Evidence for the continued safety and tolerability of fixed-dose isosorbide dinitrate/hydralazine in patients with chronic heart failure (the extension to African-American Heart Failure Trial).
The benefits of fixed-dose combination isosorbide dinitrate plus hydralazine (ID/H) in African-Americans with heart failure (HF) were established by the African-American Heart Failure Trial (A-HeFT), which was terminated early because of a significant survival benefit of ID/H. The Extension to A-HeFT trial (X-A-HeFT), designed to make ID/H available for ethical reasons after A-HeFT termination, afforded an opportunity to further observe responsiveness and compliance with ID/H. In total 198 patients completing the A-HeFT took ID/H for an additional 209 +/- 116 days. Their age (57 +/- 13 years), cause and duration of HF, and HF medications were not different from all A-HeFT patients. New York Heart Association class at X-A-HeFT baseline was > or =III in 51% of patients versus 100% of all patients at A-HeFT baseline, remained unchanged in most patients, improved in 24%, and worsened in only 9% during X-A-HeFT. The average number of ID/H tablets taken during X-A-HeFT was 3.7 +/- 1.8 per day with compliance averaging 87 +/- 25%. The most common adverse events, headache (34%) and dizziness (16%), were less than in patients taking ID/H in A-HeFT, with only 6% discontinuations for adverse events. The 6% annualized mortality rate in X-A-HeFT was the same as for ID/H in A-HeFT. There were no statistically significant differences in baseline characteristics or outcomes in X-A-HeFT patients analyzed according to their A-HeFT randomization. In conclusion, these results confirm the good compliance, tolerability, and responsiveness, with low mortality and improved symptoms, during treatment with ID/H observed in A-HeFT.


Rapid degradation of replication-dependent histone mRNAs largely occurs on mRNAs bound by nuclear cap-binding proteins 80 and 20.
The translation of mammalian messenger RNAs (mRNAs) can be driven by either cap-binding proteins 80 and 20 (CBP80/20) or eukaryotic translation initiation factor (eIF)4E. Although CBP80/20-dependent translation (CT) is known to be coupled to an mRNA surveillance mechanism termed nonsense-mediated mRNA decay (NMD), its molecular mechanism and biological role remain obscure. Here, using a yeast two-hybrid screening system, we identify a stem-loop binding protein (SLBP) that binds to a stem-loop structure at the 3'-end of the replication-dependent histone mRNA as a CT initiation factor (CTIF)-interacting protein. SLBP preferentially associates with the CT complex of histone mRNAs, but not with the eIF4E-depedent translation (ET) complex. Several lines of evidence indicate that rapid degradation of histone mRNA on the inhibition of DNA replication largely takes place during CT and not ET, which has been previously unappreciated. Furthermore, the ratio of CBP80/20-bound histone mRNA to eIF4E-bound histone mRNA is larger than the ratio of CBP80/20-bound polyadenylated β-actin or eEF2 mRNA to eIF4E-bound polyadenylated β-actin or eEF2 mRNA, respectively. The collective findings suggest that mRNAs harboring a different 3'-end use a different mechanism of translation initiation, expanding the repertoire of CT as a step for determining the fate of histone mRNAs.


Immune control and failure in HCV infection--tipping the balance.
Despite the development of potent antiviral drugs, HCV remains a global health problem; global eradication is a long way off. In this review, we discuss the immune response to HCV infection and particularly, the interplay between viral strategies that delay the onset of antiviral responses and host strategies that limit or even eradicate infected cells but also contribute to pathogenesis. Although HCV can disable some cellular virus-sensing machinery, IFN-stimulated antiviral genes are induced in the infected liver. Whereas epitope evolution contributes to escape from T cell-mediated immunity, chronic high antigen load may also blunt the T cell response by activating exhaustion or tolerance mechanisms. The evasive maneuvers of HCV limit sterilizing humoral immunity through rapid evolution of decoy epitopes, epitope masking, stimulation of interfering antibodies, lipid shielding, and cell-to-cell spread. Whereas the majority of HCV infections progress to chronic hepatitis with persistent viremia, at least 20% of patients spontaneously clear the infection. Most of these are protected from reinfection, suggesting that protective immunity to HCV exists and that a prophylactic vaccine may be an achievable goal. It is therefore important that we understand the correlates of protective immunity and mechanisms of viral persistence.


To live as mentally disabled in the risk society.
The contemporary society is to some extent characterized by longitudinal changes, towards individualization, uncertainty, and risk. Numerous risks and dangers in modern society have been mastered, while others have emerged, often created by human actions. The individual's freedom of choice has increased, but also the responsibility for the choices made. In this society, the risk society, there is a greater need for formative and situation-related knowledge to manage risks. The aims of this paper are to discuss the concept of risk society in the light of everyday experiences made by people with mental disabilities, how challenges can be mastered and positive possibilities can be utilized. Data collection was made through a multistage focus group, and the data were analysed by qualitative content analysis. The results show that characteristics of the risk society are identified by people with mental disabilities. Change and uncertainty, obstacles created by societal institutions, lack of trust, and the need of adapted working conditions are frequently experienced, impersonal relations and feelings of loneliness as well. However, these conditions can be partly counteracted by belonging to an alternative fellowship, which might lead to quality of life-related personal improvements.


Single neuron electroporation in manipulating and measuring the central nervous system.
The development and application of single neuron electroporation largely advanced the use of traditional genetics in investigations of the central nervous system. This quick and accurate manipulation of the brain at individual neuron level allowed the gain and loss of functional analyses of different genes and/or proteins. This manuscript reviewed the development of the technique and discussed some technical aspects in practical manipulations. Then the manuscript summarized the potential applications with this technique. Last but not least, the technique showed prospective future when combined with other modern methods in neuroscience research.


KPNA6 (Importin {alpha}7)-mediated nuclear import of Keap1 represses the Nrf2-dependent antioxidant response.
The transcription factor Nrf2 has emerged as a master regulator of cellular redox homeostasis. As an adaptive response to oxidative stress, Nrf2 activates the transcription of a battery of genes encoding antioxidants, detoxification enzymes, and xenobiotic transporters by binding the cis-antioxidant response element in the promoter regions of genes. The magnitude and duration of inducible Nrf2 signaling is delicately controlled at multiple levels by Keap1, which targets Nrf2 for redox-sensitive ubiquitin-mediated degradation in the cytoplasm and exports Nrf2 from the nucleus. However, it is not clear how Keap1 gains access to the nucleus. In this study, we show that Keap1 is constantly shuttling between the nucleus and the cytoplasm under physiological conditions. The nuclear import of Keap1 requires its C-terminal Kelch domain and is independent of Nrf1 and Nrf2. We have determined that importin α7, also known as karyopherin α6 (KPNA6), directly interacts with the Kelch domain of Keap1. Overexpression of KPNA6 facilitates Keap1 nuclear import and attenuates Nrf2 signaling, whereas knockdown of KPNA6 slows down Keap1 nuclear import and enhances the Nrf2-mediated adaptive response induced by oxidative stress. Furthermore, KPNA6 accelerates the clearance of Nrf2 protein from the nucleus during the postinduction phase, therefore promoting restoration of the Nrf2 protein to basal levels. These findings demonstrate that KPNA6-mediated Keap1 nuclear import plays an essential role in modulating the Nrf2-dependent antioxidant response and maintaining cellular redox homeostasis.


A large-scale comparative study of isoform expressions measured on four platforms.
Most eukaryotic genes produce different transcripts of multiple isoforms by inclusion or exclusion of particular exons. The isoforms of a gene often play diverse functional roles, and thus it is necessary to accurately measure isoform expressions as well as gene expressions. While previous studies have demonstrated the strong agreement between mRNA sequencing (RNA-seq) and array-based gene and/or isoform quantification platforms (Microarray gene expression and Exon-array), the more recently developed NanoString platform has not been systematically evaluated and compared, especially in large-scale studies across different cancer domains. In this paper, we present a large-scale comparative study among RNA-seq, NanoString, array-based, and RT-qPCR platforms using 46 cancer cell lines across different cancer types. The goal is to understand and evaluate the calibers of the platforms for measuring gene and isoform expressions in cancer studies. We first performed NanoString experiments on 59 cancer cell lines with 404 custom-designed probes for measuring the expressions of 478 isoforms in 155 genes, and additional RT-qPCR experiments for a subset of the measured isoforms in 13 cell lines. We then combined the data with the matched RNA-seq, Exon-array, and Microarray data of 46 of the 59 cell lines for the comparative analysis. In the comparisons of the platforms for measuring the expressions at both isoform and gene levels, we found that (1) the agreement on isoform expressions is lower than the agreement on gene expressions across the four platforms; (2) NanoString and Exon-array are not consistent on isoform quantification even though both techniques are based on hybridization reactions; (3) RT-qPCR experiments are more consistent with RNA-seq and Exon-array than NanoString in isoform quantification; (4) different RNA-seq isoform quantification methods show varying estimation results, and among the methods, Net-RSTQ and eXpress are more consistent across the platforms; and (5) RNA-seq has the best overall consistency with the other platforms on gene expression quantification.


Efficacy of a novel procedure sheath and closure device during diagnostic catheterization: the multicenter randomized clinical trial of the FISH device.
The aim of vascular closure devices is to safely secure the arterial access site at the conclusion of catheterization procedures, thereby increasing patient comfort and decreasing time to hemostasis and ambulation. The FISH (femoral introducer sheath and hemostasis) device is novel in that the access sheath and closure component are incorporated onto the same system. The FISH pivotal investigation was conducted at 8 catheterization laboratories throughout the United States. Eligible diagnostic patients were randomized (2 to 1) to the FISH device versus manual compression and assessed for time to hemostasis and time to ambulation. Half of the participants underwent ultrasonographic evaluation at 30-day follow up. Enrollment for an interventional cohort is ongoing and will be reported at a later date; however, the interventional patients enrolled to date were combined with the diagnostic patients to comprise the safety data of the trial. Overall, 191 patients were randomized to the FISH device and 106 patients to manual compression. Most patients received a 6 Fr sheath (approximately 70%), while the remaining patients received a 5 or 8 Fr sheath. Twenty-seven patients who received the FISH device were converted to manual compression due to anticipated suboptimal hemostasis. Among the diagnostic patients, the mean time to hemostasis was 8.9 minutes for the FISH device, compared to 17.2 minutes for manual compression (p < 0.0001). Similarly, the mean time to ambulation was 2.4 hours for the FISH device, compared to 4.3 hours for manual compression (p < 0.0001). Among the total cohort, there was 1 death and 1 episode of major access-site-related bleeding that required transfusion occurred in the FISH group (1.1%), compared to no serious adverse safety events in the manual compression group (p = 1.0). For the FISH group, there were 5 minor adverse safety events; 3 access-site hematomas and 2 pseudoaneurysms treated with thrombin injection, and in the manual compression group, there was 2 access-site hematomas and 1 pseudoaneurysm treated with thrombin injection (p = 1.0). Among diagnostic patients with good sheath placement and favorable femoral anatomy, the FISH device is superior in achieving time to hemostasis and ambulation compared to manual compression. At 30 days, there is no apparent difference in serious or minor adverse vascular events with the use of the FISH device.


Forceps biopsy and brush cytology during endoscopic retrograde cholangiopancreatography for the diagnosis of biliary stenoses.
For evaluating pancreaticobiliary stenoses during endoscopic retrograde cholangiopancreatography (ERCP) tissue sampling techniques may be important. Brush cytology and forceps biopsy during ERCP are two potential, but so far only incompletely evaluated, tools for the diagnosis of malignant biliary or pancreatic stenoses. Between 1992 and 1995 we acquired 133 cytologic and/or histologic samples from 119 patients who underwent ERCP because of biliary duct stenoses. Sixteen patients had to be excluded from the study due to insufficient follow-up information. After papillotomy, brush cytology was performed in 65 cases (63 patients), and forceps biopsy in 119 cases (106 patients under fluoroscopic guidance. Both methods were applied in combination 51 times (48 patients). The nature of the stenoses was confirmed by surgery, autopsy, or by the subsequent clinical course. The sensitivity was 46.7% for brush cytology and 64.9% for forceps biopsy. The combined application of both methods resulted in superior sensitivity (70.4%). Specificity was 100% for all methods. These numbers lead us to recommend a combined and more frequent application of brush cytology and forceps biopsy of bile duct stenoses to enhance the diagnostic yield whenever substantial influence on therapy can be expected.


Clinicopathological and molecular features of sessile serrated adenomas with dysplasia or carcinoma.
Sessile serrated adenomas (SSAs) are the precursors of at least 15% of colorectal carcinomas, but their biology is incompletely understood. We performed a clinicopathological and molecular analysis of a large number of the rarely observed SSAs with dysplasia/carcinoma to better define their features and the pathways by which they progress to carcinoma. A cross-sectional analysis of 137 SSAs containing regions of dysplasia/carcinoma prospectively collected at a community GI pathology practice was conducted. Samples were examined for BRAF and KRAS mutations, the CpG island methylator phenotype (CIMP) and immunostained for MLH1, p53, p16, β-catenin and 0-6-methylguanine DNA methyltransferase (MGMT). The median polyp size was 9 mm and 86.5% were proximal. Most were BRAF mutated (92.7%) and 94.0% showed CIMP. Mismatch repair deficiency, evidenced by loss of MLH1 (74.5%) is associated with older age (76.7 versus 71.0; p<0.0029), female gender (70% versus 36%; p<0.0008), proximal location (91% versus 72%; p<0.02), CIMP (98% versus 80%; p<0.02) and lack of aberrant p53 (7% versus 34%; p<0.001) when compared with the mismatch repair-proficient cases. Loss of p16 (43.1%) and gain of nuclear β-catenin (55.5%) were common in areas of dysplasia/cancer, irrespective of mismatch repair status. SSAs containing dysplasia/carcinoma are predominantly small (<10 mm) and proximal. The mismatch repair status separates these lesions into distinct clinicopathological subgroups, although WNT activation and p16 silencing are common to both. Cases with dysplasia occur at a similar age to cases with carcinoma. This, together with the rarity of these 'caught in the act' lesions, suggests a rapid transition to malignancy following a long dwell time as an SSA without dysplasia.


Genomic Tools in Cowpea Breeding Programs: Status and Perspectives.
Cowpea is one of the most important grain legumes in sub-Saharan Africa (SSA). It provides strong support to the livelihood of small-scale farmers through its contributions to their nutritional security, income generation and soil fertility enhancement. Worldwide about 6.5 million metric tons of cowpea are produced annually on about 14.5 million hectares. The low productivity of cowpea is attributable to numerous abiotic and biotic constraints. The abiotic stress factors comprise drought, low soil fertility, and heat while biotic constraints include insects, diseases, parasitic weeds, and nematodes. Cowpea farmers also have limited access to quality seeds of improved varieties for planting. Some progress has been made through conventional breeding at international and national research institutions in the last three decades. Cowpea improvement could also benefit from modern breeding methods based on molecular genetic tools. A number of advances in cowpea genetic linkage maps, and quantitative trait loci associated with some desirable traits such as resistance to Striga, Macrophomina, Fusarium wilt, bacterial blight, root-knot nematodes, aphids, and foliar thrips have been reported. An improved consensus genetic linkage map has been developed and used to identify QTLs of additional traits. In order to take advantage of these developments single nucleotide polymorphism (SNP) genotyping is being streamlined to establish an efficient workflow supported by genotyping support service (GSS)-client interactions. About 1100 SNPs mapped on the cowpea genome were converted by LGC Genomics to KASP assays. Several cowpea breeding programs have been exploiting these resources to implement molecular breeding, especially for MARS and MABC, to accelerate cowpea variety improvement. The combination of conventional breeding and molecular breeding strategies, with workflow managed through the CGIAR breeding management system (BMS), promises an increase in the number of improved varieties available to farmers, thereby boosting cowpea production and productivity in SSA.


Toward a quantitative theory of food consumption choices and body weight.
We propose a calibrated dynamic model of food consumption choices and body weight to study changes in daily caloric intake, weight, and the away-from-home share of calories consumed by adult men and women in the U.S. during the period between 1971 and 2006. Calibration reveals substantial preference heterogeneity between men and women. For example, utility losses stemming from weight gains are ten times greater for women compared to men. Counterfactual experiments show that changes in food prices and household income account for half of the increase in weight of adult men, but only a small fraction of women's weight. We argue that quantitative models of food consumption choices and body weight have a unique role to play in future research in the economics of obesity.


Combined chondroitinase and KLF7 expression reduce net retraction of sensory and CST axons from sites of spinal injury.
Axon regeneration in the central nervous system is limited both by inhibitory extracellular cues and by an intrinsically low capacity for axon growth in some CNS populations. Chondroitin sulfate proteoglycans (CSPGs) are well-studied inhibitors of axon growth in the CNS, and degradation of CSPGs by chondroitinase has been shown to improve the extension of injured axons. Alternatively, axon growth can be improved by targeting the neuron-intrinsic growth capacity through forced expression of regeneration-associated transcription factors. For example, a transcriptionally active chimera of Krüppel-like Factor 7 (KLF7) and a VP16 domain improves axon growth when expressed in corticospinal tract neurons. Here we tested the hypothesis that combined expression of chondroitinase and VP16-KLF7 would lead to further improvements in axon growth after spinal injury. Chondroitinase was expressed by viral transduction of cells in the spinal cord, while VP16-KLF7 was virally expressed in sensory neurons of the dorsal root ganglia or corticospinal tract (CST) neurons. After transection of the dorsal columns, both chondroitinase and VP16-KLF7 increased the proximity of severed sensory axons to the injury site. Similarly, after complete crush injuries, VP16-KLF7 expression increased the approach of CST axons to the injury site. In neither paradigm however, did single or combined treatment with chondroitinase or VP16-KLF7 enable regenerative growth distal to the injury. These results substantiate a role for CSPG inhibition and low KLF7 activity in determining the net retraction of axons from sites of spinal injury, while suggesting that additional factors act to limit a full regenerative response.


KDT501, a derivative from hops, normalizes glucose metabolism and body weight in rodent models of diabetes.
We developed KDT501, a novel substituted 1,3-cyclopentadione chemically derived from hop extracts, and evaluated it in various in vitro and in vivo models of diabetes and insulin sensitivity. KDT501 was evaluated for anti-inflammatory effects in monocyte/macrophage cells; agonistic activity for peroxisome proliferator-activated receptors (PPAR); lipogenesis and gene expression profile in human subcutaneous adipocytes. Body composition, glucose, insulin sensitivity, and lipids were assessed in diet-induced obesity (DIO) mice and Zucker Diabetic Fatty (ZDF) rats after oral administration. KDT501 mediated lipogenesis in 3T3L1 and human subcutaneous adipocytes; however, the gene expression profile of KDT501 differed from that of the full PPARγ agonist rosiglitazone, suggesting that KDT501 has pleiotropic biological activities. In addition, KDT501 showed only modest, partial PPARγ agonist activity and exhibited anti-inflammatory effects in monocytes/macrophages that were not observed with rosiglitazone. In a DIO mouse model, oral administration of KDT501 significantly reduced fed blood glucose, glucose/insulin AUC following an oral glucose bolus, and body fat. In ZDF rats, oral administration of KDT501 significantly reduced fed glucose, fasting plasma glucose, and glucose AUC after an oral glucose bolus. Significant, dose-dependent reductions of plasma hemoglobin A1c, weight gain, total cholesterol, and triglycerides were also observed in animals receiving KDT501. These results indicate that KDT501 produces a unique anti-diabetic profile that is distinct in its spectrum of pharmacological effects and biological mechanism from both metformin and pioglitazone. KDT501 may thus constitute a novel therapeutic agent for the treatment of Type 2 diabetes and associated conditions.


Gastrointestinal disorders in Curry-Jones syndrome: Clinical and molecular insights from an affected newborn.
Curry-Jones syndrome (CJS) is a pattern of malformation that includes craniosynostosis, pre-axial polysyndactyly, agenesis of the corpus callosum, cutaneous and gastrointestinal abnormalities. A recurrent, mosaic mutation of SMO (c.1234 C>T; p.Leu412Phe) causes CJS. This report describes the gastrointestinal and surgical findings in a baby with CJS who presented with abdominal obstruction and reviews the spectrum of gastrointestinal malformations in this rare disorder. A 41-week, 4,165 g, female presented with craniosynostosis, pre-axial polysyndactyly, and cutaneous findings consistent with a clinical diagnosis of CJS. The infant developed abdominal distension beginning on the second day of life. Surgical exploration revealed an intestinal malrotation for which she underwent a Ladd procedure. Multiple small nodules were found on the surface of the small and large bowel in addition to an apparent intestinal duplication that seemed to originate posterior to the pancreas. Histopathology of serosal nodules revealed bundles of smooth muscle with associated ganglion cells. Molecular analysis demonstrated the SMO c.1234 C>T mutation in varying amounts in affected skin (up to 35%) and intestinal hamartoma (26%). Gastrointestinal features including structural malformations, motility disorders, and upper GI bleeding are major causes of morbidity in CJS. Smooth muscle hamartomas are a recognized feature of children with CJS typically presenting with abdominal obstruction requiring surgical intervention. A somatic mutation in SMO likely accounts for the structural malformations and predisposition to form bowel hamartomas and myofibromas. The mutation burden in the involved tissues likely accounts for the variable manifestations.


Mechanistic Basis Of Peptide-Protein Interaction In AtPep1-PEPR1 Complex In Arabidopsis thaliana.
Peptide-mediated immunity against pathogens in plants can provide information on protein-peptide interactions and drug discovery in general. The molecular structure of AtPep1, a 23-amino acid signaling peptide isolated from Arabidopsis thaliana leaves and implicated in innate immunity, has evaded structural determination by biophysical methods. The details of molecular interaction of AtPep1 peptide with its receptor (PEPR1), a 170 kDa leucine-rich repeat (LRR) kinase is also unknown. We report a computational approach to the modeling AtPep1 by conformational sampling and its interaction with the receptor PEPR1. Molecular dynamics simulations were employed to sample and cluster energetically favorable conformations of AtPep1 and modeling of PEPR1 through homology. Docking of AtPep1 to PEPR1 and filtering of the biologically relevant poses were facilitated by the computational Ala-scanning mutations and binding energy analysis of the peptide-protein complex. This study provides the first independent in silico validation of the Structure-Activity- Relationship studies carried out on the AtPep1 and provides a molecular mechanism of the peptide-protein complex system.


Echocardiographic features of the interventricular septum in chronic constrictive pericarditis.
Echocardiographic characteristics of the interventricular septum (IVS) have been studied in eight patients with chronic constrictive pericarditis (CP). Values of septal thickening (ST) were clearly below normal in all cases. Interventricular septal systolic motion (IVSSM) was normal in four cases, hypokinetic in three and paradoxical in one. In seven out of the eight patients, an early interventricular septal diastolic motion (IVSDM) consisting of a sudden anterior displacement followed by a brisk posterior rebound was recorded. The beginning of this anomalous movement was coincident with the pericardial knock in the phonocardiogram and its peak was coincident with the simultaneously recorded deep "y" trough in the jugular pulse tracing. The tendency toward normality of IVSDM observed after pericardiectomy in six out of seven patients suggests that this peculiar interventricular septal systolic motion may be a frequent and probably specific echocardiographic finding in constrictive pericarditis.


Immunoelectron microscopic localization of the neural cell adhesion molecules L1 and N-CAM during postnatal development of the mouse cerebellum.
The cellular and subcellular localization of the neural cell adhesion molecules L1 and N-CAM was studied by pre- and postembedding immunoelectron microscopic labeling procedures in the developing mouse cerebellar cortex. The salient features of the study are: L1 displays a previously unrecognized restricted expression by particular neuronal cell types (i.e., it is expressed by granule cells but not by stellate and basket cells) and by particular subcellular compartments (i.e., it is expressed on axons but not on dendrites or cell bodies of Purkinje cells). L1 is always expressed on fasciculating axons and on postmitotic, premigratory, and migrating granule cells at sites of neuron-neuron contact, but never at contact sites between neuron and glia, thus strengthening the view that L1 is not involved in granule cell migration as a neuron-glia adhesion molecule. While N-CAM antibodies reacting with the three major components of N-CAM (180, 140, and 120 kD) show a rather uniform labeling of all cell types, antibodies to the 180-kD component (N-CAM180) stain only the postmigratory granule cell bodies supporting the notion that N-CAM180, the N-CAM component with the longest cytoplasmic domain, is not expressed before stable cell contacts are formed. Furthermore, N-CAM180 is only transiently expressed on Purkinje cell dendrites. N-CAM is present in synapses on both pre- and post-synaptic membranes. L1 is expressed only preterminally and not in the subsynaptic membranes. These observations indicate an exquisite degree of fine tuning in adhesion molecule expression during neural development and suggest a rich combinatorial repertoire in the specification of cell surface contacts.


Environment-mediated structure, surface redox activity and reactivity of ceria nanoparticles.
Nanomaterials, with potential application as bio-medicinal agents, exploit the chemical properties of a solid, with the ability to be transported (like a molecule) to a variety of bodily compartments. However, the chemical environment can change significantly the structure and hence properties of a nanomaterial. Accordingly, its surface reactivity is critically dependent upon the nature of the (biological) environment in which it resides. Here, we use Molecular Dynamics (MD) simulation, Density Functional Theory (DFT) and aberration corrected TEM to predict and rationalise differences in structure and hence surface reactivity of ceria nanoparticles in different environments. In particular we calculate reactivity 'fingerprints' for unreduced and reduced ceria nanoparticles immersed in water and in vacuum. Our simulations predict higher activities of ceria nanoparticles, towards oxygen release, when immersed in water because the water quenches the coordinative unsaturation of surface ions. Conversely, in vacuum, surface ions relax into the body of the nanoparticle to relieve coordinative unsaturation, which increases the energy barriers associated with oxygen release. Our simulations also reveal that reduced ceria nanoparticles are more active towards surface oxygen release compared to unreduced nanoceria. In parallel, experiment is used to explore the activities of ceria nanoparticles that have suffered a change in environment. In particular, we compare the ability of ceria nanoparticles, in an aqueous environment, to scavenge superoxide radicals compared to the same batch of nanoparticles, which have first been dried and then rehydrated. The latter show a distinct reduction in activity, which we correlate to a change in the redox chemistry associated with moving between different environments. The reactivity of ceria nanoparticles is therefore not only environment dependent, but is also influenced by the transport pathway or history required to reach the particular environment in which its reactivity is to be exploited.


A structural rearrangement in the sodium channel pore linked to slow inactivation and use dependence.
Voltage-gated sodium (Na(+)) channels are a fundamental target for modulating excitability in neuronal and muscle cells. When depolarized, Na(+) channels may gradually enter long-lived, slow-inactivated conformational states, causing a cumulative loss of function. Although the structural motifs that underlie transient, depolarization-induced Na(+) channel conformational states are increasingly recognized, the conformational changes responsible for more sustained forms of inactivation are unresolved. Recent studies have shown that slow inactivation components exhibiting a range of kinetic behavior (from tens of milliseconds to seconds) are modified by mutations in the outer pore P-segments. We examined the state-dependent accessibility of an engineered cysteine in the domain III, P-segment (F1236C; rat skeletal muscle) to methanethiosulfonate-ethylammonium (MTSEA) using whole-cell current recordings in HEK 293 cells. F1236C was reactive with MTSEA applied from outside, but not inside the cell, and modification was markedly increased by depolarization. Depolarized F1236C channels exhibited both intermediate (I(M); tau approximately 30 ms) and slower (I(S); tau approximately 2 s) kinetic components of slow inactivation. Trains of brief, 5-ms depolarizations, which did not induce slow inactivation, produced more rapid modification than did longer (100 ms or 6 s) pulse widths, suggesting both the I(M) and I(S) kinetic components inhibit depolarization-induced MTSEA accessibility of the cysteine side chain. Lidocaine inhibited the depolarization-dependent sulfhydryl modification induced by sustained (100 ms) depolarizations, but not by brief (5 ms) depolarizations. We conclude that competing forces influence the depolarization-dependent modification of the cysteine side chain: conformational changes associated with brief periods of depolarization enhance accessibility, whereas slow inactivation tends to inhibit the side chain accessibility. The findings suggest that slow Na(+) channel inactivation and use-dependent lidocaine action are linked to a structural rearrangement in the outer pore.


Grip strength and cardiovascular drug use in older people: findings from the Hertfordshire Cohort Study.
reduced grip strength is associated with adverse health consequences, and there is interest in identifying modifiable influences. Cardiovascular drugs are commonly used by older people, but their effect on muscle strength is unclear. we investigated associations between cardiovascular drug use and grip strength among 1,572 men and 1,415 women, aged 59-73, who participated in the Hertfordshire Cohort Study. Forty-five percent of participants were taking a cardiovascular drug. Furosemide was associated with average decreases in grip strength of 3.15 kg (95% confidence interval [CI] 0.90, 5.39, P < 0.01) among men and 2.35 kg (95% CI 0.93, 3.77, P < 0.01) among women after adjustment for age and height. Corresponding differences for nitrates were 1.84 kg (95% CI 0.29, 3.39, P = 0.02) among men and 3.66 kg (95% CI 1.99, 5.33, P < 0.01) among women. Calcium channel blockers and fibrates were associated with reduced grip among women. Statins were not associated with grip. The associations between grip strength and nitrate use in men and nitrate and fibrate use in women were robust to additional adjustment for co-morbidity. use of some cardiovascular drugs is associated with reduced grip strength in older people. These findings have potential implications for the functional ability of older people treated with these drugs.


Chemical space exploration guided by deep neural networks.
A parametric t-SNE approach based on deep feed-forward neural networks was applied to the chemical space visualization problem. It is able to retain more information than certain dimensionality reduction techniques used for this purpose (principal component analysis (PCA), multidimensional scaling (MDS)). The applicability of this method to some chemical space navigation tasks (activity cliffs and activity landscapes identification) is discussed. We created a simple web tool to illustrate our work (http://space.syntelly.com).


The renaissance man of burn surgery: Basil A. Pruitt, Jr.
Dr. Basil A. Pruitt Jr., a consummate clinical and translational surgeon-scientist, has spent over half a century at the forefront of an advancing standard of burn care. Commanding the US Army Institute for Surgical Research in San Antonio, he trained generations of leading burn clinicians and allied scientists. At his direction, there were forged discoveries in resuscitation from shock, treatment of inhalation injury, control of burn-related infections, prevention of iatrogenic complications, and understanding the sympathetic, endocrine, and immune responses to burn injury. Most consequentially, this team was among the first to recognize and define alterations in the basal metabolic rate and thermoregulation consequent to burn injury. These investigations prompted groundbreaking insights into the coordinated nervous, autonomic, endocrine, immune, and metabolic outflows that a severely burned patient uses to remain alive and restore homeostasis. Marking his scientific consequence, many of his reports continue to bear fruit when viewed through a contemporary lens. This article summarizes some of the major findings of his career thus far and is intended to complement a Festschrift recently held in his honor.


Treadmill exercise and resistance training in patients with peripheral arterial disease with and without intermittent claudication: a randomized controlled trial.
Neither supervised treadmill exercise nor strength training for patients with peripheral arterial disease (PAD) without intermittent claudication have been established as beneficial. To determine whether supervised treadmill exercise or lower extremity resistance training improve functional performance of patients with PAD with or without claudication. Randomized controlled clinical trial performed at an urban academic medical center between April 1, 2004, and August 8, 2008, involving 156 patients with PAD who were randomly assigned to supervised treadmill exercise, to lower extremity resistance training, or to a control group. Six-minute walk performance and the short physical performance battery. Secondary outcomes were brachial artery flow-mediated dilation, treadmill walking performance, the Walking Impairment Questionnaire, and the 36-Item Short Form Health Survey physical functioning (SF-36 PF) score. For the 6-minute walk, those in the supervised treadmill exercise group increased their distance walked by 35.9 m (95% confidence interval [CI], 15.3-56.5 m; P < .001) compared with the control group, whereas those in the resistance training group increased their distance walked by 12.4 m (95% CI, -8.42 to 33.3 m; P = .24) compared with the control group. Neither exercise group improved its short physical performance battery scores. For brachial artery flow-mediated dilation, those in the treadmill group had a mean improvement of 1.53% (95% CI, 0.35%-2.70%; P = .02) compared with the control group. The treadmill group had greater increases in maximal treadmill walking time (3.44 minutes; 95% CI, 2.05-4.84 minutes; P < .001); walking impairment distance score (10.7; 95% CI, 1.56-19.9; P = .02); and SF-36 PF score (7.5; 95% CI, 0.00-15.0; P = .02) than the control group. The resistance training group had greater increases in maximal treadmill walking time (1.90 minutes; 95% CI, 0.49-3.31 minutes; P = .009); walking impairment scores for distance (6.92; 95% CI, 1.07-12.8; P = .02) and stair climbing (10.4; 95% CI, 0.00-20.8; P = .03); and SF-36 PF score (7.5; 95% CI, 0.0-15.0; P = .04) than the control group. Supervised treadmill training improved 6-minute walk performance, treadmill walking performance, brachial artery flow-mediated dilation, and quality of life but did not improve the short physical performance battery scores of PAD participants with and without intermittent claudication. Lower extremity resistance training improved functional performance measured by treadmill walking, quality of life, and stair climbing ability. clinicaltrials.gov Identifier: NCT00106327.


Children at risk of giardiasis in Auckland: a case-control analysis.
The incidence rate of giardiasis in New Zealand is one of the highest among developed countries, peaking in the 1-4 year age group. A case-control study was undertaken to identify risk factors for giardiasis among Auckland children under 5 years of age. The exposure history of 69 cases and 98 controls were analysed. Ninety-five per cent cases and 86% controls used water from the Auckland Metropolitan mains (AMM) supply for domestic purpose, 44 cases and 42 controls swam and 59 cases and 54 controls wore nappies. Children wearing nappies were at significantly increased risk of the disease (OR = 30, 95% CI = 1.01-8.9), as were those from households which had more than one child wearing a nappy (6.5, 1.8-23.4). The Auckland metropolitan mains water supply was associated with a reduced risk compared to other drinking water sources. Significantly increased risks were also associated with drinking water consumed away from home (4.7, 2.2-10.1), swimming at least once a week (2.4, 1.1-5.3) and travelling domestically (2.5, 1.03-6.0). The study identified vulnerable groups and modifiable risk factors for diarrhoeal diseases, particularly Giardia infection. Nappy wearing was an independent risk factor for infection. Further study is advocated to ensure better protection of public health, especially for children.


Comparison between emission and transmission computed tomography of the liver.
Emission computed tomography (emission CT) and conventional planar gamma-camera imaging of the liver were compared in 242 patients with suspected metastatic spread to liver. Concordant data were obtained in 171 patients (71%). Single large lesions, multiple small lesions, and diffuse disease were accurately defined with this new radionuclide tomographic technique. The smallest lesion detected by emission CT was 8 mm. Emission CT, planar gamma-camera imaging, and transmission (x-ray) CT were compared in 107 patients. All three methods gave identical results in 76 patients (71%). Assessed against other criteria, such as histological findings and follow-up data, emission CT yielded the highest range of accuracy (92-96%), while transmission CT and planar gamma-camera imaging had similar but lower accuracies (78-81%). Emission CT had a false-positive rate of 2.8% and a false-negative rate of less than 1%. Thus emission CT is highly sensitive in detecting space-occupying disease in the liver.


The association between socioeconomic status and adult fast-food consumption in the U.S.
Health follows a socioeconomic status (SES) gradient in developed countries, with disease prevalence falling as SES rises. This pattern is partially attributed to differences in nutritional intake, with the poor eating the least healthy diets. This paper examines whether there is an SES gradient in one specific aspect of nutrition: fast-food consumption. Fast food is generally high in calories and low in nutrients. We use data from the 2008, 2010, and 2012 waves of the National Longitudinal Survey of Youth (NLSY79) to test whether adult fast-food consumption in the United States falls as monetary resources rise (n=8136). This research uses more recent data than previous fast-food studies and includes a comprehensive measure of wealth in addition to income to measure SES. We find little evidence of a gradient in adult fast-food consumption with respect to wealth. While adults in the highest quintile are 54.5% less likely to report fast-food consumption than those in the lowest quintile, adults in the second and third quintiles are no less likely to report fast food-food intake than the poorest. Contrary to popular belief, fast-food consumption rises as income rises from the lowest to middle quintiles. The variation in adult fast-food consumption across income and wealth groups is, however, small. Those in the wealthiest quintile ate about one less fast-food meal on average than those in the lowest quintile. Other factors play a bigger role in explaining fast-food consumption: reading ingredient labels is negatively associated while soda consumption and hours of work are positively associated with fast-food consumption.


Perceptual shift in bilingualism: brain potentials reveal plasticity in pre-attentive colour perception.
The validity of the linguistic relativity principle continues to stimulate vigorous debate and research. The debate has recently shifted from the behavioural investigation arena to a more biologically grounded field, in which tangible physiological evidence for language effects on perception can be obtained. Using brain potentials in a colour oddball detection task with Greek and English speakers, a recent study suggests that language effects may exist at early stages of perceptual integration [Thierry, G., Athanasopoulos, P., Wiggett, A., Dering, B., & Kuipers, J. (2009). Unconscious effects of language-specific terminology on pre-attentive colour perception. Proceedings of the National Academy of Sciences, 106, 4567-4570]. In this paper, we test whether in Greek speakers exposure to a new cultural environment (UK) with contrasting colour terminology from their native language affects early perceptual processing as indexed by an electrophysiological correlate of visual detection of colour luminance. We also report semantic mapping of native colour terms and colour similarity judgements. Results reveal convergence of linguistic descriptions, cognitive processing, and early perception of colour in bilinguals. This result demonstrates for the first time substantial plasticity in early, pre-attentive colour perception and has important implications for the mechanisms that are involved in perceptual changes during the processes of language learning and acculturation.


Activation of dsRNA-Dependent Protein Kinase R by miR-378 Sustains Metabolic Inflammation in Hepatic Insulin Resistance.
MicroRNAs (miRNAs) are noncoding small RNAs that regulate various pathophysiological cellular processes. Here, we report that expression of the miR-378 family was significantly induced by metabolic inflammatory inducers, a high-fructose diet, and inflammatory cytokine tumor necrosis factor-α. Hepatic miRNA profiling revealed that expression of miR-378a was highly upregulated, which, in turn, targeted the 3'-untranslated region of PPARα mRNA, impaired mitochondrial fatty acid β-oxidation, and induced mitochondrial and endoplasmic reticulum stress. More importantly, the upregulated miR-378a can directly bind to and activate the double-strand RNA (dsRNA)-dependent protein kinase R (PKR) to sustain the metabolic stress. In vivo, genetic depletion of miR-378a prevented PKR activation and ameliorated inflammatory stress and insulin resistance. Counterbalancing the upregulated miR-378a using nanoparticles encapsulated with an anti-miR-378a oligonucleotide restored PPARα activity, inhibited PKR activation and ER stress, and improved insulin sensitivity in fructose-fed mice. Our study delineated a novel mechanism of miR-378a in the pathogenesis of metabolic inflammation and insulin resistance through targeting metabolic signaling at both mRNA (e.g., PPARα) and protein (e.g., PKR) molecules. This novel finding of functional interaction between miRNAs (e.g., miR-378a) and cellular RNA binding proteins (e.g., PKR) is biologically significant because it greatly broadens the potential targets of miRNAs in cellular pathophysiological processes.


Did DNA replication evolve twice independently?
DNA replication is central to all extant cellular organisms. There are substantial functional similarities between the bacterial and the archaeal/eukaryotic replication machineries, including but not limited to defined origins, replication bidirectionality, RNA primers and leading and lagging strand synthesis. However, several core components of the bacterial replication machinery are unrelated or only distantly related to the functionally equivalent components of the archaeal/eukaryotic replication apparatus. This is in sharp contrast to the principal proteins involved in transcription and translation, which are highly conserved in all divisions of life. We performed detailed sequence comparisons of the proteins that fulfill indispensable functions in DNA replication and classified them into four main categories with respect to the conservation in bacteria and archaea/eukaryotes: (i) non-homologous, such as replicative polymerases and primases; (ii) containing homologous domains but apparently non-orthologous and conceivably independently recruited to function in replication, such as the principal replicative helicases or proofreading exonucleases; (iii) apparently orthologous but poorly conserved, such as the sliding clamp proteins or DNA ligases; (iv) orthologous and highly conserved, such as clamp-loader ATPases or 5'-->3' exonucleases (FLAP nucleases). The universal conservation of some components of the DNA replication machinery and enzymes for DNA precursor biosynthesis but not the principal DNA polymerases suggests that the last common ancestor (LCA) of all modern cellular life forms possessed DNA but did not replicate it the way extant cells do. We propose that the LCA had a genetic system that contained both RNA and DNA, with the latter being produced by reverse transcription. Consequently, the modern-type system for double-stranded DNA replication likely evolved independently in the bacterial and archaeal/eukaryotic lineages.


Auxin Function in the Brown Alga Dictyota dichotoma.
Auxin controls body plan patterning in land plants and has been proposed to play a similar role in the development of brown algae (Phaeophyta) despite their distant evolutionary relationship with land plants. The mechanism of auxin action in brown algae remains controversial because of contradicting conclusions derived from pharmacological studies on Fucus In this study, we used Dictyota dichotoma as a model system to show that auxin plays a role during the apical-basal patterning of the embryo of brown algae. Indole-3-acetic acid was detectable in D. dichotoma germlings and mature tissue. Although two-celled D. dichotoma zygotes normally develop a rhizoid from one pole and a thallus meristem from the other, addition of exogenous auxins to one-celled embryos affected polarization, and both poles of the spheroidal embryo developed into rhizoids instead. The effect was strongest at lower pH and when variable extrinsic informational cues were applied. 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, an inhibitor of the ABC-B/multidrug resistance/P-glycoprotein subfamily of transporters in land plants, affected rhizoid formation by increasing rhizoid branching and inducing ectopic rhizoids. An in silico survey of auxin genes suggested that a diverse range of biosynthesis genes and transport genes, such as PIN-LIKES, and the ATP-binding cassette subfamily (ABC-B/multidrug resistance/P-glycoprotein) transporters from land plants have homologs in D. dichotoma and Ectocarpus siliculosus Together with reports on auxin function in basal lineages of green algae, these results suggest that auxin function predates the divergence between the green and brown lineage and the transition toward land plants.


Combined effect of polymorphisms of MTHFR and MTR and arsenic methylation capacity on developmental delay in preschool children in Taiwan.
Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) are related to cognitive dysfunction and mental disability. These genes, along with folate and vitamin B12 levels, are regulators of one-carbon metabolism, which synthesizes S-adenosylmethionine (SAM) as a methyl donor for arsenic methylation. The aim of this study was to explore whether polymorphisms of MTHFR and MTR influence arsenic methylation capacity and plasma folate and vitamin B12 levels and if these influences cause developmental delay in preschool children. A total of 178 children with developmental delay and 88 without developmental delay were recruited from August 2010 to March 2014. A high-performance liquid chromatography-hydride generator and atomic absorption spectrometer were used to determine urinary arsenic species. Plasma folate and vitamin B12 concentrations were measured by SimulTRAC-SNB radioassay. Polymorphisms of MTHFR C677T, MTHFR A1298C, and MTR A2756G were examined by polymerase chain reaction and restriction fragment length variation. The results show that MTHFR C677T C/T and T/T genotypes had a lower risk of developmental delay than the C/C genotype (odds ratio [OR] = 0.47; 95% confidence interval, 0.26-0.85). Subjects with the MTHFR C677T C/C genotype had significantly lower plasma folate and vitamin B12 levels than those with the MTHFR C677T C/T and T/T genotype. The MTHFR C677T C/C genotype combined with high total urinary arsenic and poor arsenic methylation capacity indices significantly increased the OR of developmental delay in a dose-response manner. This is the first study to show the combined effect of MTHFR C677T genotype and poor arsenic methylation capacity on developmental delay.


Multisite phosphorylation of the Sum1 transcriptional repressor by S-phase kinases controls exit from meiotic prophase in yeast.
Activation of the meiotic transcription factor Ndt80 is a key regulatory transition in the life cycle of Saccharomyces cerevisiae because it triggers exit from pachytene and entry into meiosis. The NDT80 promoter is held inactive by a complex containing the DNA-binding protein Sum1 and the histone deacetylase Hst1. Meiosis-specific phosphorylation of Sum1 by the protein kinases Cdk1, Ime2, and Cdc7 is required for NDT80 expression. Here, we show that the S-phase-promoting cyclin Clb5 activates Cdk1 to phosphorylate most, and perhaps all, of the 11 minimal cyclin-dependent kinase (CDK) phospho-consensus sites (S/T-P) in Sum1. Nine of these sites can individually promote modest levels of meiosis, yet these sites function in a quasiadditive manner to promote substantial levels of meiosis. Two Cdk1 sites and an Ime2 site individually promote high levels of meiosis, likely by preparing Sum1 for phosphorylation by Cdc7. Chromatin immunoprecipitation reveals that the phosphorylation sites are required for removal of Sum1 from the NDT80 promoter. We also find that Sum1, but not its partner protein Hst1, is required to repress NDT80 transcription. Thus, while the phosphorylation of Sum1 may lead to dissociation from DNA by influencing Hst1, it is the presence of Sum1 on DNA that determines whether NDT80 will be expressed.


Randomized comparison of strategies for reducing treatment in mild persistent asthma.
Treatment guidelines recommend the use of inhaled corticosteroids in patients with asthma who have persistent symptoms and the "stepping down" of therapy to the minimum needed to maintain control of asthma. Whether patients with asthma that is well controlled with the use of inhaled corticosteroids twice daily can receive a step-down treatment with once-daily montelukast (our primary hypothesis) or once-daily fluticasone propionate plus salmeterol (our secondary hypothesis) has not yet been determined. We randomly assigned 500 patients with asthma that was well controlled by inhaled fluticasone (100 microg twice daily) to receive continued fluticasone (100 microg twice daily) (169 patients), montelukast (5 or 10 mg each night) (166 patients), or fluticasone (100 microg) plus salmeterol (50 microg) each night (165 patients). Treatment was administered for 16 weeks in a double-blind manner. The primary outcome was the time to treatment failure. Approximately 20% of patients assigned to receive continued fluticasone or switched to treatment with fluticasone plus salmeterol had treatment failure, as compared with 30.3% of subjects switched to montelukast. The hazard ratio for both comparisons was 1.6 (95% confidence interval, 1.1 to 2.6; P=0.03). The percentage of days on which patients were free of asthma symptoms (78.7 to 85.8%) was similar across the three groups. Patients with asthma that is well controlled with the use of twice-daily inhaled fluticasone can be switched to once-daily fluticasone plus salmeterol without increased rates of treatment failure. A switch to montelukast results in an increased rate of treatment failure and decreased asthma control; however, patients taking montelukast remained free of symptoms on 78.7% of treatment days. (ClinicalTrials.gov number, NCT00156819 [ClinicalTrials.gov].).


Sweet-taste receptors, low-energy sweeteners, glucose absorption and insulin release.
The present review explores the interactions between sweeteners and enteroendocrine cells, and consequences for glucose absorption and insulin release. A combination of in vitro, in situ, molecular biology and clinical studies has formed the basis of our knowledge about the taste receptor proteins in the glucose-sensing enteroendocrine cells and the secretion of incretins by these cells. Low-energy (intense) sweeteners have been used as tools to define the role of intestinal sweet-taste receptors in glucose absorption. Recent studies using animal and human cell lines and knockout mice have shown that low-energy sweeteners can stimulate intestinal enteroendocrine cells to release glucagon-like peptide-1 and glucose-dependent insulinotropic peptide. These studies have given rise to major speculations that the ingestion of food and beverages containing low-energy sweeteners may act via these intestinal mechanisms to increase obesity and the metabolic syndrome due to a loss of equilibrium between taste receptor activation, nutrient assimilation and appetite. However, data from numerous publications on the effects of low-energy sweeteners on appetite, insulin and glucose levels, food intake and body weight have shown that there is no consistent evidence that low-energy sweeteners increase appetite or subsequent food intake, cause insulin release or affect blood pressure in normal subjects. Thus, the data from extensive in vivo studies in human subjects show that low-energy sweeteners do not have any of the adverse effects predicted by in vitro, in situ or knockout studies in animals.


Design and Baseline Characteristics of the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease Trial.
Among diabetics, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality, and progression of their underlying disease. Finerenone is a novel, non-steroidal, selective mineralocorticoid-receptor antagonist which has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD), while revealing only a low risk of hyperkalemia. However, the effect of finerenone on renal and CV outcomes has not been investigated in long-term trials yet. The Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease -(FIDELIO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important renal and CV outcomes in T2D patients with CKD. FIDELIO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 5.5 years. FIDELIO-DKD randomized 5,734 patients with an estimated glomerular filtration rate (eGFR) ≥25-<75 mL/min/1.73 m2 and albuminuria (urinary albumin-to-creatinine ratio ≥30-≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of kidney failure, a sustained decrease of eGFR ≥40% from baseline over at least 4 weeks, or renal death. FIDELIO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of renal and CV events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen.


Top-Down Attention Is Limited Within but Not Between Feature Dimensions.
In natural vision, processing of spatial and nonspatial features occurs simultaneously; however, the two types of attention in charge of facilitating this processing have distinct mechanisms. Here, we tested the independence of spatial and feature-based attention at different stages of visual processing by examining color-based attentional selection while spatial attention was focused or divided. Human observers attended to one or two of four fields of randomly moving dots presented in both left and right visual hemifields. In the focused attention condition, the target stimulus was defined both by color and location, whereas in the divided attention condition stimuli of the target color had to be attended in both hemifields. Sustained attentional selection was measured by means of steady-state visual evoked potentials elicited by each of the frequency-tagged flickering dot fields. Additionally, target and distractor selection was assessed with ERPs to these stimuli. We found that spatial and color-based attention independently modulated the amplitude of steady-state visual evoked potentials, confirming independent top-down influences on early visual areas. In contrast, P3 amplitudes elicited only by targets and distractors of the attended color were subject to space-based enhancement, suggesting increasing integration of spatial and feature-based selection over the course of perceptual processing.


Cluster Randomized Controlled Trial Evaluation of a Gender Equity and Family Planning Intervention for Married Men and Couples in Rural India.
Despite ongoing recommendations to increase male engagement and gender-equity (GE) counseling in family planning (FP) services, few such programs have been implemented and rigorously evaluated. This study evaluates the impact of CHARM, a three-session GE+FP counseling intervention delivered by male health care providers to married men, alone (sessions 1&2) and with their wives (session 3) in India. A two-armed cluster randomized controlled trial was conducted with young married couples (N = 1081 couples) recruited from 50 geographic clusters (25 clusters randomized to CHARM and a control condition, respectively) in rural Maharashtra, India. Couples were surveyed on demographics, contraceptive behaviors, and intimate partner violence (IPV) attitudes and behaviors at baseline and 9 &18-month follow-ups, with pregnancy testing at baseline and 18-month follow-up. Outcome effects on contraceptive use and incident pregnancy, and secondarily, on contraceptive communication and men's IPV attitudes and behaviors, were assessed using logistic generalized linear mixed models. Most men recruited from CHARM communities (91.3%) received at least one CHARM intervention session; 52.5% received the couple's session with their wife. Findings document that women from the CHARM condition, relative to controls, were more likely to report contraceptive communication at 9-month follow-up (AOR = 1.77, p = 0.04) and modern contraceptive use at 9 and 18-month follow-ups (AORs = 1.57-1.58, p = 0.05), and they were less likely to report sexual IPV at 18-month follow-up (AOR = 0.48, p = 0.01). Men in the CHARM condition were less likely than those in the control clusters to report attitudes accepting of sexual IPV at 9-month (AOR = 0.64, p = 0.03) and 18-month (AOR = 0.51, p = 0.004) follow-up, and attitudes accepting of physical IPV at 18-month follow-up (AOR = 0.64, p = 0.02). No significant effect on pregnancy was seen. Findings demonstrate that men can be engaged in FP programming in rural India, and that such an approach inclusive of GE counseling can improve contraceptive practices and reduce sexual IPV in married couples. ClinicalTrials.gov NCT01593943.


Continuous non-invasive optical monitoring of cerebral blood flow and oxidative metabolism after acute brain injury.
Rapid detection of ischemic conditions at the bedside can improve treatment of acute brain injury. In this observational study of 11 critically ill brain-injured adults, we employed a monitoring approach that interleaves time-resolved near-infrared spectroscopy (TR-NIRS) measurements of cerebral oxygen saturation and oxygen extraction fraction (OEF) with diffuse correlation spectroscopy (DCS) measurement of cerebral blood flow (CBF). Using this approach, we demonstrate the clinical promise of non-invasive, continuous optical monitoring of changes in CBF and cerebral metabolic rate of oxygen (CMRO2). In addition, the optical CBF and CMRO2 measures were compared to invasive brain tissue oxygen tension (PbtO2), thermal diffusion flowmetry CBF, and cerebral microdialysis measures obtained concurrently. The optical CBF and CMRO2 information successfully distinguished between ischemic, hypermetabolic, and hyperemic conditions that arose spontaneously during patient care. Moreover, CBF monitoring during pressor-induced changes of mean arterial blood pressure enabled assessment of cerebral autoregulation. In total, the findings suggest that this hybrid non-invasive neurometabolic optical monitor (NNOM) can facilitate clinical detection of adverse physiological changes in brain injured patients that are otherwise difficult to measure with conventional bedside monitoring techniques.


Beyond corporate-style downsizing: a better way for medical schools to succeed in a changing world.
There is a critical need for medical schools and universities to consider strategies beyond corporate-style downsizing to address revenue needs and reposition their organizations. The author presents considerable evidence and three reasons to reject downsizing as a way to facilitate long-term organizational success. Instead, she recommends that institutions use a comprehensive approach to individual and organizational development to assure a flexible, enduring organization. Specifically, medical schools and universities should take an institution-wide perspective and approach to continually training, retraining, or reassigning faculty and should continually adapt their organizational structures and procedures as necessary to achieve changing institutional goals. The result will be the retention of able and dedicated faculty, who will be crucial in helping their schools continue to be successful while adapting to a changing world.


Early experience shapes amygdala sensitivity to race: an international adoption design.
In the current study, we investigated how complete infant deprivation to out-group race impacts behavioral and neural sensitivity to race. Although monkey models have successfully achieved complete face deprivation in early life, this is typically impossible in human studies. We overcame this barrier by examining youths with exclusively homogenous racial experience in early postnatal development. These were youths raised in orphanage care in either East Asia or Eastern Europe as infants and later adopted by American families. The use of international adoption bolsters confidence of infant exposure to race (e.g., to solely Asian faces or European faces). Participants completed an emotional matching task during functional MRI. Our findings show that deprivation to other-race faces in infancy disrupts recognition of emotion and results in heightened amygdala response to out-group faces. Greater early deprivation (i.e., later age of adoption) is associated with greater biases to race. These data demonstrate how early social deprivation to race shapes amygdala function later in life and provides support that early postnatal development may represent a sensitive period for race perception.


'You're putting thoughts into my head': a qualitative study of the readiness of patients with breast, lung or prostate cancer to address emotional needs through the first 18 months after diagnosis.
To investigate the readiness of patients to address emotional needs up to 18 months following a diagnosis of breast, lung or prostate cancer. Patients (N = 42) attending pre-treatment, treatment and follow-up clinics were provided with information designed to help them manage their emotional reactions to cancer. Patients were interviewed 3-4 weeks later about their emotional experience of cancer and their attitudes towards managing emotional problems. Qualitative data analysis followed a constant comparative approach. Patients early in the cancer trajectory, who had not yet been engaged in chemotherapy or radiotherapy, described emotional distress as a temporary and understandable reaction that did not warrant professional intervention. They valued knowing that support was available, but did not want to use it, and were reluctant to acknowledge or address emotional needs. Conversely, patients currently or recently engaged in treatment readily acknowledged their emotional needs and welcomed help to address these. Drawing on social cognitive and other theories, we suggest that engagement in physical treatment and care allows patients to address emotional needs following a cancer diagnosis. Guidance that emotional needs should routinely be assessed and addressed at key points in the cancer trajectory should therefore be implemented cautiously when patients are only recently diagnosed; psychological intervention may be less appropriate at this time than later.


Aims and results of the NIMH systematic treatment enhancement program for bipolar disorder (STEP-BD).
The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was funded as part of a National Institute of Mental Health initiative to develop effectiveness information about treatments, illness course, and assessment strategies for severe mental disorders. STEP-BD studies were planned to be generalizable both to the research knowledge base for bipolar disorder and to clinical care of bipolar patients. Several novel methodologies were developed to aid in illness characterization, and were combined with existing scales on function, quality of life, illness burden, adherence, adverse effects, and temperament to yield a comprehensive data set. The methods integrated naturalistic treatment and randomized clinical trials, which a portion of STEP-BD participants participated. All investigators and other researchers in this multisite program were trained in a collaborative care model with the objective of retaining a high percentage of enrollees for several years. Articles from STEP-BD have yielded evidence on risk factors impacting outcomes, suicidality, functional status, recovery, relapse, and caretaker burden. The findings from these studies brought into question the widely practiced use of antidepressants in bipolar depression as well as substantiated the poorly responsive course of bipolar depression despite use of combination strategies. In particular, large studies on the characteristics and course of bipolar depression (the more pervasive pole of the illness), and the outcomes of treatments concluded that adjunctive psychosocial treatments but not adjunctive antidepressants yielded outcomes superior to those achieved with mood stabilizers alone. The majority of patients with bipolar depression concurrently had clinically significant manic symptoms. Anxiety, smoking, and early age of bipolar onset were each associated with increased illness burden. STEP-BD has established procedures that are relevant to future collaborative research programs aimed at the systematic study of the complex, intrinsically important elements of bipolar disorders.


Discontinuation symptoms after treatment with serotonin reuptake inhibitors: a literature review.
The discontinuation of many pharmacologic agents is associated with characteristic withdrawal symptoms. Antidepressants, particularly the tricyclic antidepressants (TCAs), are known to be associated with a group of common symptoms upon discontinuation. Serotonin reuptake inhibitors (SRIs) are also taking their respective place in the literature with reports of discontinuation symptoms. This review summarizes case reports and reports that allow systematic assessment of discontinuation symptoms following SRI discontinuation. A computerized literature search was conducted using a MEDLINE search to identify reports of withdrawal effects following discontinuation of SRIs. Additional reports were found in the bibliographies of various published reports. SRI discontinuation symptoms in adults are summarized in 24 case reports and 9 reports from controlled clinical trials. Additionally, 3 case reports addressing SRI discontinuation in the neonate are described. The reports describe clusters of symptoms commonly associated with the discontinuation of an SRI. We propose to define an antidepressant discontinuation syndrome as the onset of a cluster of somatic and psychic symptoms following the discontinuation of an SRI and not attributable to other causes (e.g., concomitant medication, illness). These symptoms include dizziness, light-headedness, insomnia, fatigue, anxiety/agitation, nausea, headache, and sensory disturbance. The syndrome may last up to 3 weeks and may be improved by restarting the antidepressant or starting an antidepressant with a similar pharmacologic profile.


Identification of a novel HLA B*57 restricted cytotoxic T-lymphocyte epitope within HIV-1 rev.
HLA-B5701 and its related allele B5703 have been shown to be strongly associated with slow HIV-1 disease progression. To elucidate the effect of these alleles fully on disease progression it is essential to identify key HIV-1 epitopes that are restricted by these alleles. Here we describe the identification of a novel HLA-B5701, B5703 restricted epitope within HIV-1 rev, which accounted for up to 25 and 40% of the total cytotoxic T-lymphocyte responses in two patients.


Intrusive imagery in severe health anxiety: Prevalence, nature and links with memories and maintenance cycles.
Increased understanding of the nature and role of intrusive imagery has contributed to the development of effective treatment protocols for some anxiety disorders. However, intrusive imagery in severe health anxiety (hypochondriasis) has been comparatively neglected. Hence, the current study investigates the prevalence, nature and content of intrusive imagery in 55 patients who met DSM-IV-TR (APA, 2000) criteria for the diagnosis of hypochondriasis. A semi-structured interview was used to assess the prevalence, nature and possible role of intrusive imagery in this disorder. Over 78% of participants reported experiencing recurrent, distressing intrusive images, the majority (72%) of which either were a memory of an earlier event or were strongly associated with a memory. The images tended to be future orientated, and were reliably categorised into four themes: i) being told 'the bad news' that you have a serious/life threatening-illness (6.9%), ii) suffering from a serious or life-threatening illness (34.5%), iii) death and dying due to illness (22.4%) and iv) impact of own death or serious illness on loved ones (36.2%). Participants reported responding to experiencing intrusive images by engaging in avoidance, checking, reassurance seeking, distraction and rumination. Potential treatment implications and links to maintenance cycles are considered.


Identifying Iron-Nitrogen/Carbon Active Structures for Oxygen Reduction Reaction under the Effect of Electrode Potential.
Transition-metal-nitrogen/carbon (TM-N/C) materials are promising alternatives to Pt-based oxygen reduction reaction (ORR) electrocatalysts of fuel cells. Identifying the highly active sites is the prerequisite for the design of high-performance electrocatalysts, in which the density functional theory (DFT) calculation is an important tool. However, the DFT simulation was usually conducted with a charge-neutral model, which is far away from the working condition, that is, under certain potentials. Herein, by using the DFT method with the explicit consideration of electrode potential, we systematically compared the activities of the Fe-N/C moieties previously proposed in the literature and identified the best one. This study not only demonstrates the significance of the electrode potential in computational electrochemistry but also suggests a feasible experimental strategy to increase the ORR performance of Fe-N/C electrocatalysts by creating edges defects and coordinating with the axial ligands on the Fe center, which is of practical significance for exploring the advanced non-precious-metal-based ORR electrocatalysts and related devices.


Tailoring of electromagnetic field localizations by two-dimensional graphene nanostructures.
Graphene has great potential for enhancing light-matter interactions in a two-dimensional regime due to surface plasmons with low loss and strong light confinement. Further utilization of graphene in nanophotonics relies on the precise control of light localization properties. Here, we demonstrate the tailoring of electromagnetic field localizations in the mid-infrared region by precisely shaping the graphene into nanostructures with different geometries. We generalize the phenomenological cavity model and employ nanoimaging techniques to quantitatively calculate and experimentally visualize the two-dimensional electromagnetic field distributions within the nanostructures, which indicate that the electromagnetic field can be shaped into specific patterns depending on the shapes and sizes of the nanostructures. Furthermore, we show that the light localization performance can be further improved by reducing the sizes of the nanostructures, where a lateral confinement of λ0/180 of the incidence light can be achieved. The electromagnetic field localizations within a nanostructure with a specific geometry can also be modulated by chemical doping. Our strategies can, in principle, be generalized to other two-dimensional materials, therefore providing new degrees of freedom for designing nanophotonic components capable of tailoring two-dimensional light confinement over a broad wavelength range.


Unmet need for treatment of substance use disorders and serious psychological distress among veterans: a nationwide analysis using the NSDUH.
Many veterans returning from Afghanistan and Iraq experience serious mental health (MH) concerns including substance use disorders (SUD), post-traumatic stress disorder, traumatic brain injury, depression, or serious psychological distress (SPD). This article uses data from the 2004 to 2010 National Survey on Drug Use and Health to examine the prevalence of unmet MH needs among veterans aged 21 to 34 in the general population. The prevalence of untreated SUD among veterans (16%) was twice as high as untreated SPD (8%), a nonspecific diagnosis of serious MH concerns. Surprisingly, similar rates of untreated SUD and SPD were found among a nonveteran comparison sample matched on gender and age. These findings suggest that reducing unmet need for MH treatment for veterans in the general population may require improving outreach to all Americans and creating greater acceptance for MH treatment. The need for further analyses of reasons for not obtaining treatment is discussed.


Lnk adaptor: novel negative regulator of B cell lymphopoiesis.
Originally thought to have the functions now ascribed to the linker for activation of T cells protein (LAT), Lnk is coming into its own as an adaptor protein that mediates signaling through several receptor pathways. An essential role for Lnk in B cell development and maturation was recently uncovered by Perlmutter and colleagues. Rudd discusses the role of Lnk in B cells and hypothesizes a mechanism whereby Lnk, and its closely related protein family members, the adaptor molecules containing pleckstrin homology (PH) and Src-homology 2 (SH2) domains (APS), and Src-homology 2-B protein (SH2-B), may mediate signal promotion or attenuation.


Benthic bacterial biomass supported by streamwater dissolved organic matter.
Bacterial biomass in surface sediments of a headwater stream was measured as a function of dissolved organic carbon (DOC) flux and temperature. Bacterial biomass was estimated using epifluorescence microscopic counts (EMC) and ATP determinations during exposure to streamwater containing 1,788μg DOC/liter and after transfer to groundwater containing 693μg DOC/liter. Numbers of bacteria and ATP concentrations averaged 1.36×10(9) cells and 1,064 ng per gram dry sediment, respectively, under initial DOC exposure. After transfer to low DOC water, biomass estimates dropped by 53 and 55% from EMC and ATP, respectively. The decline to a new steady state occurred within 4 days from ATP assays and within 11 days from EMC measures. A 4°C difference during these exposures had little effect on generation times. The experiment indicated that 27.59 mg/hour of natural DOC supported a steady state bacterial biomass of approximately 10μg C/g dry weight of sediment (from EMC determinations). Steady state bacterial biomass estimates on sediments that were previously muffled to remove organic matter were approximately 20-fold lower. The ratio of GTP∶ATP indicated differences in physiological condition or community composition between natural and muffled sediments.


The Role of Maintenance Strategies in Metastatic Colorectal Cancer: A Systematic Review and Network Meta-analysis of Randomized Clinical Trials.
In metastatic colorectal cancer, induction combination chemotherapy with a targeted agent is considered the mainstay of treatment. Multiple randomized clinical trials have examined different strategies of continuing cytotoxic therapy until progression compared with a period of either observation or the use of various maintenance agents. However, those randomized clinical trials have shown inconsistent efficacy results that make it challenging to draw any conclusion on which strategy is preferred. Therefore, a network meta-analysis is helpful to compare different agents across randomized clinical trials. To evaluate the comparative effectiveness of different treatment strategies for patients with metastatic colorectal cancer. MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials were searched for randomized clinical trials evaluating different strategies for patients with previously untreated metastatic colorectal cancer. Trials of interest included those including patients with metastatic colorectal cancer who were treated with an initial period of cytotoxic chemotherapy (with or without a biologic) and then switched to one of the following strategies: observation; maintenance with bevacizumab (Bev), fluoropyrimidine (FP), or both (FP + Bev); or continuing the induction regimen until progression. Outcomes of interest included overall survival (OS) and progression-free survival (PFS). The overall effect was pooled using the DerSimonian and Laird random-effects model. Network meta-analysis was conducted using a random-effects consistency model to pool evidence from direct and indirect comparisons. Agents were ranked using surface under the cumulative ranking (SUCRA) probabilities. Higher SUCRA scores correspond to greater efficacy. Initial analysis was performed on December 18, 2018. An updated search was performed in April 2019, and no additional studies were added. Twelve trials at low risk of bias (5540 patients; age range, 23-85 years; 64.4 % male) were included. Network meta-analysis showed no benefit of continuing full cytotoxic chemotherapy until progression vs observation in terms of PFS (hazard ratio, 0.71; 95% CI, 0.46-1.09) and OS (hazard ratio, 0.95; 95% CI, 0.85-1.07). Compared with observation, maintenance therapy showed a PFS benefit (hazard ratio, 0.58; 95% CI, 0.43-0.77) but not an OS benefit (hazard ratio, 0.91; 95% CI, 0.83-1.01). All maintenance strategies (FP, FP + Bev, and Bev) showed significant improvement in PFS vs observation. On SUCRA analysis, maintenance treatment (FP or FP + Bev) had the highest likelihood of achieving improved PFS (67.1% for FP, 99.8% for FP + Bev, and 36.5% for Bev) and OS (81.3% for FP, 73.2% for FP + Bev, and 32.6% for Bev). For patients with metastatic colorectal cancer, there is no benefit to continuing the full induction regimen until progression, without a period of either observation or maintenance treatment. A maintenance strategy with a fluoropyrimidine, with or without the addition of bevacizumab, is preferred. However, given the lack of a clear OS benefit, shared decision-making should include observation as an acceptable alternative.


Field deployment of thin film passive air samplers for persistent organic pollutants: a study in the urban atmospheric boundary layer.
This paper reports on the first field deployment of rapidly equilibrating thin-film passive air samplers under ambient conditions. The POlymer-coated Glass (POG) samplers have a coating of ethylene vinyl acetate (EVA) less than 1 microm thick applied to a glass surface. This can be dissolved off after exposure and prepared for the quantification of persistent organic pollutants (POPs) that have partitioned into the film during field exposure. In this study, POGs were deployed at various heights on the CN Tower in Toronto, Canada, to investigate the vertical distribution of selected compounds (PCBs, PAHs, organochlorine pesticides) in the atmospheric boundary layer of an urban area. The feasibility of the method to detect POPs from a few cubic meters of air was demonstrated, indicating the potential for rapid, low-volume sampling of air for ambient levels of POPs. PAH levels declined sharply with height, confirming ground-level emissions in urban areas as sources of these compounds; PCBs did the same, although less strongly. Different sampling events detected different vertical distributions of OC pesticides which could be related to local or distantsources, and variations in POPs on the samplers in these different events/heights demonstrate the dynamic nature of sources and atmospheric mixing of POPs.


Increases in Psychological Flexibility Mediate Relationship Between Acute Psychedelic Effects and Decreases in Racial Trauma Symptoms Among People of Color.
Previous research showed acute psychedelic effects were associated with decreases in racial trauma (RT) symptoms among black, indigenous, and people of color (BIPOC). Among samples comprised primarily of white participants, positive outcomes of psychedelic experiences have been mediated by increases in psychological flexibility. Therefore, we examined whether changes in psychological flexibility from before to after a psychedelic experience mediated the relationship between acute psychedelic effects and changes in RT symptoms among BIPOC. This cross-sectional online survey study included 313 BIPOC (mean age = 33.1; SD = 11.2; female = 57%). A multiple linear regression analysis was used to examine the association between acute psychedelic effects and decreases in RT symptoms in a nonclinical setting; a path analysis was used to explore whether changes in psychological flexibility mediated this relationship. Acute insight and challenging effects were significantly (p < .001) associated with decreases in RT symptoms following a psychedelic experience. Increases in psychological flexibility partially mediated relationships between greater intensity of psychological insight and less intensity of challenging experiences and decreases in RT symptoms (ps<.001). This research suggests psychedelics confer potential benefits in decreasing RT symptoms among BIPOC and psychological flexibility may be an important mediator of these effects. Future research should test this hypothesis in a longitudinal clinical trial among BIPOC.


Caregiving at the end of life: perspectives from spousal caregivers and care recipients.
The purpose of this study is to examine the perspectives of both the spousal caregiver and care recipient on the caregiving experience in home-based palliative care. A qualitative research strategy involving home-based face-to-face interviews with older palliative care patients and their spousal caregivers was used to examine the caregiving experience. Ten spousal caregivers and care recipient dyads participated in the study. Most informal caregivers viewed caregiving as an extension of the family relationship where caregiving responsibilities evolved over time. Spousal caregivers identified many negative reactions to caregiving, such as fatigue or weariness, depression, anger and sadness, financial stresses, and lack of time. Care recipients acknowledged the emotional and financial strain and expressed concern for their spouses. Both caregivers and care recipients were appreciative of home care services although they identified the need for additional services. They also identified difficulties in communication with formal providers and poor coordination of care among the various services. Both caregivers and care recipients disclosed some challenges with informal supports, but on the whole felt that their presence was positive. Additional positive aspects of caregiving reported by spouses included strengthened relationship with their spouse and discovering emotional strength and physical abilities in managing care. Health care and social service professionals need to recognize and understand both caregiver and care recipient perspectives if they are to successfully meet the needs of both members of the dyad.


Antitumor effects of an adenovirus expressing antisense insulin-like growth factor I receptor on human lung cancer cell lines.
Insulin-like growth factors (IGFs) are often essential for the maintenance of the malignant phenotype, and in lung cancer the IGF-I receptor (IGF-Ir) is often expressed at high levels. Stable transfection of antisense plasmids expressing the first 300 bp of the IGF-Ir reduces the tumorigenicity of a variety of tumor cell lines and has been reported to induce systemic antitumor effects on established, non-gene-modified tumors in animal model systems. We have constructed an adenovirus expressing an antisense IGF-Ir (Ad-IGF-Ir/as) in an attempt to develop these observations into a clinical therapeutic approach. A single transduction by Ad-IGF-Ir/as (at a multiplicity of infection of 10:1) decreased the IGF-Ir number by about 50% in human lung cancer cell lines NCI H460 and SCC5, as measured by an 125I-labeled IGF-I competitive binding assay. After the transduction of these human lung cancer cell lines by Ad-IGF-Ir/as, the soft agar clonogenicity was reduced by 84%. The i.p. treatment of nude mice bearing established i.p. NCI H460 cells resulted in prolonged survival compared to that of nude mice treated with a reporter virus. These results suggest that Ad-IGF-Ir/as has a therapeutic effect on established human lung cancer xenografts and may represent an effective and practical cancer gene therapy strategy.


A comprehensive model for trauma research design.
Concomitant research and education are invaluable for patient care and medical practice in trauma. Elucidation of a foundation for the integration of training and service that can be combined with research in trauma is crucial, and every trauma case should be studied for this purpose. In this study, we investigated the unique features of trauma research to formulate a generic comprehensive model that can be used at any point at which one may desire to develop a research plan. The framework of this model is designed to enable proper trauma research plain in combination with the best routine trauma care. Selection of the appropriate method of study, the corresponding basic questions raised, aims, and the relevant epidemiologic context are factors that are included in this review. Furthermore, suitable sources, proper time for data collection, reliable and valid measures, and criteria for the scaling and quantification of the findings are indicated. In addition, the levels, orders, operational stages, and steps to be taken in planning research projects are logically set based on the principles of cognitive task analysis, and correspond to the entire spectrum of trauma care situations. Lastly, a measure of utility value is assigned in terms of the expected extent of efficiency and presumed level of effectiveness.


Efficacy and tolerability of antidepressants in people aged 65 years or older with major depressive disorder - A systematic review and a meta-analysis.
There has been a steady increase in the prescription of antidepressants for the elderly. This study comprises a systematic review of randomized, placebo-controlled trials of antidepressants for treatment of depressive disorder in people aged 65 years or more. PubMed, EMBASE, Cochrane Library, CINAL, and PsycINFO were searched until May 2016. Where appropriate, the results were synthesized in meta-analyses. Twelve trials met the inclusion criteria. For patients with major depressive disorder, selective serotonin re-uptake inhibitors (SSRI) were not superior to placebo in achieving remission (OR: 0.79, 95% CI: 0.61-1.03) or response (OR=0.86, 95% CI: 0.51-1.10) after 8 weeks of treatment (three trials). However, maintenance treatment with SSRIs was superior to placebo in preventing relapse (OR: 0.22, 95% CI: 0.13-0.36; NNT=5, 95% CI: 3-6; two trials). Duloxetine was superior to placebo in achieving remission (OR: 1.78, 95% CI: 1.20-2.65; NNT=9, 95% CI: 6-20; three trials) and response (OR: 1.83, 95% CI: 1.96-4.08; two trials) in recurrent major depression after 8 weeks, but increased the risk of adverse events that can be problematic in the elderly. The quality of evidence was generally low or moderate, emphasizing the uncertainty of the results. Study populations only partly covered the heterogeneous population of elderly with depressed mood, limiting the generalizability. The results underscore the importance of close monitoring of the effects of antidepressants in treatment of elderly patients with a depressive disorder. Methods for early detection of non-responders and effective treatment options for this group are needed.


National trends, complications, and outcomes following transsphenoidal surgery for Cushing's disease from 1993 to 2002.
Information about complications, patient outcomes, and mortality rate after transsphenoidal surgery (TSS) for Cushing's disease has been derived largely from single-institution series. In this study the authors report on inpatient death, morbidity, and outcomes following TSS for Cushing's disease on a national level. All patients in the Nationwide Inpatient Sample (NIS) database who had undergone transsphenoidal resection of a pituitary tumor for Cushing's disease between 1993 and 2002 were included in the study. The number of cases per year, length of stay (LOS), and rates of inpatient complications, death, and adverse outcomes (death or discharge to institution other than home) were abstracted. Univariate and multivariate analyses were performed to determine the effects of patient and hospital characteristics on outcome measures. According to the NIS, there were an estimated 3525 cases of TSS for Cushing's disease in the US between 1993 and 2002. During this period, there was a trend toward a small increase in the number of TSSs for Cushing's disease. The in-hospital mortality rate was 0.7%, and the complication rate was 42.1%. Diabetes insipidus (15%), fluid and electrolyte abnormalities (12.5%), and neurological deficits (5.6%) were the most common complications reported. Multivariate analysis showed that complications were more likely in patients with pre-operative comorbidities. Patients older than 64 years were much more likely to have an adverse outcome (odds ratio [OR] 20.8) and a prolonged hospital stay (OR 2.2). Women were less likely than men to have an adverse outcome (OR 0.3). A single postoperative complication increased the mean LOS by 3 days, more than tripled the odds of an adverse outcome, and increased the hospital charges by more than US $7000. The authors provided a national perspective on trends, inpatient complications, and outcomes after TSS for Cushing's disease in the US. Postoperative complications had a significantly negative effect on LOS, adverse outcome, and resource utilization. Advanced age and multiple preoperative comorbidities were identified as important risk factors, and their effects on patient outcomes were quantified.


Prevalence of Group C Streptococcus and Fusobacterium Necrophorum in Patients With Sore Throat: A Meta-Analysis.
The prevalence of Group C beta-hemolytic streptococcus and Fusobacterium necrophorum among patients with sore throat in the outpatient setting has not been previously summarized. We set out to derive prevalence information from the existing literature. We performed a systematic review of MEDLINE for studies reporting the prevalence of F necrophorum or Group C streptococcus or both in prospective, consecutive series of outpatients with sore throat, as well as laboratory-based studies of throat cultures submitted from primary care. We limited searches to studies where the majority of data was collected after January 1, 2000, to reflect contemporary microbiological methods and prevalences. Each author independently reviewed the articles for inclusion and abstraction of data; we resolved discrepancies by consensus discussion. We then performed a meta-analysis to calculate the pooled prevalence estimates using a random effects model of raw proportions. A total of 16 studies met our inclusion criteria. The overall prevalences of Group C streptococcus and F necrophorum were 6.1% (95% CI, 3.2%-9.0%) and 18.9% (95% CI, 10.5%-27.2%), respectively. When stratified by study type, the prevalences of Group C streptococcus and F necrophorum in laboratory-based studies were 6.6% (95% CI, -1.0% to 14.2%) and 18.8% (95% CI, 6.5%-31.1%), respectively. In primary care patients with sore throat, Group C streptococcus had a prevalence of 6.1% (95% CI, 3.1%-9.2%), while F necrophorum had a prevalence of 19.4% (95% CI, 14.7%-24.1%). Group C streptococcus and Fusobacterium necrophorum are commonly detected in patients with acute pharyngitis. Research is needed, however, to determine whether these bacteria are truly pathogenic in patients with pharyngitis and whether antibiotics reduce the duration of symptoms or the likelihood of complications.