T-cell large granular lymphocytic leukemia of donor origin occurring after allogeneic bone marrow transplantation for B-cell lymphoproliferative disorders.
T-cell lymphoproliferative disorders are uncommon occurrences after bone marrow transplantation (BMT). We describe 2 patients in whom a monoclonal T-cell large granular lymphocytosis (T-LGL) developed after allogeneic BMT for B-cell lymphoproliferative disorders. Both patients showed a persistent expansion of CD3+, CD8+, and CD57+ large granular lymphocytes of donor origin with clonally rearranged T-cell receptor gamma genes and no evidence of Epstein-Barr virus-related infection. The manifestations were consistent with T-LGL leukemia as defined by the World Health Organization criteria. In both patients, graft-vs-host disease developed, and 1 had recurrent episodes of cytomegalovirus viremia. The other patient had received a graft from a hepatitis C antibody-positive donor without developing any signs of hepatitis C infection. Both patients remain in complete remission from their B-cell lymphoproliferative disorders and do not have symptoms related to T-LGL leukemia. These data show that T-LGL leukemia should be included as one of the types of posttransplantation lymphoproliferative disorders that can occur after allogeneic BMT for B-cell neoplasms.


Yoga therapy decreases dyspnea-related distress and improves functional performance in people with chronic obstructive pulmonary disease: a pilot study.
There has been limited study of yoga training as a complementary exercise strategy to manage the symptom of dyspnea in patients with chronic obstructive pulmonary disease (COPD). The primary purpose of this pilot study was to evaluate a yoga program for its safety, feasibility, and efficacy for decreasing dyspnea intensity (DI) and dyspnea-related distress (DD) in older adults with COPD. Clinically stable patients with COPD (n = 29; age 69.9 +/- 9.5; forced expiratory volume in 1 second (FEV(1)) 47.7 +/- 15.6% predicted; female = 21) were randomized to a 12-week yoga program specifically designed for people with COPD or usual-care control (UC). The twice-weekly yoga program included asanas (yoga postures) and visama vritti pranayama (timed breathing). Safety measure outcomes included heart rate, oxygen saturation, dyspnea, and pain. Feasibility was measured by patient-reported enjoyment, difficulty, and adherence to yoga sessions. At baseline and at 12 weeks, DI and DD were measured during incremental cycle ergometry and a 6-minute walk (6MW) test. Secondary efficacy outcomes included physical performance, psychologic well-being, and health-related quality of life (HRQoL). Yoga training was safe and feasible for patients with COPD. While yoga training had only small effects on DI after the 6MW test (effect size [ES], 0.20; p = 0.60), there were greater reductions in DD in the yoga group compared to UC (ES, 0.67; p = 0.08). Yoga training also improved 6MW distance (+71.7 +/- 21.8 feet versus -27.6 +/- 36.2 feet; ES = 0.78, p = 0.04) and self-reported functional performance (ES = 0.79, p = 0.04) compared to UC. There were small positive changes in muscle strength and HRQoL. Elderly patients with COPD participated safely in a 12-week yoga program especially designed for patients with this chronic illness. After the program, the subjects tolerated more activity with less DD and improved their functional performance. These findings need to be confirmed in a larger, more sufficiently powered efficacy study.


Hedgehog signaling in biliary fibrosis.
Congenital and acquired diseases of the biliary tree, or cholangiopathies, represent a significant source of morbidity and mortality in both children and adults. In late stages of the disease, cholangiocytes can no longer proliferate, resulting in loss of bile ducts, increased fibrosis, and ultimately cirrhosis and liver failure. Epithelial-mesenchymal transition has been proposed as a potential mechanism underlying both cholangiocyte proliferation and fibrogenesis in biliary diseases. In this issue of the JCI, using a myofibroblast-cholangiocyte coculture system and genetically modified mice, Omenetti and colleagues present evidence supporting the importance of paracrine hedgehog signaling between the two cell types and increased expression of mesenchymal markers in cholangiocytes (see the related article beginning on page 3331). These findings set the stage for future studies to further investigate the contribution of hedgehog signaling in both cholangiocyte repair and fibrogenesis in biliary diseases.


Effects of Agricultural Pesticides in Aquafeeds on Wild Fish Feeding on Leftover Pellets Near Fish Farms.
Screening has revealed that modern-day feeds used in Atlantic salmon aquaculture might contain trace amounts of agricultural pesticides. To reach slaughter size, salmon are produced in open net pens in the sea. Uneaten feed pellets and undigested feces deposited beneath the net pens represent a source of contamination for marine organisms. To examine the impacts of long-term and continuous dietary exposure to an organophosphorus pesticide found in Atlantic salmon feed, we fed juvenile Atlantic cod (Gadus morhua), an abundant species around North Atlantic fish farms, three concentrations (0.5, 4.2, and 23.2 mg/kg) of chlorpyrifos-methyl (CPM) for 30 days. Endpoints included liver and bile bioaccumulation, liver transcriptomics and metabolomics, as well as plasma cholinesterase activity, cortisol, liver 7-ethoxyresor-ufin-O-deethylase activity, and hypoxia tolerance. The results show that Atlantic cod can accumulate relatively high levels of CPM in liver after continuous exposure, which is then metabolized and excreted via the bile. All three exposure concentrations lead to significant inhibition of plasma cholinesterase activity, the primary target of CPM. Transcriptomics profiling pointed to effects on cholesterol and steroid biosynthesis. Metabolite profiling revealed that CPM induced responses reflecting detoxification by glutathione-S-transferase, inhibition of monoacylglycerol lipase, potential inhibition of carboxylesterase, and increased demand for ATP, followed by secondary inflammatory responses. A gradual hypoxia challenge test showed that all groups of exposed fish were less tolerant to low oxygen saturation than the controls. In conclusion, this study suggests that wild fish continuously feeding on leftover pellets near fish farms over time may be vulnerable to organophosphorus pesticides.


A multicentre prospective controlled study to determine the safety of trazodone and nefazodone use during pregnancy.
Trazodone and nefazodone are phenylpiperazine antidepressants. Currently, there are no adequate, well-controlled studies on the fetal safety of these drugs. Our primary objective was to determine whether the use of trazodone or nefazodone during pregnancy is associated with an increased risk for major malformations. Secondary outcomes of interest included rates of spontaneous and therapeutic abortions, rates of premature labour, and birth weight. Pregnant women from 5 centres who had been exposed to these drugs (n = 147) were enrolled in the study during their first trimester. We compared the women with 2 groups of women who took either other antidepressant drugs (n = 147) or nonteratogenic drugs (n = 147). All the women were followed up after delivery to ascertain pregnancy outcome and the health of the baby. We have completed 147 follow-ups. There were 121 (82.4%) live births, 20 (13.6%) spontaneous abortions, and 6 (4%) therapeutic abortions. Of the live births, there were 2 (1.6%) major malformations. In all cases, drug exposure occurred during the first trimester, with 52 (35%) of the women using these drugs throughout pregnancy. The mean gestational age at birth was 38 weeks (SD 4.2), and the mean birth weight was 3306.34 g (SD 655). We found no statistically significant differences among the 3 groups in any of the endpoints of interest that we examined. Of the sample, 58 women were exposed to trazodone, and 89 were exposed to nefazodone. Our results suggest that these drugs do not increase the rates of major malformations above the baseline rate of 1% to 3%.


Evaluation of contrast-enhanced FLAIR sequence in MR assessment of intracranial tumours.
Magnetic resonance (MR) has become the most important imaging method in the diagnosis of intracranial tumours. However, conventional MR protocol often fails to obtain all morphological details which are necessary for precise planning of the treatment. Therefore, there are attempts of introducing other MR techniques, to gain new information concerning tumour morphology. One such technique is FLAIR sequence. In previous papers we presented the value of plain FLAIR in patients with intracranial tumours. The aim of the present study was evaluation of contrast enhanced FLAIR (CE FLAIR) in assessment of intracranial tumours. MR examinations, including conventional T1 (pre-and postcontrast) and T2 images, as well as plain and contrast-enhanced FLAIR sequences were performed in 27 patients with intracranial tumours. In all patients the degree and localization of contrast enhancement in post-contrast T1-weighted sequence (CE T1w) and CE FLAIR images have been compared. Contrast enhancement of the tumour in both CE T1-w and CE FLAIR sequences was found in 18 patients. In 5 patients the enhancement was visible only on T1-weighted images, while in 2 cases only on FLAIR images. Among 18 patients, who demonstrated enhancement both in T1-weighted and FLAIR sequences, in 9 cases the effect of enhancement was better on T1-weighted images, in 7-CE FLAIR gave superior results, and in 2 patients - both methods were equivalent. In the whole material in 9 cases CE-FLAIR was superior in 14-inferior and in 4-equal to CE-T1-w. Among 9 cases in which CE- FLAIR was superior, in 7 patients the enhancement concerned the border of the tumour or postoperative cave. Contrast-enhanced FLAIR has limited value in assessment of intracranial tumours and should be used as a supplementary technique if there are difficulties in evaluation of tumour morphology in other sequences.


Influence of subject eligibility criteria on compliance with National Institutes of Health guidelines for inclusion of women, minorities, and children in treatment research.
Many alcohol treatment outcome studies exclude some patients with particular problems, such as psychiatric disorders, noncompliance, and homelessness. Such criteria may increase the likelihood of a study being successfully conducted, but may also have the unintended consequence of reducing a study's ability to comply with National Institutes of Health guidelines for inclusion of racial minorities, women, and children in treatment research. This paper examined this issue empirically using 5 prior studies of treatment systems enrolling over 100,000 alcohol patients. Widely used eligibility criteria in the alcohol treatment field typically exclude between one-fifth to one-third of patients from enrolling in research. Under several eligibility criteria, most notably those for drug use and social/residential instability, women and African-American patients are substantially more likely to be excluded than are men and non-African-American patients, respectively. In designing treatment studies with many eligibility criteria, researchers may therefore inadvertently be thwarting their own good faith efforts to ensure that a range of vulnerable populations are able to participate in research. We analyze the implications of this dilemma for the generalizability of treatment results and for research design, and provide data that may help researchers working in different treatment systems estimate the impact of various eligibility criteria.


Peptide-biphenyl hybrid-capped AuNPs: stability and biocompatibility under cell culture conditions.
In this study, we explored the biocompatibility of Au nanoparticles (NPs) capped with peptide-biphenyl hybrid (PBH) ligands containing glycine (Gly), cysteine (Cys), tyrosine (Tyr), tryptophan (Trp) and methionine (Met) amino acids in the human hepatocellular carcinoma cell line Hep G2. Five AuNPs, Au[(Gly-Tyr-Met)2B], Au[(Gly-Trp-Met)2B], Au[(Met)2B], Au[(Gly-Tyr-TrCys)2B] and Au[(TrCys)2B], were synthesised. Physico-chemical and cytotoxic properties were thoroughly studied. Transmission electron micrographs showed isolated near-spherical nanoparticles with diameters of 1.5, 1.6, 2.3, 1.8 and 2.3 nm, respectively. Dynamic light scattering evidenced the high stability of suspensions in Milli-Q water and culture medium, particularly when supplemented with serum, showing in all cases a tendency to form agglomerates with diameters approximately 200 nm. In the cytotoxicity studies, interference caused by AuNPs with some typical cytotoxicity assays was demonstrated; thus, only data obtained from the resazurin based assay were used. After 48-h incubation, only concentrations ≥50 μg/ml exhibited cytotoxicity. Such doses were also responsible for an increase in reactive oxygen species (ROS). Some differences were observed among the studied NPs. Of particular importance is the AuNPs capped with the PBH ligand (Gly-Tyr-TrCys)2B showing remarkable stability in culture medium, even in the absence of serum. Moreover, these AuNPs have unique biological effects on Hep G2 cells while showing low toxicity. The production of ROS along with supporting optical microscopy images suggests cellular interaction/uptake of these particular AuNPs. Future research efforts should further test this hypothesis, as such interaction/uptake is highly relevant in drug delivery systems.


Impact of Increasing Age on Outcomes of Spinal Fusion in Adult Idiopathic Scoliosis.
To investigate the role of advancing age on postoperative complications and revision surgery after fusion for scoliosis. A retrospective, cohort study was performed using the Thomson Reuters MarketScan database, examining patients with adult scoliosis who underwent spinal fusion from 2000 to 2009. Primary outcomes included infection, hemorrhage and pulmonary embolism (PE) within 90 days of surgery, and refusion. The effect of increasing age was estimated using the odds ratio (OR) of complications in a multivariate logistic regression analysis, and a Cox proportional hazard model estimated the hazard ratio of refusion. A total of 8432 patients were included in this study. Overall, the average age was 53.3 years, with 26.90% males and 39% with a Charlson Comorbidity Score of ≥ 1. Most patients had commercial insurance (66.81%), with 26.03% and 7.16% covered by Medicare and Medicaid, respectively. Increasing age (per 5-year increment) was a significant predictor of hemorrhagic complication (OR, 1.06; confidence interval [CI], 1.01-1.11; P = 0.0196), PE (OR, 1.09; CI, 1.03-1.16; P = 0.0031), infection (OR, 1.04; CI, 1.01-1.07; P = 0.0053), and refusion (hazard ratio, 1.07; CI, 1.02-1.13; P = 0.0103). In this study, age was associated with increased risk of hemorrhage, PE, infection, and refusion. With the aging population, the role of patient age on postoperative healing and outcomes deserves deeper investigation after repair of adult idiopathic scoliosis.


The effect of physical activity on cognitive function in patients with dementia: A meta-analysis of randomized control trials.
Non-pharmacological therapies, such as physical activity interventions, are an appealing alternative or add-on to current pharmacological treatment of cognitive symptoms in patients with dementia. In this meta-analysis, we investigated the effect of physical activity interventions on cognitive function in dementia patients, by synthesizing data from 802 patients included in 18 randomized control trials that applied a physical activity intervention with cognitive function as an outcome measure. Post-intervention standardized mean difference (SMD) scores were computed for each study, and combined into pooled effect sizes using random effects meta-analysis. The primary analysis yielded a positive overall effect of physical activity interventions on cognitive function (SMD[95% confidence interval]=0.42[0.23;0.62], p<.01). Secondary analyses revealed that physical activity interventions were equally beneficial in patients with Alzheimer's disease (AD, SMD=0.38[0.09;0.66], p<.01) and in patients with AD or a non-AD dementia diagnosis (SMD=0.47[0.14;0.80], p<.01). Combined (i.e. aerobic and non-aerobic) exercise interventions (SMD=0.59[0.32;0.86], p<.01) and aerobic-only exercise interventions (SMD=0.41[0.05;0.76], p<.05) had a positive effect on cognition, while this association was absent for non-aerobic exercise interventions (SMD=-0.10[-0.38;0.19], p=.51). Finally, we found that interventions offered at both high frequency (SMD=0.33[0.03;0.63], p<.05) and at low frequency (SMD=0.64[0.39;0.89], p<.01) had a positive effect on cognitive function. This meta-analysis suggests that physical activity interventions positively influence cognitive function in patients with dementia. This beneficial effect was independent of the clinical diagnosis and the frequency of the intervention, and was driven by interventions that included aerobic exercise.


Electroencephalographic identifiers of motor adaptation learning.
Recent brain-computer interface (BCI) assisted stroke rehabilitation protocols tend to focus on sensorimotor activity of the brain. Relying on evidence claiming that a variety of brain rhythms beyond sensorimotor areas are related to the extent of motor deficits, we propose to identify neural correlates of motor learning beyond sensorimotor areas spatially and spectrally for further use in novel BCI-assisted neurorehabilitation settings. Electroencephalographic (EEG) data were recorded from healthy subjects participating in a physical force-field adaptation task involving reaching movements through a robotic handle. EEG activity recorded during rest prior to the experiment and during pre-trial movement preparation was used as features to predict motor adaptation learning performance across subjects. Subjects learned to perform straight movements under the force-field at different adaptation rates. Both resting-state and pre-trial EEG features were predictive of individual adaptation rates with relevance of a broad network of beta activity. Beyond sensorimotor regions, a parieto-occipital cortical component observed across subjects was involved strongly in predictions and a fronto-parietal cortical component showed significant decrease in pre-trial beta-powers for users with higher adaptation rates and increase in pre-trial beta-powers for users with lower adaptation rates. Including sensorimotor areas, a large-scale network of beta activity is presented as predictive of motor learning. Strength of resting-state parieto-occipital beta activity or pre-trial fronto-parietal beta activity can be considered in BCI-assisted stroke rehabilitation protocols with neurofeedback training or volitional control of neural activity for brain-robot interfaces to induce plasticity.


Chronic kidney disease causes disruption of gastric and small intestinal epithelial tight junction.
Integrity of the tight junction (TJ) which seals the gap between the epithelial cells of the gastrointestinal tract is critical in preventing the entry of the microbial toxins, antigens, and other harmful products in the subepithelial tissues and the internal milieu. By enabling the absorption of these products, impairment of the intestinal epithelial barrier leads to local and systemic inflammation. We have recently found depletion of the key protein constituents of colonic epithelial TJ in animals with chronic kidney disease (CKD). Postmortem studies have revealed the presence of inflammation throughout the gastrointestinal tract in uremic humans. This observation suggests that uremia may cause disruption of the epithelial barrier in all segments of the gastrointestinal tract including the stomach, jejunum, and ileum. The present study was undertaken to explore this possibility. Sprague-Dawley rats were randomized to CKD or control groups. The CKD group was subjected to 5/6 nephrectomy while the control group underwent a sham operation. The animals were observed for 10 weeks at which time they were euthanized and their stomachs, jejunums, and ileums were removed and processed for measurement of TJ proteins. The CKD rats showed marked azotemia, systemic oxidative stress, and marked depletion of the key protein constituents of the epithelial TJ (claudin-1, occludin, and ZO1) in the stomach, jejunum, and ileum. The present study extends the earlier finding of uremia-induced disruption of colonic epithelial TJ by documenting the involvement of the stomach, jejunum, and ileum as well.


Emerging role of AMP-activated protein kinase in endocrine control of metabolism in the liver.
This review summarizes the emerging role of AMP-activated protein kinase (AMPK) in mediating endocrine regulation of metabolic fluxes in the liver. There are a number of hormones which, when acting on the liver, alter AMPK activation. Here we describe those hormones associated with activation and de-activation of AMPK and the potential mechanisms for changes in AMPK activation state. The actions of these hormones, in many cases, are consistent with downstream effects of AMPK signaling thus strengthening the circumstantial case for AMPK-mediated hormone action. In recent years, genetic mouse models have also been used in an attempt to establish the role of AMPK in hormone-stimulated metabolism in the liver. Few experiments have, however, firmly established a causal relationship between hormone action at the liver and AMPK signaling.


A Simple Dynamic Strategy to Deliver Stem Cells to Decellularized Nerve Allografts.
The addition of adipose-derived mesenchymal stromal cells to decellularized nerve allografts may improve outcomes of nerve reconstruction. Prior techniques used for cell seeding are traumatic to both the mesenchymal stromal cells and nerve graft. An adequate, reliable, and validated cell seeding technique is an essential step for evaluating the translational utility of mesenchymal stromal cell-enhanced decellularized nerve grafts. The purpose of this study was to develop a simple seeding strategy with an optimal seeding duration. A dynamic bioreactor was used to seed rat and human mesenchymal stromal cells separately onto rat and human decellularized nerve allografts. Cell viability was evaluated by MTS assays and cellular topology after seeding was determined by scanning electron microscopy. Cell density and distribution were determined by Live/Dead assays and Hoechst staining at four different time points (6, 12, 24, and 72 hours). The validity and reliability of the seeding method were calculated. Cells remained viable at all time points, and mesenchymal stromal cells exhibited exponential growth in the first 12 hours of seeding. Seeding efficiency increased significantly from 79.5 percent at 6 hours to 89.2 percent after 12 hours of seeding (p = 0.004). Both intrarater reliability (r = 0.97) and interrater reliability (r = 0.92) of the technique were high. This study describes and validates a new method of effectively seeding decellularized nerve allografts with mesenchymal stromal cells. This method is reproducible, distributes cells homogenously over the graft, and does not traumatize the intraneural architecture of the allograft. Use of this validated seeding technique will permit critical comparison of graft outcomes.


Differential gene expression during capillary morphogenesis in 3D collagen matrices: regulated expression of genes involved in basement membrane matrix assembly, cell cycle progression, cellular differentiation and G-protein signaling.
We have performed a screening analysis of differential gene expression using a defined in vitro model of human capillary tube formation. Gene array, differential display and cDNA library screening were used to identify both known and novel differentially expressed genes. Major findings include: the upregulation and functional importance of genes associated with basement membrane matrix assembly; the upregulation of growth factors, transcription factors, anti-apoptotic factors, markers of endothelial cell differentiation, JAK-STAT signalling molecules, adhesion receptors, proteinase inhibitors and actin regulatory proteins; and expression changes consistent with inhibition of cell cycle progression, increased cholesterol biosynthesis, decreased ubiquitin-proteasome mediated degradation, and activation of G-protein signaling pathways. Using DNA microarray analysis, the most induced genes at 8, 24 and 48 hours compared with those at 0 hours were jagged-1, stanniocalcin and angiopoietin-2, whereas the most repressed genes were connective tissue growth factor, fibulin-3 and RGS-5. In addition, the full length coding sequence of two novel regulated capillary morphogenesis genes (CMGs) are presented. CMG-1 encodes a predicted intracellular 65 kDa protein with coiled-coil domains. A CMG-1-green fluorescent protein (GFP) chimera was observed to target to an intracellular vesicular compartment. A second novel gene, CMG-2, was found to encode a predicted intracellular protein of 45 kDa containing a transmembrane segment and a CMG-2-GFP chimera was observed to target to the endoplasmic reticulum. A recombinant portion of CMG-2 was found to bind collagen type IV and laminin, suggesting a potential role in basement membrane matrix synthesis and assembly. These data further elucidate the genetic events regulating capillary tube formation in a 3D matrix environment.


DNA beta-amyloid(1-42) trimer immunization for Alzheimer disease in a wild-type mouse model.
DNA beta-amyloid(1-42) (Abeta42) trimer immunization was developed to produce specific T helper 2 cell (T(H)2)-type antibodies to provide an effective and safe therapy for Alzheimer disease (AD) by reducing elevated levels of Abeta42 peptide that occur in the brain of patients with AD. To compare the immune response in wild-type mice after immunization with DNA Abeta42 trimer and Abeta42 peptide. Wild-type mice received either 4 microg of DNA Abeta42 trimer immunization administered with gene gun (n = 8) or intraperitoneal injection of 100 microg of human Abeta42 peptide with the adjuvant Quil A (n = 8). Titers, epitope mapping, and isotypes of the Abeta42-specific antibodies were analyzed. Antibody titers, mapping of binding sites (epitopes), isotype profiles of the Abeta42-specific antibodies, and T-cell activation. DNA Abeta42 trimer immunization resulted in antibody titers with a mean of 15 microg per milliliter of plasma. The isotype profile of the antibodies differed markedly. A predominant IgG1 antibody response was found in the DNA-immunized mice, indicating a T(H)2 type of immune response (IgG1/IgG2a ratio of 10). The peptide-immunized mice showed a mixed T(H)1/T(H)2 immune response (IgG1/IgG2a ratio of 1) (P < .001). No increased T-cell proliferation was observed in the DNA-immunized mice (P = .03). In this preliminary study in a wild-type mouse model, DNA Abeta42 trimer immunization protocol produced a T(H)2 immune response and appeared to have low potential to cause an inflammatory T-cell response.


Step and shoot IMRT to mobile targets and techniques to mitigate the interplay effect.
The purpose of this work is to evaluate a method to mitigate temporal dose variation due to the interplay effect as well as investigate the effect of randomly varying motion patterns. The multi-leaf collimator (MLC) settings from 5, 9 and 11 field step and shoot intensity modulated radiation therapy (IMRT) of non-small cell lung cancer (NSCLC) treatment plans with tumor motion of 1.53, 1.03 and 1.95 cm, respectively, were used. Static planar dose distributions were determined for each treatment field using the Planar Dose Module in the Pinnacle(3) treatment planning system. The MotionSIM XY/4D robotic diode array was used to recreate the tumor motion orthogonal to each treatment beam. Dose rate modulation was investigated as a method to mitigate temporal dose variation due to the interplay effect. Computer simulation was able to identify individual fields where interplay effects are greatest. Computer simulation and physical measurement have shown that temporal dose variation can be mitigated by the selection of the dose rate or by selective dose rate modulation within a given IMRT treatment field. Selective dose rate modulation within a given IMRT treatment field reduced temporal dose variation to levels comparable to whole field dose rate reduction, while also producing shorter radiation delivery times in six of the seven cases investigated. For the cases considered, the interplay effect did not appear to have a greater effect on hypofractionation compared to traditional fractionation even though fewer fractions were delivered. Randomized motion kernel variation was also considered. For this portion of the study, a nine field step and shoot IMRT configuration was considered with a 1.03 cm tumor motion rather than the five field case. In general, if the extent of the variant motion pattern was mostly contained within the target volume, limited impact on the temporal dose variation was observed. In cases where the variant motion kernels increasingly exceeded the target volume limits, increases in temporal dose variation were observed.


Impacts of COPD on family carers and supportive interventions: a narrative review.
Caring for a relative with chronic disease influences multiple dimensions of family carers' lives. This study aimed to provide an overview of the impacts of chronic obstructive pulmonary disease (COPD) on family carers and identify interventions aimed at supporting them. A narrative review was conducted. Searches were performed in electronic databases using a combination of keywords. Articles were screened for relevance and selected articles were analysed in two groups considering the study aims. Eighteen articles were selected. Fifteen studies evaluated the impacts of COPD on family carers and three studies presented interventions aimed at supporting them. Carers reported negative impacts of caring on physical health, emotional, social, relational and financial/employment life dimensions. Positive aspects of care-giving were reported in four studies and were related to carers' personal growth and satisfaction in being able to do something useful for their relatives. The existing interventions were directed at both patients and carers; however, studies provided limited information on how carers were involved, hindering the interpretation of findings. In conclusion, COPD poses several unique challenges to family carers related to the specificities of the disease. Further research with appropriate intervention studies is needed to promote carers' healthy adjustment to the disease.


Elevated serum levels of soluble Tac peptide in adult T-cell leukemia: correlation with clinical status during chemotherapy.
Adult T-cell leukemia associated with human T-cell leukemia virus type I (HTLV-I) is characterized by a clonal expansion of a CD4-positive subset of T lymphocytes that constitutively express high numbers of interleukin-2 receptors and that frequently infiltrate the skin; osteolytic bone lesions, and hypercalcemia. Using an enzyme-linked immunosorbent assay (ELISA) test, we measured the level of soluble Tac peptide, one chain of the human interleukin-2 receptor, in the serum of 50 patients with adult T-cell leukemia (38 Japanese and 12 American patients), 8 patients with other hematologic malignancies, 8 asymptomatic HTLV-I-antibody-positive carriers, and 17 normal controls. The serum level of soluble Tac peptide (geometric mean U/mL, 95% CI) was elevated at presentation in all patients with adult T-cell leukemia (16,461; 819 to 330,896) when compared with normal controls (238; 112 to 502), patients with other hematologic malignancies (1302; 475 to 3569), and healthy HTLV-I antibody-positive carriers (490; 115 to 2086). The highest levels were seen in patients (n = 33) with acute (32,154; 2587 to 399,598) compared with chronic (5464; 661 to 45,156) disease (n = 14). Serum levels of Tac peptide also tended to be more elevated in patients with adult T-cell leukemia with hypercalcemia (32,072; 2461 to 417,908) compared with normocalcemic patients (13,885; 496 to 388,436). Serial measurements of soluble Tac peptide levels in serum were done in four patients with adult T-cell leukemia during chemotherapy and the levels reflected disease activity. These observations suggest that the measurement of soluble Tac peptide levels in patients with adult T-cell leukemia is useful as a noninvasive measure of tumor burden and will help in the diagnosis of the disease and management of these patients.


Predictive factors of incomplete aneurysm occlusion after endovascular treatment with the Pipeline embolization device.
The Pipeline embolization device (PED) is a routine choice for the endovascular treatment of select intracranial aneurysms. Its success is based on the high rates of aneurysm occlusion, followed by near-zero recanalization probability once occlusion has occurred. Therefore, identification of patient factors predictive of incomplete occlusion on the last angiographic follow-up is critical to its success. A multicenter retrospective cohort analysis was conducted on consecutive patients treated with a PED for unruptured aneurysms in 3 academic institutions in the US. Patients with angiographic follow-up were selected to identify the factors associated with incomplete occlusion. Among all 3 participating institutions a total of 523 PED placement procedures were identified. There were 284 procedures for 316 aneurysms, which had radiographic follow-up and were included in this analysis (median age 58 years; female-to-male ratio 4.2:1). Complete occlusion (100% occlusion) was noted in 76.6% of aneurysms, whereas incomplete occlusion (≤ 99% occlusion) at last follow-up was identified in 23.4%. After accounting for factor collinearity and confounding, multivariable analysis identified older age (> 70 years; OR 4.46, 95% CI 2.30-8.65, p < 0.001); higher maximal diameter (≥ 15 mm; OR 3.29, 95% CI 1.43-7.55, p = 0.005); and fusiform morphology (OR 2.89, 95% CI 1.06-7.85, p = 0.038) to be independently associated with higher rates of incomplete occlusion at last follow-up. Thromboembolic complications were noted in 1.4% and hemorrhagic complications were found in 0.7% of procedures. Incomplete aneurysm occlusion following placement of a PED was independently associated with age > 70 years, aneurysm diameter ≥ 15 mm, and fusiform morphology. Such predictive factors can be used to guide individualized treatment selection and counseling in patients undergoing cerebrovascular neurosurgery.


A dual-ion electrochemistry deionization system based on AgCl-Na0.44MnO2 electrodes.
Novel desalination technologies with high ion removal capacity and low energy consumption are desirable to tackle the water shortage challenge. Herein, we report a dual-ion electrochemistry deionization (DEDI) system with silver chloride as the electrochemical chloride release/capture anode, sodium manganese oxide as the electrochemical sodium release/capture cathode, and flow salt solution as the electrolyte. Sodium and chloride ions are synergistically released to the flow electrolyte feed at an applied positive current. Under negative current conditions, the two ions are extracted from the flow electrolyte feed to their corresponding electrodes at the same time, which can cause a conductivity decrease indicating salt removal. The salt absorption/desorption capacity of the novel deionization system is stable and reversible, up to 57.4 mg g-1 for 100 cycles, which is much higher than that obtained by conventional or hybrid capacitive deionization devices. The charge efficiency is 0.979/0.956 during the salt desorption/absorption process. This research will be of great significance for high efficiency and low energy consumption seawater desalination.


Effect of bilateral sequential cataract extraction on intraocular pressure in non-glaucomatous Asian eyes.
To determine the effect of cataract extraction on intraocular pressure (IOP) of both eyes in patients undergoing sequential cataract extractions. Retrospective review of 116 consecutive treatment-naive non-glaucomatous patients who underwent sequential cataract extractions of bilateral eyes. Baseline and postsurgical IOP measurements of eyes after cataract extraction were reviewed. Postsurgical IOP of the first surgical eye was compared with the IOP of the (unoperated) second eye. Before surgery, there was no significant difference between the mean IOP of both eyes (15.4±2.6 mm Hg vs 15.2±2.5 mm Hg, p=0.22), and good correlation of presurgical IOP in both eyes was observed. After surgery, mean IOP in the first surgical eye decreased to 14.0±3.1 mm Hg at 1 month (p≤0.001). There was sustained and statistically significant (p<0.001) decrease in IOP in that eye for 2 years. Mean decrease in IOP ranged from 1.6 (8.6%) to 2.3 mm Hg (14.0%). In contrast, the IOP in the fellow (non-surgical) eye remained unchanged. Subsequently, cataract surgery to the fellow eye resulted in a decrease in IOP to a level similar to that of the previously operated eye, which was similarly sustained. Presurgical IOP was the only factor affecting the magnitude of decrease in IOP. There is sustained decrease in IOP after cataract extraction in non-glaucomatous eyes. This decrease is of greater magnitude in eyes with higher presurgical IOP and is not affected by the type of surgery performed. The effect of IOP decrease after surgery is unilateral and does not affect the fellow eye.


Characteristics of dose-dependent antagonism by beta-funaltrexamine of the antinociceptive effects of intrathecal mu agonists.
Using rats with chronic i.t. catheters, dose-response curves were carried out using the hot plate (HP) test for a number of receptor-preferring opioids. The ordering of activity (i.t. ED50; nmol) on the HP was: (D-Ala2, N-Me-Phe4, Gly5-ol) enkephalin (DAMGO 0.5); sufentanil (0.4); and morphine (6.6). To assess the effects of pretreatment with the irreversible mu ligand beta-funaltrexamine (beta-FNA), rats received saline, 0.2, 2.0 or 20.0 nmol of beta-FNA. After 24 hr, base-line response latencies were not different from control animals. Dose-response curves for morphine, sufentanil and DAMGO were then obtained. Pretreatment with beta-FNA resulted in a concentration-dependent rightward shift in the agonist dose-response curves with the dose-ratio values of the respective doses of beta-FNA being for morphine: 3.5, 15.7, and 37.3; sufentanil: 1.2, 1.9, and 5.3; and DAMGO: 1.9, 4.0 and 7.3. The slopes of the agonist dose-response curves also displayed mild reductions in slope, the magnitude of which was dependent upon beta-FNA pretreatment concentrations. Testing at 6 days after beta-FNA treatment revealed a significant recovery of effect. beta-FNA (20 nmol, i.t.) had no effect on a just maximally effective dose of ST-91 (90 nmol, i.t.), an alpha-2 adrenergic agonist. beta-FNA (20 nmol, i.t.), but not 2.0 nmol resulted in a modest but significant reduction in the effect of the delta agonist DPLPE (120 nmol). These data are interpreted as supportive of the hypothesis that the mu-preferring ligands differ in the number of spinal receptors that must be occupied to produce a given antinociceptive effect (i.e., they differ in intrinsic efficacy).


Refractive-index profiling of embedded microstructures in optical materials.
We describe use of a phase-sensitive low-coherence reflectometer to measure spatial variation of refractive index in optical materials. The described interferometric technique is demonstrated to be a valuable tool to profile the refractive index of optical elements such as integrated waveguides and photowritten optical microstructures. As an example, a refractive-index profile is mapped of a microstructure written in a microscope glass slide with an ultrashort-pulse laser.


The accuracy of diagnosing pulmonary tuberculosis at a teaching hospital.
Accuracy of the clinical diagnosis of tuberculosis and of the mycobacteriology laboratory test results was assessed in a teaching hospital by reviewing clinical and microbiologic data on patients from whom Mycobacterium tuberculosis had been recovered. Mycobacteria were isolated in 230 of 6,550 specimens (3.5%). Clinical data were available for 42 patients with tuberculosis, 20 of whom had significant underlying nonmycobacterial disease. Positive tuberculin skin tests wee recorded for 90% of the patients with no underlying disease and for 29% of the patients with underlying disease. Tuberculosis was not suspected initially in 16 of 32 patients with pulmonary disease, and had not been diagnosed by the time of discharge in 10 patients. Of all respiratory specimens from patients with cavitary disease, 57% of the acid-fast stains and 96% of the cultures were positive. In contrast, 32% of stains and 70% of cultures were positive from patients with noncavitary pulmonary tuberculosis. One false-positive acid-fast stain was observed during this study.


Abeta-specific Th2 cells provide cognitive and pathological benefits to Alzheimer's mice without infiltrating the CNS.
We have found that a small number of purified Th2-biased Abeta-specific T cells are sufficient to provide profound cognitive and pathological benefits in an APP+PS1 mouse model for Alzheimer's disease. Six weeks after receiving T cell infusions, cognitively-impaired mice performed significantly better in working memory tasks, which correlated with higher plasma levels of soluble Abeta. Pathological analysis of the hippocampus revealed a 30% decrease of plaque-associated microglia and less vascular amyloidosis in T cell treated mice. The infusion of Abeta-specific Th2 cells also reduced plasma levels of IFN-gamma, TNF-alpha, GM-CSF, IL-2 and IL-4, which are elevated in untreated APP+PS1 mice. No significant immune cell infiltration and no anti-Abeta antibody titers occurred in the T cell treated mice. These results demonstrate that Abeta-specific Th2 cells are sufficient to reverse cognitive impairment and provide multiple pathological benefits in an Alzheimer's mouse model.


Quantitative analysis of the combined effect of substrate rigidity and topographic guidance on cell morphology.
Live cells are exquisitely sensitive to both the substratum rigidity and texture. To explore cell responses to both these types of inputs in a precisely controlled fashion, we analyzed the responses of Chinese hamster ovary (CHO) cells to nanotopographically defined substrata of different rigidities, ranging from 1.8 MPa to 1.1 GPa. Parallel arrays of nanogrooves (800-nm width, 800-nm space, and 800-nm depth) on polyurethane (PU)-based material surfaces were fabricated by UV-assisted capillary force lithography (CFL) over an area of 5 mm × 3 mm. We observed dramatic morphological responses of CHO cells, evident in their elongation and polarization along the nanogrooves direction. The cells were progressively more spread and elongated as the substratum rigidity increased, in an integrin β1 dependent manner. However, the degree of orientation was independent of substratum rigidity, suggesting that the cell shape is primarily determined by the topographical cues.


The Efficacy of Immediate Implant Placement in Extraction Sockets for Alveolar Bone Preservation: A Clinical Evaluation Using Three-Dimensional Cone Beam Computerized Tomography and Resonance Frequency Analysis Value.
The aim of this study was to determine the efficacy of immediate implant placement with alveolar bone augmentation on socket preservation following atraumatic tooth extraction and comparing it with a tooth alveolar socket that was allowed to heal in a conventional way.Twenty medically fit patients (8 males and 12 females aged between 18 and 40 years) who needed noncomplicated tooth extraction of mandibular premolar teeth were divided randomly and equally into 2 groups. In Group I, the empty extraction socket was left untreated and allowed to heal in a conventional way. In Group II, the immediate implant was placed and the gap between the implant and the inner buccal plate surface of the socket wall was filled with lyophilized bovine bone granules and the wound was covered with pericardium membrane. The patients were followed up clinically and radiologically for regular reviews at 1 week, 3 months, and 9 months postoperative. Cone beam computerized tomography images of the alveolar ridge and socket were analyzed to determine the structural changes of the alveolar ridge. Resonance frequency analysis was measured at 9 months for Group II to assess the degree of secondary stability of the implants by using Osstell machine.A significant difference of bone resorption of 1.49 mm (confidence interval, CI 95%, 0.63-2.35) was observed within the control group at 3 months, and 1.84 mm (P ≤ 0.05) at 9 months intervals. No significant changes of bone resorption were observed in Group II. Comparison between groups showed a highly significant difference at 3 months; 2.56 mm (CI 95% 4.22-0.90) and at 9 months intervals; 3.2 mm (CI 95%, 4.70-1.62) P ≤ 0.001 between Group I and II. High resonance frequency analysis values were observed at 9 months postoperative in Group II.In conclusion, the insertion of immediate implants in fresh extraction sockets together with grafting the circumferential gap between the bony socket wall and the implant surface with bovine bone granules was able to preserve a greater amount of alveolar ridge volume when compared with an extraction socket that was left to heal in a conventional way.


In Silico Pharmacoepidemiologic Evaluation of Drug-Induced Cardiovascular Complications Using Combined Classifiers.
Drug-induced cardiovascular complications are the most common adverse drug events and account for the withdrawal or severe restrictions on the use of multitudinous postmarketed drugs. In this study, we developed new in silico models for systematic identification of drug-induced cardiovascular complications in drug discovery and postmarketing surveillance. Specifically, we collected drug-induced cardiovascular complications covering the five most common types of cardiovascular outcomes (hypertension, heart block, arrhythmia, cardiac failure, and myocardial infarction) from four publicly available data resources: Comparative Toxicogenomics Database, SIDER, Offsides, and MetaADEDB. Using these databases, we developed a combined classifier framework through integration of five machine-learning algorithms: logistic regression, random forest, k-nearest neighbors, support vector machine, and neural network. The totality of models included 180 single classifiers with area under receiver operating characteristic curves (AUC) ranging from 0.647 to 0.809 on 5-fold cross-validations. To develop the combined classifiers, we then utilized a neural network algorithm to integrate the best four single classifiers for each cardiovascular outcome. The combined classifiers had higher performance with an AUC range from 0.784 to 0.842 compared to single classifiers. Furthermore, we validated our predicted cardiovascular complications for 63 anticancer agents using experimental data from clinical studies, human pluripotent stem cell-derived cardiomyocyte assays, and literature. The success rate of our combined classifiers reached 87%. In conclusion, this study presents powerful in silico tools for systematic risk assessment of drug-induced cardiovascular complications. This tool is relevant not only in early stages of drug discovery but also throughout the life of a drug including clinical trials and postmarketing surveillance.


Developmental gene expression and tissue distribution of the CHIP28 water-channel protein.
The CHIP28 water channel is a major component of red cell and renal tubule membranes; however, its ontogeny and tissue distribution remain undefined. Three patterns of expression were identified when CHIP28 mRNA was surveyed by in situ hybridization histochemistry in rats between embryonic day 14 and maturity. (i) CHIP28 mRNA and protein were very abundant in hematopoietic tissue and kidneys of mature rats, but strong expression did not occur until after birth, when it appeared in renal proximal tubules and descending thin limbs, red pulp of the spleen, and membranes of circulating red cells. (ii) CHIP28 mRNA was abundant in choroid plexus epithelium throughout fetal development and maturity. (iii) CHIP28 mRNA was transiently observed in periosteum, heart, vascular endothelium, and cornea during fetal development. The ontogeny of kidney and red cell CHIP28 expression coincides with the ability of kidneys to concentrate urine, suggesting that CHIP28 promotes water reabsorption in the proximal nephron and provides red cell osmoregulation needed for passage through the hypertonic medulla. Its presence in the choroid plexus suggests that CHIP28-mediated water transport contributes to secretion of cerebrospinal fluid. The functional role of CHIP28 in developing bone, heart, and eye is unclear. These findings further establish the general physiologic role of CHIP28 as a water channel involved in reabsorption, osmoregulation, and secretion. The studies also suggest other possible functions during fetal development and predict that complex mechanisms will be needed for regulation of CHIP28 gene expression in diverse tissues at distinct points in development.


Evaluation of coronary plaque characteristics with coronary computed tomography angiography in patients with non-obstructive coronary artery disease: a long-term follow-up study.
Recent studies suggested that even non-obstructive coronary artery disease (CAD) increases major cardiovascular adverse events (MACE) rate. Aim of this study was to evaluate whether coronary computed tomography angiography (CCTA) may detect specific plaque characteristics that may affect prognosis in patients with non-obstructive CAD. We enrolled 245 patients who underwent CCTA between April 2004 and April 2007 for suspected CAD and were found to have non-obstructive CAD. Positive remodelling index (PRI), low-attenuation plaque (LAP), plaque burden (PB), spotty calcification (SC), and napkin-ring sign (NRS) have been evaluated for each coronary plaque detected. Acute coronary syndrome, all-cause/cardiac death, and very late elective revascularization (vl-ER) were the endpoints of the study. A total of 28 events were recorded (2 STEMI, 4 NSTEMI, 6 UA, 2 cardiac deaths, 4 non-cardiac death, and 10 vl-ERs) at long-term follow-up (98 ± 20 months). When adjusted for significant clinical variables PRI > 1.4 (HR 3.31 CI 95% 1.11-9.91, P = 0.0392), LAP (HR 8.45 CI 95% 2.22-32.21, P = 0.0019), PB > 0.7 (HR 5.25 CI 95% 1.45-19.03, P = 0.0120), and NRS (HR 12.52 CI 95% 1.51-103.90, P = 0.0198) were still significantly associated with higher rate of hard cardiac events at follow-up. The Kaplan-Meyer curves confirmed lower cumulative hard cardiac events-free survival in patients presenting at least one coronary plaque with two or more high-risk characteristics when compared with patients with no lesion with more than one high-risk plaque characteristics (log-rank P < 0.0001). High-risk plaque characteristics at CCTA (PRI > 1.4, PB > 0.7, LAP, and NRS) seem to be promising for risk stratification of patients with non-obstructive CAD.


The Oyster River Protocol: a multi-assembler and kmer approach for de novo transcriptome assembly.
Characterizing transcriptomes in non-model organisms has resulted in a massive increase in our understanding of biological phenomena. This boon, largely made possible via high-throughput sequencing, means that studies of functional, evolutionary, and population genomics are now being done by hundreds or even thousands of labs around the world. For many, these studies begin with a de novo transcriptome assembly, which is a technically complicated process involving several discrete steps. The Oyster River Protocol (ORP), described here, implements a standardized and benchmarked set of bioinformatic processes, resulting in an assembly with enhanced qualities over other standard assembly methods. Specifically, ORP produced assemblies have higher Detonate and TransRate scores and mapping rates, which is largely a product of the fact that it leverages a multi-assembler and kmer assembly process, thereby bypassing the shortcomings of any one approach. These improvements are important, as previously unassembled transcripts are included in ORP assemblies, resulting in a significant enhancement of the power of downstream analysis. Further, as part of this study, I show that assembly quality is unrelated with the number of reads generated, above 30 million reads. Code Availability: The version controlled open-source code is available at https://github.com/macmanes-lab/Oyster_River_Protocol. Instructions for software installation and use, and other details are available at http://oyster-river-protocol.rtfd.org/.


Hepatocellular Carcinoma: Tumorigenesis and Prediction Markers.
Hepatocellular carcinoma (HCC) is one of the most common malignancies. Although many advances have been made in the clinical study of HCC, the prognosis remains poor. Despite the discoveries in cancer biology in respect with physiological and pathological factors in relation to prognosis, HCC remains still a fatal disease due to late diagnosis. For improving the outcomes of patients with HCC, it is important to identify the factors predisposing to patient death. In recent years, based on cellular and molecular biology techniques, many tumor markers related to invasion, metastasis, recurrence and survival have been explored. However, routine biomarkers for the prediction of HCC evolution and prognosis are available in small number and less specific. These reviews focus on the recent advances in HCC tumorigenesis, revealing those biomarkers with prognosis significance or can be used for early detection.


Sociomics: Using Omic Approaches to Understand Social Evolution.
All of life is social, from genes cooperating to form organisms, to animals cooperating to form societies. Omic approaches offer exceptional opportunities to solve major outstanding problems in the study of how sociality evolves. First, omics can be used to clarify the extent and form of sociality in natural populations. This is especially useful in species where it is difficult to study social traits in natural populations, such as bacteria and other microbes. Second, omics can be used to examine the consequences of sociality for genome evolution and gene expression. This is especially useful in cases where there is clear variation in the level of sociality, such as the social insects. Major tasks for the future are to apply these approaches to a wider range of non-model organisms, and to move from exploratory analyses to the testing of evolutionary theory.


Characterization of the novel HLA-C*06:312 allele by two next-generation sequencing methods.
The novel HLA-C*06:312 allele was characterized using two next generation sequencing technologies.


Skin microvascular endothelial dysfunction is associated with type 2 diabetes independently of microalbuminuria and arterial stiffness.
Skin and kidney microvascular functions may be affected independently in diabetes mellitus. We investigated skin microcirculatory function in 79 subjects with diabetes type 2, where 41 had microalbuminuria and 38 not, and in 41 age-matched controls. The oxygen saturation, fraction of red blood cells and speed-resolved microcirculatory perfusion (% red blood cells × mm/s) divided into three speed regions: 0-1, 1-10 and above 10 mm/s, were assessed during baseline and after local heating of the foot with a new device integrating diffuse reflectance spectroscopy and laser Doppler flowmetry. Arterial stiffness was assessed as carotid-femoral pulse wave velocity. Subjects with diabetes and microalbuminuria had significantly higher carotid-femoral pulse wave velocity compared to subjects without microalbuminuria and to controls. The perfusion for speeds 0-1 mm/s and red blood cell tissue fraction were reduced in subjects with diabetes at baseline and after heating, independent of microalbuminuria. These parameters were correlated to HbA1c. In conclusion, the reduced nutritive perfusion and red blood cell tissue fraction in type 2 diabetes were related to long-term glucose control but independent of microvascular changes in the kidneys and large-vessel stiffness. This may be due to different pathogenic pathways in the development of nephropathy, large-vessel stiffness and cutaneous microvascular impairment.


Characterization of missing human genome sequences and copy-number polymorphic insertions.
The extent of human genomic structural variation suggests that there must be portions of the genome yet to be discovered, annotated and characterized at the sequence level. We present a resource and analysis of 2,363 new insertion sequences corresponding to 720 genomic loci. We found that a substantial fraction of these sequences are either missing, fragmented or misassigned when compared to recent de novo sequence assemblies from short-read next-generation sequence data. We determined that 18-37% of these new insertions are copy-number polymorphic, including loci that show extensive population stratification among Europeans, Asians and Africans. Complete sequencing of 156 of these insertions identified new exons and conserved noncoding sequences not yet represented in the reference genome. We developed a method to accurately genotype these new insertions by mapping next-generation sequencing datasets to the breakpoint, thereby providing a means to characterize copy-number status for regions previously inaccessible to single-nucleotide polymorphism microarrays.


Integrating across memory episodes: Developmental trends.
Memory enables us to use information from our past experiences to guide new behaviours, calling for the need to integrate or form inference across multiple distinct episodic experiences. Here, we compared children (aged 9-10 years), adolescents (aged 12-13 years), and young adults (aged 19-25 years) on their ability to form integration across overlapping associations in memory. Participants first encoded a set of overlapping, direct AB- and BC-associations (object-face and face-object pairs) as well as non-overlapping, unique DE-associations. They were then tested on these associations and inferential AC-associations. The experiment consisted of four such encoding/retrieval cycles, each consisting of different stimuli set. For accuracy on both unique and inferential associations, young adults were found to outperform teenagers, who in turn outperformed children. However, children were particularly slower than teenagers and young adults in making judgements during inferential than during unique associations. This suggests that children may rely more on making inferences during retrieval, by first retrieving the direct associations, followed by making the inferential judgement. Furthermore, young adults showed a higher correlation between accuracy in direct (AB, BC) and inferential AC-associations than children. This suggests that, young adults relied closely on AB- and BC-associations for making AC decisions, potentially by forming integrated ABC-triplets during encoding or retrieval. Taken together, our findings suggest that there may be an age-related shift in how information is integrated across experienced episodes, namely from relying on making inferences at retrieval during middle childhood to forming integrated representations at different memory processing stages in adulthood.


Can targeted therapy be successful without metronomic scheduling?
In medical oncology, targeted therapy has emerged over the last decade, as the most promising strategy to fight cancer. In addition, a more complete understanding of tumor heterogeneity and pharmacology of the more conventional anti-cancer agents has led to development of metronomic chemotherapy (MC) (i.e. a more frequent administration of anticancer agents at lower doses then the usual maximally tolerated dose because it has been realized that time of exposure to an effective drug concentration is more important than simply the dose/m2 or kg.), Here, we discuss the nature of the specificity of targeted anti-cancer treatments and conclude that optimizing the schedule is an effective way to improve treatment selectivity.


Discrepancies in cigarette brand sales and adult market share: are new teen smokers filling the gap?
To examine the extent and type of cigarette brand switching by adult smokers. To evaluate discrepancies between actual and projected cigarette brand sales based on changes in adult smoking patterns. Data analysed come from a cohort tracking survey of 11966 cigarette smokers aged 25-64 years from 20 communities in the United States who were followed between 1988 and 1993 as part of the National Cancer Institute's Community Intervention Trial for Smoking Cessation. Respondents were asked about their current cigarette brand in 1988 and 1993. Brand switching was inferred when a smoker reported a different cigarette brand in 1988 and 1993. Company switching was defined as brand switching for whom a different parent company was identified for the 1993 brand compared with the brand used in 1988. A ratio measure was computed to reflect gains in market share from brand switching and losses from brand switching, quitting, and death, for specific cigarette brands, between 1988 and 1993. This ratio measure was used to estimate the projected unit sales for top-selling premium brands in 1993 and was compared with actual unit sales for the same year. We estimate that an average of 9.5% of smokers switched cigarettes brands and 7.6% switched companies each year. Most of those who did switch cigarette brands changed from a premium brand to a discount or generic brand. Between 1988 and 1993, top-selling premium brands such as Marlboro, Camel, and Newport, lost about four times as many adult smokers as they gained. Whereas premium brand cigarettes lost some smokers to discount and generic cigarettes, over 50% of losses were due to smokers quitting or dying. Actual unit sales were substantially higher than projected sales (based on adult market share) for Marlboro and Camel, but not for other brands. Most smokers are brand loyal. Price seems to be an important factor motivating brand switching among adult smokers. It appears that recruitment of new customers among the ranks of non-smokers is necessary for premium cigarette brands such as Marlboro and Camel to maintain sales comparable to previous years.


Association between low-back pain and lumbar spine bone density: a population-based cross-sectional study.
The authors undertook this study to investigate the relationships between low-back pain (LBP) and spinal bone density. Low-back pain is a major health issue and contributes to increases in medical and economic costs. Epidemiological studies have identified individual, sociodemographic, psychosocial, and occupational risk factors for LBP. However, there have been limited studies addressing the relationships between LBP and spinal bone density. Data were obtained from the population-based Fourth Korea National Health and Nutrition Examination Survey (K-NHANES IV, 2009). From 10,533 K-NHANES participants, the authors identified 7144 (3099 men and 4045 women) 21 years of age or older who underwent dual-energy x-ray absorptiometry and anthropometric measurements for inclusion in this study. Low-back pain patients were defined as those who had been diagnosed with LBP by a medical doctor. Chi-square tests, t-tests, and multivariable logistic regression analyses were used to examine the relationships between LBP and spinal bone density. The total prevalence of LBP in the patient sample was 17.1%. More females (21.0%) reported LBP than males (12.1%). A number of sociodemographic and medical factors-sex, age, place of residence, occupation, education, hypertension, diabetes mellitus, and depression-were all associated with LBP, while LBP was not associated with income or exercise levels. Regression analyses indicated that higher lumbar spine T-scores (OR 1.11, 95% CI 1.02-1.20) were associated with LBP. Higher bone density in the lumbar spine is associated with LBP, independent of confounding factors such as sociodemographic status, education, and medical-psychiatric disorders. Cause and effect relationship between higher bone density and LBP, such as degenerative changes in spine, requires further investigation.


First Report of Citrus exocortis viroid in a Verbena sp. in Montenegro.
Numerous ornamental plants have been found to be symptomless hosts of various pospiviroids including Citrus exocortis viroid (CEVd), and hence, may serve as potential inoculum reservoirs for susceptible vegetable plants. Production of tomato, potato, and pepper, on which viroids from the genus Pospiviroid can cause severe damage, represents two-thirds of the vegetable production in Montenegro. We tested vegetable, ornamental, and weed host plants for the presence of pospiviroids in September 2011. Altogether 80 samples were taken. Samples of ornamental plants (15 of Petunia spp., 7 of Impatiens spp., 4 of Verbena spp., 3 of Dahlia spp., 3 of Pittosporum tobira, 3 of Vinca spp., 2 of Brugmansia spp., 2 of avocado, 2 of Portulaca spp., and 1 of Datura sp.) were taken from three places of production. One sample per species was collected from symptomless eggplants, tomatoes, sweet peppers, and avocados in the vicinity of one glasshouse with ornamental plants. Twenty-two samples from sweet pepper and seven samples from tomato, all grown under cover and all showing potential virus-like symptoms, were collected from three places of vegetable production. Two samples of Solanum nigrum and three samples of unidentified weed species belonging to genus Solanum were taken from two glasshouses. With the exception of weed plants, samples consisted of fully developed leaves collected from five plants. All sampled ornamental and weed plants were symptomless. RNA was extracted from approximately 15 mg of leaf tissue with the MagMAX-96 Total RNA Isolation Kit (Life Technologies, Foster City, CA) in accordance with the manufacturer's instructions for the MagMAX Express Magnetic Particle Processor. Samples were tested by reverse transcription (RT)-PCR using semi-universal pospiviroid primers (Pospi1-RE/FW and Vid-RE/FW [3]). None of the samples reacted with the Vid-RE/FW primer pair. An amplicon of an expected size (approximately 196 nt) was produced with the Pospi1-RE/FW primer pair from one Verbena sp. sample. Direct sequencing was performed by Macrogen (Amsterdam, The Netherlands). Sequence analysis indicated the presence of CEVd. This finding was confirmed by sequence analysis of the DNA product obtained by RT-PCR using Pospi1-FW/RE from a new extraction. Further analyses using primer pairs CEVd-AS/S (1) and CEVd-FW2/RE2 (4) were performed to obtain the full viroid sequence. The sequence of 372 nt was deposited in GenBank (Accession No. JN872140) and had 99% identity with two CEVd sequences from Verbena spp. (Accession Nos. EF192396 and DQ094297). To our knowledge, this is the first report of CEVd in a Verbena sp. in Montenegro and the second report in Europe (4). CEVd has been detected in Verbena spp. also in India and Canada and can be transmitted by seed (2). The infected Verbena sp. plants were not destroyed, since CEVd is not listed as a quarantine organism in Montenegro. The spread of CEVd infection to tomato could devastate the production of this crop in Montenegro. References: (1) A. Elleuch et al. Plant Protect. Sci. 39:139, 2003. (2) R. P. Singh et al. Eur. J. Plant Pathol. 124:691, 2009. (3) J. Th. J. Verhoeven et al. Eur. J. Plant Pathol. 110:823, 2004. (4) J. Th. J. Verhoeven et al. Plant Dis. 92:973, 2008.


Are fatty nuts a weighty concern? A systematic review and meta-analysis and dose-response meta-regression of prospective cohorts and randomized controlled trials.
Nuts are recommended for cardiovascular health, yet concerns remain that nuts may contribute to weight gain due to their high energy density. A systematic review and meta-analysis of prospective cohorts and randomized controlled trials (RCTs) was conducted to update the evidence, provide a dose-response analysis, and assess differences in nut type, comparator and more in subgroup analyses. MEDLINE, EMBASE, and Cochrane were searched, along with manual searches. Data from eligible studies were pooled using meta-analysis methods. Interstudy heterogeneity was assessed (Cochran Q statistic) and quantified (I2 statistic). Certainty of the evidence was assessed by Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Six prospective cohort studies (7 unique cohorts, n = 569,910) and 86 RCTs (114 comparisons, n = 5873) met eligibility criteria. Nuts were associated with lower incidence of overweight/obesity (RR 0.93 [95% CI 0.88 to 0.98] P < 0.001, "moderate" certainty of evidence) in prospective cohorts. RCTs presented no adverse effect of nuts on body weight (MD 0.09 kg, [95% CI -0.09 to 0.27 kg] P < 0.001, "high" certainty of evidence). Meta-regression showed that higher nut intake was associated with reductions in body weight and body fat. Current evidence demonstrates the concern that nut consumption contributes to increased adiposity appears unwarranted.


In support of an individualized approach to assessing quality of life: comparison between Patient Generated Index and standardized measures across four health conditions.
Individualized measures of health-related quality life (HRQL) have been used for decades and shown to provide unique information, but little work has been done to explain this uniqueness particularly across health conditions. To estimate, across four health conditions, the magnitude of the association between scores derived from the Patient Generated Index (PGI) and those from fully standardized generic and disease-specific measures of the HRQL; to identify the extent to which the areas generated from the PGI are covered by the content of the fully standardized measures. The PGI and other generic and disease-specific measures had been used in four different samples of people: stroke (n = 222), multiple sclerosis (MS; n = 185); advanced cancer (n = 173), and HIV+ (n = 690). Areas nominated on the PGI were harmonized to a standard nomenclature. Pearson correlations were estimated between PGI and other measures. Data from 1263 people indicated that PGI provided the lowest rating for HRQL across all health conditions. The areas nominated differed across conditions with walking/mobility: the most common for stroke (42%), work/school for MS (62%), health for HIV+ (97%), and fatigue for cancer (39%). Many of the aspects of health included in generic measures were not nominated using the PGI and vice versa. The highest correlations between the PGI and other measures were observed for people with MS, with correlations between 0.53 and 0.59; lowest correlations were observed for people with HIV and cancer, ≤0.33. The PGI scores reflect those aspects of quality of life that are important to patients in which they would most value an improvement. Heterogeneity in HRQL across health conditions is poorly discriminated using standardized measures. A "one-size-fits-all" approach to HRQL assessment may not provide the most useful representation of this important construct.


Twelve Principles Trainees, PIs, Departments, and Faculties Can Use to Reduce Bias and Discrimination in STEM.
There is an overwhelming amount of evidence demonstrating that people from marginalized groups, including women, racialized and Indigenous peoples, people with disabilities, immigrants, and LGBTQ+ individuals, continue to face substantial discrimination in STEM, manifested as both overt bias and unconscious bias. These biases result in discrimination against individuals in marginalized groups, and independent biases collectively contribute to a culture that systematically discriminates against people from marginalized groups. Representation from marginalized groups in postsecondary degrees in natural science and engineering has not substantially improved in over a decade. A set of 10 concrete principles are presented that trainees, principle investigators, departments, and faculties can use to enhance the participation and lived experiences of people in marginalized groups in STEM.


Acid sensing ion channels regulate neuronal excitability by inhibiting BK potassium channels.
Acid sensing ion channels (ASICs), Ca(2+) and voltage-activated potassium channels (BK) are widely present throughout the central nervous system. Previous studies have shown that when expressed together in heterologous cells, ASICs inhibit BK channels, and this inhibition is relieved by acidic extracellular pH. We hypothesized that ASIC and BK channels might interact in neurons, and that ASICs may regulate BK channel activity. We found that ASICs inhibited BK currents in cultured wild-type cortical neurons, but not in ASIC1a/2/3 triple knockout neurons. The inhibition in the wild-type was partially relieved by a drop in extracellular pH to 6. To test the consequences of ASIC-BK interaction for neuronal excitability, we compared action potential firing in cultured cortical neurons from wild-type and ASIC1a/2/3 null mice. We found that in the knockout, action potentials were narrow and exhibited increased after-hyperpolarization. Moreover, the excitability of these neurons was significantly increased. These findings are consistent with increased BK channel activity in the neurons from ASIC1a/2/3 null mice. Our data suggest that ASICs can act as endogenous pH-dependent inhibitors of BK channels, and thereby can reduce neuronal excitability.


Topographical and compositional engineering of core-shell Ni@Pt ORR electro-catalysts.
Complex faceted geometries and compositional anisotropy in alloy nanoparticles (NPs) can enhance catalytic performance. We report on the preparation of binary PtNi NPs via a co-thermolytic approach in which we optimize the synthesis variables, which results in significantly improved catalytic performance. We used scanning transmission electron microscopy to characterise the range of morphologies produced, which included spherical and concave cuboidal core-shell structures. Electrocatalytic activity was evaluated using a rotating disc electrode (1600 rpm) in 0.1 M HClO4; the electrocatalytic performance of these Ni@Pt NPs showed significant (∼11-fold) improvement compared to a commercial Pt/C catalyst. Extended cycling revealed that electrochemical surface area was retained by cuboidal PtNi NPs post 5000 electrochemical cycles (0.05-1.00 V, vs. SHE). This is attributed to the enclosure of Ni atoms by a thick Pt shell, thus limiting Ni dissolution from the alloy structures. The novel synthetic strategy presented here results in a high yield of Ni@Pt NPs which show excellent electro-catalytic activity and useful durability.


Managing a moral identity in debt advice conversations.
Previous research has found that stigma can be a barrier to service use but there has been little work examining actual service encounters involving members of stigmatized groups. One such group are those with problematic or unmanageable debts. Providing advice to members of this group is likely to be particularly difficult due to the stigma associated with being in debt. Using conversation analysis and discursive psychology, this study examines 12 telephone advice conversations between debt advisors and individuals in debt. Both clients and advisors oriented to the negative moral implications of indebtedness and typically worked collaboratively to manage these issues. Clients often claimed a moral disposition as a way to disclaim any unwanted associations with debt, but could find it difficult to reconcile this with an insolvency agreement. Moreover, the institutional requirements of the interaction could disrupt the collaborative management of stigma and advisors could manage the subsequent resistance from clients in either client-centred or institution-centred ways. The findings suggest that the products offered by debt advice agencies, as well as the manner in which they are offered to clients, can either help or hinder debtors negotiate the stigma-related barriers to service engagement.


Living with Uncertainty: Older Persons' Lived Experience of Making Independent Decisions over Time.
The aim of the study was to illuminate the meaning of older persons' independent decision making concerning their daily care. Autonomy when in care is highly valued in the western world. However, research shows that autonomy can give rise to problematic issues. The complexity of independence and dependence for older people when living at home with help has also been highlighted. In Sweden, older people are increasingly expected to live at home with help from municipal home care services, and study into this aspect of care is limited. This study is a part of an ongoing project and has a qualitative life world perspective. Audiotaped narrative interviews were conducted and analysed using a phenomenological hermeneutic method. Findings revealed a main theme: "living with uncertainty as to how to relate one's own independence and dependence with regard to oneself, and others." This involves a constant process of relating to one's independence controlled by others or oneself, and adjusting one's independence and dependence with regard to oneself and others. The conclusion is that professional carers need to acknowledge the changing vulnerability of dependent older persons over time. The implication is a relational approach to autonomy beyond the traditional individualistic approach.


Repair or Replacement for Isolated Tricuspid Valve Pathology? Insights from a Surgical Analysis on Long-Term Survival.
BACKGROUND Long-term follow-up data concerning isolated tricuspid valve pathology after replacement or reconstruction is limited. Current American Heart Association guidelines equally recommend repair and replacement when surgical intervention is indicated. Our aim was to investigate and compare operative mortality and long-term survival in patients undergoing isolated tricuspid valve repair surgery versus replacement. MATERIAL AND METHODS Between 1995 and 2011, 109 consecutive patients underwent surgical correction of tricuspid valve pathology at our institution for varying structural pathologies. A total of 41 (37.6%) patients underwent tricuspid annuloplasty/repair (TAP) with or without ring implantation, while 68 (62.3%) patients received tricuspid valve replacement (TVR) of whom 36 (53%) were mechanical and 32 (47%) were biological prostheses. RESULTS Early survival at 30 days after surgery was 97.6% in the TAP group and 91.1% in the TVR group. After 6 months, 89.1% in the TAP group and 87.8% in the TVR group were alive. In terms of long-term survival, there was no further mortality observed after one year post surgery in both groups (Log Rank p=0.919, Breslow p=0.834, Tarone-Ware p=0.880) in the Kaplan-Meier Survival analysis. The 1-, 5-, and 8-year survival rates were 85.8% for TAP and 87.8% for TVR group. CONCLUSIONS Surgical repair of the tricuspid valve does not show survival benefit when compared to replacement. Hence valve replacement should be considered generously in patients with reasonable suspicion that regurgitation after repair will reoccur.


Fluconazole therapy in neonatal candidemia.
We reviewed 62 episodes (from 59 infants) of neonatal candidemia that occurred between January 1994 and June 1999. Except 5 term babies, all infants were premature (median gestational age [GA], 30 weeks) and birth weight was less than 2,500 g (median, 1,300 g). Most infants had reported risk factors and other neonatal problems. The age at onset of candidemia ranged from 15 to 173 days with a median of 34 days. In addition to catheter removal, all but one infants received antifungal agents and candidemia was eradicated subsequently in 46 episodes (75%). Eighteen infants with 19 episodes ever received fluconazole therapy. Fluconazole was administered as the first line agent in 6 episodes and successfully cleared candidemia in 5 episodes. Fluconazole was used as an alternative agent in an additional 13 episodes after amphotericin B (am B) +/- flucytosine were given for a period without a satisfactory result and eradication of candidemia was achieved in 8 episodes subsequently. All 18 infants tolerated fluconazole well and no withdrawal was required on account of its adverse effect. In contrast, am B alone was administered as the first line agent in 55 episodes and successfully cleared candidemia in 32 episodes (58%). This retrospective analysis suggests that fluconazole appears to be safe in neonates and can be used as an alternative agent in treating neonatal candidemia. A large-scaled prospective study may be needed.


Parallel evolution of chordate cis-regulatory code for development.
Urochordates are the closest relatives of vertebrates and at the larval stage, possess a characteristic bilateral chordate body plan. In vertebrates, the genes that orchestrate embryonic patterning are in part regulated by highly conserved non-coding elements (CNEs), yet these elements have not been identified in urochordate genomes. Consequently the evolution of the cis-regulatory code for urochordate development remains largely uncharacterised. Here, we use genome-wide comparisons between C. intestinalis and C. savignyi to identify putative urochordate cis-regulatory sequences. Ciona conserved non-coding elements (ciCNEs) are associated with largely the same key regulatory genes as vertebrate CNEs. Furthermore, some of the tested ciCNEs are able to activate reporter gene expression in both zebrafish and Ciona embryos, in a pattern that at least partially overlaps that of the gene they associate with, despite the absence of sequence identity. We also show that the ability of a ciCNE to up-regulate gene expression in vertebrate embryos can in some cases be localised to short sub-sequences, suggesting that functional cross-talk may be defined by small regions of ancestral regulatory logic, although functional sub-sequences may also be dispersed across the whole element. We conclude that the structure and organisation of cis-regulatory modules is very different between vertebrates and urochordates, reflecting their separate evolutionary histories. However, functional cross-talk still exists because the same repertoire of transcription factors has likely guided their parallel evolution, exploiting similar sets of binding sites but in different combinations.


Application of the spacing effect to improve learning and memory for functional tasks in traumatic brain injury: a pilot study.
Research has indicated that many people with traumatic brain injury (TBI) experience learning and memory difficulties because of impairments in the initial acquisition of information. We examined a strategy, the spacing effect, known to enhance new learning in a laboratory setting in healthy control participants (HCs) and in people with TBI. The spacing effect indicates that information is learned better when presentation trials are distributed over time (spaced presentation) rather than consecutively (massed presentation). In this study, we examined the application of the spacing effect in improving functional tasks. We used a within-subject design and included 10 participants with TBI and 15 HCs. In both the TBI and the HC groups, material learned under the spaced learning condition was recalled better than that learned under massed learning conditions. These results provide initial evidence supporting the use of the spacing effect to improve new learning of functional tasks for people with TBI.


Measuring ocular aberrations in the peripheral visual field using Hartmann-Shack aberrometry.
We have used the Hartmann-Shack technique previously to measure ocular aberrations along the horizontal meridian of the visual field. This requires considerable modifications from the technique for measuring the aberrations corresponding to the fovea. We now further develop the technique so that it can be used for any meridian of the visual field. Allowance is made for any auxiliary optics placed in front of the eye to compensate for the limited range of the Hartmann-Shack technique and for the case where aberrations are estimated at a wavelength other than the measuring wavelength. Zernike wave aberrations are converted to peripheral refractions. Examples are presented showing the developments, and we discuss change in wave aberrations when converting from a circular to an elliptical pupil.


Tug of War between Condensate Phases in a Minimal Macromolecular System.
Membraneless organelles, comprising dozens to hundreds of macromolecular components, form heterogeneous phases in space and evolve over time in material properties. Here, using four macromolecules, we demonstrate a range of phase behaviors associated with membraneless organelles and uncover the underlying physicochemical rules. The macromolecules are SH35 (S) and PRM5 (P), two pentameric, oppositely charged protein constructs; heparin (H), an anionic polymer; and lysozyme (L), a cationic single-domain protein. The S:P, S:L, and P:H binaries form droplets, but the H:L binary forms network-like precipitates, therefore setting up a tug of war between different condensate phases within the S:P:H:L quaternary. The H:L exception can partly be attributed to the compactness of L, as supported by ThT binding data. Increasing amounts of P alone or both S and P, but not S alone, can dissolve H:L precipitates into droplets. These differential effects can be explained by the order of the strengths of pairwise attraction: H:L > P:H > S:P > S:L, deduced from the shapes of ternary phase boundaries. When S and P are at subdissolution concentrations, S:P:H:L precipitates change over time to become droplet-like in appearance, although not completely fluidic according to fluorescence recovery after photobleaching. In fact, confocal microscopy reveals separated S:L-rich and P:H-rich foci inside the droplet-like condensates. Therefore, complex phase behaviors of membraneless organelles, including rescue of aberrant phase transitions, demixing of condensates, and time evolution of material properties, can all be reconstituted and understood via a minimal macromolecular system.


Clinical risk factors and periventricular leucomalacia.
Two hundred infants of below 1501 g at birth were regularly examined with real time ultrasound using a 7.5 MHz transducer. Abnormalities were categorized as periventricular haemorrhage (PVH) (n = 107) or periventricular leucomalacia (PVL), with or without PVH (n = 52). Of the group with PVL, 25 had the appearances of prolonged flare without cavitation. Prospective assessments of up to 50 potential clinical risk factors were made wherever possible on each infant including stratification of all blood gas and systolic blood pressure data. Multivariate logistic regression analyses confirmed a strong correlation between immaturity and PVH but this was not found in cases of PVL. Independent variables associated with PVL included pneumothorax, maximum bilirubin concentration, surgery, and the proportion of time the infant's PaCO2 remained above 7 kPa. There was a very strong inverse correlation between anaemia and PVL. Systolic blood pressure data were carefully analysed and there was no relation between either hypotension or antepartum haemorrhage and the development of PVL.


Socio-Economic Differentials in Impoverishment Effects of Out-of-Pocket Health Expenditure in China and India: Evidence from WHO SAGE.
The provision of affordable health care is generally considered a fundamental goal of a welfare state. In addition to its role in maintaining and improving the health status of individuals and households, it impacts the economic prosperity of a society through its positive effects on labor productivity. Given this context, this paper assesses socioeconomic-differentials in the impact of out-of-pocket-health-expenditure (OOPHE) on impoverishment in China and India, two of the fastest growing economies of the world. The paper uses data from the World Health Organisation's Study on Global Ageing and Adult Health (WHO SAGE), and Bivariate as well as Multivariate analyses for investigating the socioeconomic-differentials in the impact of out-of-pocket-health-expenditure (OOPHE) on impoverishment in China and India. Annually, about 7% and 8% of the population in China and India, respectively, fall in poverty due to OOPHE. Also, the percentage shortfall in income for the population from poverty line due to OOPHE is 2% in China and 1.3% in India. Further, findings from the multivariate analysis indicate that lower wealth status and inpatient as well as outpatient care increase the odds of falling below poverty line significantly (with the extent much higher in the case of in-patient care) due to OOPHE in both China and India. In addition, having at least an under-5 child in the household, living in rural areas and having a household head with no formal education increases the odds of falling below poverty line significantly (compared to a head with college level education) due to OOPHE in China; whereas having at least an under-5 child, not having health insurance and residing in rural areas increases the odds of becoming poor significantly due to OOPHE in India.


Interfacial redox processes in memristive devices based on valence change and electrochemical metallization.
Memristive devices based on electrochemical processes are promising candidates for next-generation memory and neuromorphic applications. The redox processes happening at the interfaces are crucial steps for the ionization as well as generation of counter charges, and are thus indispensable for successful resistive switching, but their detailed mechanism has not been fully clarified. Here, we study the interfacial redox reactions in the forming process of memristive devices based on valence change and electrochemical metallization, using high-resolution electron microscopy and electrostatic force microscopy observations. We show direct evidence for the anodic oxidation of oxygen ions and cathodic reduction of moisture in HfO2- and Ta2O5-based valence change cells, which could take place in different horizontal locations. We further found that the anodic reactions always led to more pronounced structural damage to the electrode, indicating the possibility of additional cathodic reactions without producing gaseous products. When an active electrode is present, oxidation of metal atoms takes place at the anodic interface instead. Further investigations on electrochemical metallization cells have identified Cu ionization and moisture reduction as the anodic and cathodic reactions, respectively, and formation of Cu nuclei at the cathodic interface was directly observed. These findings with microscopic evidence could facilitate future development of memristive devices.


The reconstruction of two large full-thickness wounds of the upper lip with different operative techniques: when possible, a local flap repair is preferable to reconstruction with free tissue transfer.
Large full-thickness wounds of the upper lip are often referred to operating room-based surgeons for repair given the perceived difficulties in restoring upper lip form and function with simpler operative techniques. To illustrate the functional, aesthetic, and cost differences between two techniques used to repair full-thickness wounds of the upper lip. Two patients with difficult full-thickness wounds of the majority of the upper lip were reviewed. One patient underwent reconstruction with a composite free flap in an operating room, and one underwent repair using local tissue rearrangement using bilateral modified nasolabial flaps in an outpatient setting. Both patients were adequately reconstructed, but the patient repaired using local tissue rearrangement had a better aesthetic outcome and superior preservation of oral competency. In addition, the costs of this patient's reconstructive care were less than 2.4% of the costs of the care of the patient repaired using a free flap. When possible, large, full-thickness wounds of the upper lip should be repaired with local tissue rearrangement in an outpatient setting to offer patients potential improvements in functional and aesthetic outcomes while minimizing treatment costs.


CRH Affects the Phenotypic Expression of Sepsis-Associated Virulence Factors by Streptococcus pneumoniae Serotype 1 In vitro.
Sepsis is a life-threatening health condition caused by infectious pathogens of the respiratory tract, and accounts for 28-50% of annual deaths in the US alone. Current treatment regimen advocates the use of corticosteroids as adjunct treatment with antibiotics, for their broad inhibitory effect on the activity and production of pro-inflammatory mediators. However, despite their use, corticosteroids have not proven to be able to reverse the death incidence among septic patients. We have previously demonstrated the potential for neuroendocrine factors to directly influence Streptococcus pneumoniae virulence, which may in turn mediate disease outcome leading to sepsis and septic shock. The current study investigated the role of Corticotropin-releasing hormone (CRH) in mediating key markers of pneumococcal virulence as important phenotypic determinants of sepsis and septic shock risks. In vitro cultures of serotype 1 pneumococcal strain with CRH promoted growth rate, increased capsule thickness and penicillin resistance, as well as induced pneumolysin gene expression. These results thus provide significant insights of CRH-pathogen interactions useful in understanding the underlying mechanisms of neuroendocrine factor's role in the onset of community acquired pneumonias (CAP), sepsis and septic shock.


Population mean scores predict child mental disorder rates: validating SDQ prevalence estimators in Britain.
For adult physical and mental health, the population mean predicts the proportion of individuals with 'high' scores. This has not previously been investigated for child mental health. It is also unclear how far symptom scores on brief questionnaires provide an unbiased method of comparing children with different individual, family or social characteristics. Subjects were 18,415 British children aged 5-16 years. Parents, teachers, and children aged 11-16 completed Strengths and Difficulties Questionnaires (SDQs) and diagnostic interviews; the latter were used to assign multi-informant clinician-rated diagnoses. We examined how closely the prevalence of child mental disorder was predicted by SDQ mean total difficulty scores, and how these mean scores compared to alternative SDQ-based summary statistics. We did this for populations defined in terms of a wide range of risk factors using one randomly selected half of the study sample. Using these results we generated SDQ prevalence estimator equations, and validated these on the second half of the study sample. Mean symptom scores closely predicted the prevalence of clinician-rated child mental disorder (R(2) = .89-.95) and performed better than alternative summary statistics based on binary SDQ outcomes. The predictions of the SDQ prevalence estimators were on average only 1-2% different from the true prevalence, with no systematic tendency towards under- or overestimation. There were only a few outlier subpopulations, all relating to children with learning difficulties. The proportion of children with a disorder is closely predicted by mean symptom scores, highlighting the potential importance of population-wide interventions to improve child mental health. In Britain, SDQ mean total difficulty scores generally provide an accurate and unbiased method of assessing the mental health of different subgroups. SDQ prevalence estimators may facilitate presenting these research findings as proportions that are more easily interpreted by policymakers and service providers.


Helicobacter pylori usurps cell polarity to turn the cell surface into a replicative niche.
Helicobacter pylori (Hp) intimately interacts with the gastric epithelial surface and translocates the virulence factor CagA into host cells in a contact-dependent manner. To study how Hp benefits from interacting with the cell surface, we developed live-cell microscopy methods to follow the fate of individual bacteria on the cell surface and find that Hp is able to replicate and form microcolonies directly over the intercellular junctions. On polarized epithelia, Hp is able to grow directly on the apical cell surface in conditions that do not support the growth of free-swimming bacteria. In contrast, mutants in CagA delivery are defective in colonization of the apical cell surface. Hp perturbs the polarized epithelium in a highly localized manner, since wild-type Hp does not rescue the growth defect of the CagA-deficient mutants upon co-infection. CagA's ability to disrupt host cell polarity is a key factor in enabling colonization of the apical cell surface by Hp, as disruption of the atypical protein kinase C/Par1b polarity pathway leads to rescue of the mutant growth defect during apical infection, and CagA-deficient mutants are able to colonize the polarized epithelium when given access to the basolateral cell surface. Our study establishes the cell surface as a replicative niche and the importance of CagA and its effects on host cell polarity for this purpose.