPN. These data show that OPN in milk is highly susceptible to proteolytic cleavage in the region containing the integrin-binding motifs, and the generated fragments are highly capable of binding cells via the αVβ₃-integrin.


Out of the silos: embedding injury prevention into the Sustainable Development Goals.
Globally, unintentional injuries contribute significantly to disability and death. Prevention efforts have traditionally focused on individual injury mechanisms and their specific risk factors, which has resulted in slow progress in reducing the burden. The Sustainable Development Goals (SDGs) represent a global agenda for promoting human prosperity while respecting planetary boundaries. While injury prevention is currently only recognised in the SDG agenda via two road safety targets, the relevance of the SDGs for injury prevention is much broader. In this State of the Art Review, we illustrate how unintentional injury prevention efforts can be advanced substantially within a broad range of SDG goals and advocate for the integration of safety considerations across all sectors and stakeholders. This review uncovers injury prevention opportunities within broader global priorities such as urbanisation, population shifts, water safeguarding and corporate social responsibility. We demonstrate the relevance of injury prevention efforts to the SDG agenda beyond the health goal (SDG 3) and the two specific road safety targets (SDG 3.6 and SDG 11.2), highlighting 13 additional SDGs of relevance. We argue that all involved in injury prevention are at a critical juncture where we can continue with the status quo and expect to see more of the same, or mobilise the global community in an 'Injury Prevention in All Policies' approach.


Slip-stacked perylenediimides as an alternative strategy for high efficiency nonfullerene acceptors in organic photovoltaics.
Perylenediimide (PDI)-based acceptors offer a potential replacement for fullerenes in bulk-heterojunction (BHJ) organic photovoltaic cells (OPVs). The most promising efforts have focused on creating twisted PDI dimers to disrupt aggregation and thereby suppress excimer formation. Here, we present an alternative strategy for developing high-performance OPVs based on PDI acceptors that promote slip-stacking in the solid state, thus preventing the coupling necessary for rapid excimer formation. This packing structure is accomplished by substitution at the PDI 2,5,8,11-positions ("headland positions"). Using this design principle, three PDI acceptors, N,N-bis(n-octyl)-2,5,8,11-tetra(n-hexyl)-PDI (Hexyl-PDI), N,N-bis(n-octyl)-2,5,8,11-tetraphenethyl-PDI (Phenethyl-PDI), and N,N-bis(n-octyl)-2,5,8,11-tetraphenyl-PDI (Phenyl-PDI), were synthesized, and their molecular and electronic structures were characterized. They were then blended with the donor polymer PBTI3T, and inverted OPVs of the structure ITO/ZnO/Active Layer/MoO3/Ag were fabricated and characterized. Of these, 1:1 PBTI3T:Phenyl-PDI proved to have the best performance with Jsc = 6.56 mA/cm(2), Voc = 1.024 V, FF = 54.59%, and power conversion efficiency (PCE) = 3.67%. Devices fabricated with Phenethyl-PDI and Hexyl-PDI have significantly lower performance. The thin film morphology and the electronic and photophysical properties of the three materials are examined, and although all three materials undergo efficient charge separation, PBTI3T:Phenyl-PDI is found to have the deepest LUMO, intermediate crystallinity, and the most well-mixed domains. This minimizes geminate recombination in Phenyl-PDI OPVs and affords the highest PCE. Thus, slip-stacked PDI strategies represent a promising approach to fullerene replacements in BHJ OPVs.


Structural basis for the recognition of the S2, S5-phosphorylated RNA polymerase II CTD by the mRNA anti-terminator protein hSCAF4.
The C-terminal domain (CTD) of RNA polymerase II serves as a binding platform for numerous enzymes and transcription factors involved in nascent RNA processing and the transcription cycle. The S2, S5-phosphorylated CTD is recognized by the transcription factor SCAF4, which functions as a transcription anti-terminator by preventing early mRNA transcript cleavage and polyadenylation. Here, we measured the binding affinities of differently modified CTD peptides by hSCAF4 and solved the complex structure of the hSCAF4-CTD-interaction domain (CID) bound to a S2, S5-quadra-phosphorylated CTD peptide. Our results revealed that the S2, S5-quadra-phosphorylated CTD peptide adopts a trans conformation and is located in a positively charged binding groove of hSCAF4-CID. Although hSCAF4-CID has almost the same binding pattern to the CTD as other CID-containing proteins, it preferentially binds to the S2, S5-phosphorylated CTD. Our findings provide insight into the regulatory mechanism of hSCAF4 in transcription termination.


Photodynamic drug delivery enhancement in tumours does not depend on leukocyte-endothelial interaction in a human mesothelioma xenograft model.
The pre-treatment of tumour neovessels by low-level photodynamic therapy (PDT) improves the distribution of concomitantly administered systemic chemotherapy. The mechanism by which PDT permeabilizes the tumour vessel wall is only partially known. We have recently shown that leukocyte-endothelial cell interaction is essential for photodynamic drug delivery to normal tissue. The present study investigates whether PDT enhances drug delivery in malignant mesothelioma and whether it involves comparable mechanisms of actions. Human mesothelioma xenografts (H-meso-1) were grown in the dorsal skinfold chambers of 28 nude mice. By intravital microscopy, the rolling and recruitment of leukocytes were assessed in tumour vessels following PDT (Visudyne(®) 400 μg/kg, fluence rate 200 mW/cm(2) and fluence 60 J/cm(2)) using intravital microscopy. Likewise, the distribution of fluorescently labelled macromolecular dextran (FITC-dextran, MW 2000 kDa) was determined after PDT. Study groups included no PDT, PDT, PDT plus a functionally blocking anti-pan-selectin antibody cocktail and PDT plus isotype control antibody. PDT significantly enhanced the extravascular accumulation of FITC-dextran in mesothelioma xenografts, but not in normal tissue. PDT significantly increased leukocyte-endothelial cell interaction in tumour. While PDT-induced leukocyte recruitment was significantly blunted by the anti-pan-selectin antibodies in the tumour xenograft, this manipulation did not affect the PDT-induced extravasation of FITC-dextran. Low-level PDT pre-treatment selectively enhances the uptake of systemically circulating macromolecular drugs in malignant mesothelioma, but not in normal tissue. Leukocyte-endothelial cell interaction is not required for PDT-induced drug delivery to malignant mesothelioma.


Personalization of pictorial structures for anatomical landmark localization.
We propose a method for accurately localizing anatomical landmarks in 3D medical volumes based on dense matching of parts-based graphical models. Our novel approach replaces population mean models by jointly leveraging weighted combinations of labeled exemplars (both spatial and appearance) to obtain personalized models for the localization of arbitrary landmarks in upper body images. We compare the method to a baseline population-mean graphical model and atlas-based deformable registration optimized for CT-CT registration, by measuring the localization accuracy of 22 anatomical landmarks in clinical 3D CT volumes, using a database of 83 lung cancer patients. The average mean localization error across all landmarks is 2.35 voxels. Our proposed method outperforms deformable registration by 73%, 93% for the most improved landmark. Compared to the baseline population-mean graphical model, the average improvement of localization accuracy is 32%; 67% for the most improved landmark.


Invasive meningococcal disease in the University of Malaya Medical Centre, Kuala Lumpur, Malaysia.
Neisseria meningitidis (N. meningitidis) remains the leading worldwide cause of acute bacterial meningitis and fatal sepsis in healthy individuals. A total of 12 cases of N. meningitidis from patients with invasive meningococcal infections in University of Malaya Medical Centre, Kuala Lumpur during the years 1987-2004 were reviewed together with details of age, sex, disease, risk factors treatment and outcome of these patients. Their ages ranged from 10 months to 64 years (median age 29.75 years). The male to female ratio was 1.42:1. Fever, neck stiffness, headache, vomiting and confusion were predominant symptoms. Upper respiratory tract viral infection and Hajj pilgrimage were directly associated with invasive meningococcal disease. Penicillin or ceftriaxone or both in some cases were administered as empirical therapy. All isolates were sensitive to penicillin, ceftriaxone, chloramphenicol and rifampicin. The case fatality ratio was 1:4. One Hajj pilgrim died despite having received polyvalent meningococcal vaccine. Amongst the survivors, two patients had neurological deficit, hearing loss and arthritis. Early antimicrobial therapy has been shown to reduce these adverse outcomes. Clinicians need to be alerted to the presence of the disease in the community and the disease should be made notifiable within 24 hours of detection both for early treatment of cases and to facilitate contact tracing, institution of prophylactic treatment and prevention of secondary cases.


Pulmonary hyperinflation and left ventricular mass: the Multi-Ethnic Study of Atherosclerosis COPD Study.
Left ventricular (LV) mass is an important predictor of heart failure and cardiovascular mortality, yet determinants of LV mass are incompletely understood. Pulmonary hyperinflation in chronic obstructive pulmonary disease (COPD) may contribute to changes in intrathoracic pressure that increase LV wall stress. We therefore hypothesized that residual lung volume in COPD would be associated with greater LV mass. The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited smokers 50 to 79 years of age who were free of clinical cardiovascular disease. LV mass was measured by cardiac magnetic resonance. Pulmonary function testing was performed according to guidelines. Regression models were used to adjust for age, sex, body size, blood pressure, and other cardiac risk factors. Among 119 MESA COPD Study participants, the mean age was 69±6 years, 55% were male, and 65% had COPD, mostly of mild or moderate severity. Mean LV mass was 128±34 g. Residual lung volume was independently associated with greater LV mass (7.2 g per 1-SD increase in residual volume; 95% confidence interval, 2.2-12; P=0.004) and was similar in magnitude to that of systolic blood pressure (7.6 g per 1-SD increase in systolic blood pressure; 95% confidence interval, 4.3-11; P<0.001). Similar results were observed for the ratio of LV mass to end-diastolic volume (P=0.02) and with hyperinflation measured as residual volume to total lung capacity ratio (P=0.009). Pulmonary hyperinflation, as measured by residual lung volume or residual lung volume to total lung capacity ratio, is associated with greater LV mass.


Use of Inotropic Agents in Treatment of Systolic Heart Failure.
The most common use of inotropes is among hospitalized patients with acute decompensated heart failure, with reduced left ventricular ejection fraction and with signs of end-organ dysfunction in the setting of a low cardiac output. Inotropes can be used in patients with severe systolic heart failure awaiting heart transplant to maintain hemodynamic stability or as a bridge to decision. In cases where patients are unable to be weaned off inotropes, these agents can be used until a definite or escalated supportive therapy is planned, which can include coronary revascularization or mechanical circulatory support (intra-aortic balloon pump, extracorporeal membrane oxygenation, impella, left ventricular assist device, etc.). Use of inotropic drugs is associated with risks and adverse events. This review will discuss the use of the inotropes digoxin, dopamine, dobutamine, norepinephrine, milrinone, levosimendan, and omecamtiv mecarbil. Long-term inotropic therapy should be offered in selected patients. A detailed conversation with the patient and family shall be held, including a discussion on the risks and benefits of use of inotropes. Chronic heart failure patients awaiting heart transplants are candidates for intravenous inotropic support until the donor heart becomes available. This helps to maintain hemodynamic stability and keep the fluid status and pulmonary pressures optimized prior to the surgery. On the other hand, in patients with severe heart failure who are not candidates for advanced heart failure therapies, such as transplant and mechanical circulatory support, inotropic agents can be used for palliative therapy. Inotropes can help reduce frequency of hospitalizations and improve symptoms in these patients.


Effects of on-pump and off-pump surgery in the Arterial Revascularization Trial.
The Arterial Revascularization Trial (ART) is a randomized comparison of bilateral internal mammary artery (BIMA) versus single internal mammary artery (SIMA) grafting in coronary artery bypass graft (CABG) surgery and is one of the largest randomized trials of surgery ever conducted. ART is also one of the largest studies of contemporary CABG with a high proportion of off-pump surgeries (41%). The objective of this post hoc analysis was to evaluate the surgical process and 1-year outcomes for surgery performed on-pump compared with off-pump. ART randomized 3102 patients with multivessel coronary artery disease (CAD) to SIMA or BIMA grafts to determine if BIMA grafts have an additional survival advantage at 10 years. The 1-year interim analysis showed an overall very low mortality and major morbidity rate irrespective of whether the procedure was with an SIMA or BIMA. The surgical process and 1-year outcomes were analysed according to whether surgery was performed on-pump or off-pump. Baseline variables were not statistically significantly different between on- and off-pump surgery within each treatment group after taking account of the effects of clustering by individual surgeons. At both 30 days and 1 year, there was a low incidence of death (1.2%, 2.3%), stroke (1.1%, 1.7%), myocardial infarction (MI) (1.4%, 1.9%), repeat revascularization (0.5%, 1.5%) and wound reconstruction (1.2%). A similar average number of grafts were performed with on- and off-pump surgery (median = 3), but the duration of surgery was 20-30 min and ventilation time ∼ 2 h shorter with off-pump surgery. Blood loss and platelet transfusions were lower in the off-pump group, with no difference in the need for balloon pump or renal support. Sternal wound reconstruction was similar with off-pump surgery in the SIMA group (0.5 vs 0.6%) and lower with off-pump surgery in the BIMA group (1.4 vs 2.2%). Repeat revascularization was marginally higher in off-pump patients at 30 days (0.8 vs 0.3%) and at 1 year (1.7 vs 1.3%). The outcomes of contemporary CABG are excellent with low mortality, stroke, myocardial infarction and need for wound reconstruction and repeat revascularization whether performed on-pump or off-pump. Controlled-trials.com (ISRCTN46552265).