Effect of decellularized adipose tissue particle size and cell density on adipose-derived stem cell proliferation and adipogenic differentiation in composite methacrylated chondroitin sulphate hydrogels.
An injectable composite scaffold incorporating decellularized adipose tissue (DAT) as a bioactive matrix within a hydrogel phase capable of in situ polymerization would be advantageous for adipose-derived stem cell (ASC) delivery in the filling of small or irregular soft tissue defects. Building on previous work, the current study investigates DAT milling methods and the effects of DAT particle size and cell seeding density on the response of human ASCs encapsulated in photo-cross-linkable methacrylated chondroitin sulphate (MCS)-DAT composite hydrogels. DAT particles were generated by milling lyophilized DAT and the particle size was controlled through the processing conditions with the goal of developing composite scaffolds with a tissue-specific 3D microenvironment tuned to enhance adipogenesis. ASC proliferation and adipogenic differentiation were assessed in vitro in scaffolds incorporating small (average diameter of 38 ± 6 μm) or large (average diameter of 278 ± 3 μm) DAT particles in comparison to MCS controls over a period of up to 21 d. Adipogenic differentiation was enhanced in the composites incorporating the smaller DAT particles and seeded at the higher density of 5 × 10(5) ASCs/scaffold, as measured by glycerol-3-phosphate dehydrogenase (GPDH) enzyme activity, semi-quantitative analysis of perilipin expression and oil red O staining of intracellular lipid accumulation. Overall, this study demonstrates that decellularized tissue particle size can impact stem cell differentiation through cell-cell and cell-matrix interactions, providing relevant insight towards the rational design of composite biomaterial scaffolds for adipose tissue engineering.


Linked CD4 T Cell Help: Broadening Immune Attack Against Cancer by Vaccination.
In the last decade, immunotherapy with monoclonal antibodies targeting immunological check points has become a breakthrough therapeutic modality for solid cancers. However, only up to 50 % of patients benefit from this powerful approach. For others vaccination might provide a plausible addition or alternative. For induction of effective anticancer immunity CD4+ T cell help is required, which is often difficult to induce to self cancer targets because of tolerogenic mechanisms. Our approach for cancer vaccines has been to incorporate into the vaccine design sequences able to activate foreign T cell help, through genetically linking cancer targets to microbial sequences (King et al. in Nat Med 4(11):1281-1286, 1998; Savelyeva et al. in Nat Biotechnol 19(8):760-764, 2001). This harnesses the non-tolerized CD4 T cell repertoire available in patients to help induction of effective immunity against fused cancer antigens. Multiple immune effector mechanisms including antibody, CD8+ T cells as well as CD4 effector T cells can be activated using this strategy. Delivery via DNA vaccines has already indicated clinical efficacy. The same principle of linked T cell help has now been transferred to other novel vaccine modalities to further potentiate immunity against cancer targets.


Evaluation of Venous Thromboembolic Event Prophylaxis in Hospitalized Cancer Patients: A Single-Centered Retrospective Study.
Venous thromboembolic events (VTEs) are one of the main causes of death in cancer patients. About one-third of newly diagnosed VTEs are later proved to be associated with cancers. Attempts have been made to prevent these events and reduce substantial burden on patient health. Previous studies have revealed underutilization of thromboprophylaxis in cancer patients. With respect to the high rate of enoxaparin prescription in our institute, irrational utilization of prophylactic measures was anticipated. This study aimed to evaluate the appropriateness of thromboprophylaxis in hospitalized cancer patients. Medical records of 199 cancer patients hospitalized in two oncology wards of a tertiary care teaching hospital were investigated retrospectively. Data extraction was performed by two clinical pharmacists. Appropriateness of thromboprophylaxis was determined using a local protocol prepared based on international guidelines. Forty-seven out of 199 prescriptions (23.5%) were appropriate according to the local protocol. About 76% (149/199) of patients did not have any acute medical illness or risk factors for thromboembolism and were admitted only to receive short-course chemotherapy. Enoxaparin was the drug used for 197 patients and unfractionated heparin was used for only 2 patients. Dose adjustment was not performed in three patients who needed dose modification with respect to renal impairment or obesity. This study has found that the frequency of thromboprophylaxis was considerably high in the study population. In the absence of an acute medical illness or other risk factors, hospitalization per se does not justify the administration of pharmacologic agents for thromboembolism prophylaxis. Implementation of local protocols prepared based on international guidelines seems necessary to rationalize thromboprophylaxis.


Nitrilase enzymes and their role in plant-microbe interactions.
Nitrilase enzymes (nitrilases) catalyse the hydrolysis of nitrile compounds to the corresponding carboxylic acid and ammonia, and have a wide range of industrial and biotechnological applications, including the synthesis of industrially important carboxylic acids and bioremediation of cyanide and toxic nitriles. Nitrilases are produced by a wide range of organisms, including plants, bacteria and fungi, but despite their biotechnological importance, the role of these enzymes in living organisms is relatively underexplored. Current research suggests that nitrilases play important roles in a range of biological processes. In the context of plant-microbe interactions they may have roles in hormone synthesis, nutrient assimilation and detoxification of exogenous and endogenous nitriles. Nitrilases are produced by both plant pathogenic and plant growth-promoting microorganisms, and their activities may have a significant impact on the outcome of plant-microbe interactions. In this paper we review current knowledge of the role of nitriles and nitrilases in plants and plant-associated microorganisms, and discuss how greater understanding of the natural functions of nitrilases could be applied to benefit both industry and agriculture.


Neonatal neural networks predict children behavioral profiles later in life.
This study aimed to examine heterogeneity of neonatal brain network and its prediction to child behaviors at 24 and 48 months of age. Diffusion tensor imaging (DTI) tractography was employed to construct brain anatomical network for 120 neonates. Clustering coefficients of individual structures were computed and used to classify neonates with similar brain anatomical networks into one group. Internalizing and externalizing behavioral problems were assessed using maternal reports of the Child Behavior Checklist (CBCL) at 24 and 48 months of age. The profile of CBCL externalizing and internalizing behaviors was then examined in the groups identified based on the neonatal brain network. Finally, support vector machine and canonical correlation analysis were used to identify brain structures whose clustering coefficients together significantly contribute the variation of the behaviors at 24 and 48 months of age. Four meaningful groups were revealed based on the brain anatomical networks at birth. Moreover, the clustering coefficients of the brain regions that most contributed to this grouping of neonates were significantly associated with childhood internalizing and externalizing behaviors assessed at 24 and 48 months of age. Specially, the clustering coefficient of the right amygdala was associated with both internalizing and externalizing behaviors at 24 months of age, while the clustering coefficients of the right inferior frontal cortex and insula were associated with externalizing behaviors at 48 months of age. Our findings suggested that neural organization established during fetal development could to some extent predict individual differences in behavioral-emotional problems in early childhood. Hum Brain Mapp 38:1362-1373, 2017. © 2016 Wiley Periodicals, Inc.


Unifying Large- and Small-Scale Theories of Coordination.
Coordination is a ubiquitous feature of all living things. It occurs by virtue of informational coupling among component parts and processes and can be quite specific (as when cells in the brain resonate to signals in the environment) or nonspecific (as when simple diffusion creates a source-sink dynamic for gene networks). Existing theoretical models of coordination-from bacteria to brains to social groups-typically focus on systems with very large numbers of elements (N→∞) or systems with only a few elements coupled together (typically N = 2). Though sharing a common inspiration in Nature's propensity to generate dynamic patterns, both approaches have proceeded largely independent of each other. Ideally, one would like a theory that applies to phenomena observed on all scales. Recent experimental research by Mengsen Zhang and colleagues on intermediate-sized ensembles (in between the few and the many) proves to be the key to uniting large- and small-scale theories of coordination. Disorder-order transitions, multistability, order-order phase transitions, and especially metastability are shown to figure prominently on multiple levels of description, suggestive of a basic Coordination Dynamics that operates on all scales. This unified coordination dynamics turns out to be a marriage of two well-known models of large- and small-scale coordination: the former based on statistical mechanics (Kuramoto) and the latter based on the concepts of Synergetics and nonlinear dynamics (extended Haken-Kelso-Bunz or HKB). We show that models of the many and the few, previously quite unconnected, are thereby unified in a single formulation. The research has led to novel topological methods to handle the higher-dimensional dynamics of coordination in complex systems and has implications not only for understanding coordination but also for the design of (biorhythm inspired) computers.


Shared Reading at Age 1 Year and Later Vocabulary: A Gene-Environment Study.
To assess the extent to which associations between shared reading at age 1 years and child vocabulary at age 3 years differ based on the presence of sensitizing alleles in the dopaminergic and serotonergic neurotransmitter systems. We conducted a secondary analysis of data from a national urban birth cohort using mother reports in conjunction with child assessments and salivary genetic data. Child vocabulary was assessed using the Peabody Picture Vocabulary Test. The primary exposure was mother-reported shared reading. We used data on gene variants that may affect the function of the dopaminergic and serotonergic systems. We examined associations between shared reading and Peabody Picture Vocabulary Test score using multiple linear regression. We then included interaction terms between shared reading and the presence of sensitizing alleles for each polymorphism to assess potential moderator effects adjusting for multiple comparisons. Of the 1772 children included (56% black, 52% male), 31% of their mothers reported reading with their child daily. Daily shared reading was strongly associated with child Peabody Picture Vocabulary Test scores in unadjusted (B = 7.9; 95% CI, 4.3-11.4) and adjusted models (B = 5.3; 95% CI, 2.0-8.6). The association differed based on the presence of sensitizing alleles in the dopamine receptor 2 and serotonin transporter genes. Among urban children, shared reading at age 1 years was associated with greater vocabulary at age 3 years. Although children with sensitizing alleles on the dopamine receptor 2 and serotonin transporter genes were at greater risk when not read to, they fared as well as children without these alleles when shared reading occurred.


The relationship between early changes in the HAMD-17 anxiety/somatization factor items and treatment outcome among depressed outpatients.
The 17-item Hamilton Rating Scale for Depression (HAMD-17) Anxiety/Somatization factor includes six items: Anxiety (psychic), Anxiety (somatic), Somatic Symptoms (gastrointestinal), Somatic Symptoms (general), Hypochondriasis and Insight. This study examines the relationship between early changes (defined as those observed between baseline and week 1) in these HAMD-17 Anxiety/Somatization Factor items and treatment outcome among major depressive disorder (MDD) patients who participated in a study comparing the antidepressant efficacy of a standardized extract of hypericum with both placebo and fluoxetine. Following a 1-week, single-blind washout, patients with MDD diagnosed by the Structured Clinical Interview for DSM-IV (SCID) were randomized to 12 weeks of double-blind treatment with hypericum extract (900 mg/day), fluoxetine (20 mg/day) or placebo. The relationship between early changes in HAMD-17 anxiety/somatization factor items and treatment outcome was assessed separately for patients who received study treatment (hypericum or fluoxetine) versus placebo with a logistic regression method. One hundred and thirty-five patients (female 57%, mean age=37.3+/-11.0 years; mean baseline HAMD-17=19.7+/-3.2 years) were randomized to double-blind treatment and were included in the intent-to-treat (ITT) analyses. After adjusting for baseline HAMD-17 scores and for multiple comparisons with the Bonferroni correction, patients who remitted (HAMD-17 score <8) after study treatment had significantly greater early improvement in Somatic Symptoms (General) scores than non-remitters. No other significant differences in early changes were noted for the remaining items between remitters versus non-remitters who received active treatment. For patients treated with placebo, early change was not predictive of remission for any of the items after Bonferroni correction. In conclusion, the presence of early improvement on the HAMD-17 item concerning fatigue and general somatic symptoms is significantly predictive of achieving remission at endpoint with active study treatment but not with placebo.


Trial-based cost-effectiveness analysis comparing surgical and endoscopic drainage in patients with obstructive chronic pancreatitis.
Published evidence indicates that surgical drainage of the pancreatic duct was more effective than endoscopic drainage for patients with chronic pancreatitis. This analysis assessed the cost-effectiveness of surgical versus endoscopic drainage in obstructive chronic pancreatitis. This trial-based cost-utility analysis (ISRCTN04572410) was conducted from a UK National Health Service (NHS) perspective and during a 79-month time horizon. During the trial the details of the diagnostic and therapeutic procedures, and pancreatic insufficiency were collected. The resource use was varied in the sensitivity analysis based on a review of the literature. The health outcome was the Quality-Adjusted Life Year (QALY), generated using EQ-5D data collected during the trial. There were no pancreas-related deaths in the trial. All-cause mortality from the trial was incorporated into the QALY estimates in the sensitivity analysis. Hospital. Patients with obstructive chronic pancreatitis. Costs, QALYs and cost-effectiveness. The result of the base-case analysis was that surgical drainage dominated endoscopic drainage, being both more effective and less costly. The sensitivity analysis varied mortality and resource use and showed that the surgical option remained dominant in all scenarios. The probability of cost-effectiveness for surgical drainage was 100% for the base case and 82% in the assessed most conservative case scenario. In obstructive chronic pancreatitis, surgical drainage is highly cost-effective compared with endoscopic drainage from a UK NHS perspective.


Agonist-induced endocytosis of rat somatostatin receptor 1.
Somatostatin-receptor 1 (sst1) is an autoreceptor in the central nervous system that regulates the release of somatostatin. Sst1 is present intracellularly and at the cell surface. To investigate sst1 trafficking, rat sst1 tagged with epitope was expressed in rat insulinoma cells 1046-38 (RIN-1046-38) and tracked by antibody labeling. Confocal microscopic analysis revealed colocalization of intracellularly localized rat sst1-human simplex virus (HSV) with Rab5a-green fluorescent protein and Rab11a-green fluorescent protein, indicating the distribution of the receptor in endocytotic and recycling organelles. Somatostatin-14 induced internalization of cell surface receptors and reduction of binding sites on the cell surface. It also stimulated recruitment of intracellular sst1-HSV to the plasma membrane. Confocal analysis of sst1-HSV revealed that the receptor was initially transported within superficial vesicles. Prolonged stimulation of the cells with the peptide agonist induced intracellular accumulation of somatostatin-14. Because the number of cell surface binding sites did not change during prolonged stimulation, somatostatin-14 was internalized through a dynamic process of continuous endocytosis, recycling, and recruitment of intracellularly present sst1-HSV. Accumulated somatostatin-14 bypassed degradation via the endosomal-lysosomal route and was instead rapidly released as intact and biologically active somatostatin-14. Our results show for the first time that sst1 mediates a dynamic process of endocytosis, recycling, and re-endocytosis of its cognate ligand.


Cortical Brain Abnormalities in 4474 Individuals With Schizophrenia and 5098 Control Subjects via the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) Consortium.
The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group. The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide. Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset. The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia.


Contact pressure effects on vibrational bands of kaolinite during infrared spectroscopic measurements in a diamond attenuated total reflection cell.
Over the last decades infrared spectroscopy has become a frequently used method to investigate the structure and bonding properties of clay minerals. Along with classic transmission techniques, attenuated total reflection (ATR) spectroscopy has been applied as a very fast and easy method. In this study we compared transmission spectra of kaolinite with ATR spectra obtained by a single-reflection diamond ATR accessory (Golden Gate Mark II). The ATR spectra showed anomalous band positions that were obviously affected by the applied contact pressure of the sapphire anvil. Most of these vibrations can be assigned to basal Si-O bonds and all of them shifted their positions to lower wavenumbers. It is suggested that these peak shifts are due to changes in the Si-O-Si bond angle Theta. They are caused by distortions and rotations of SiO(4) units within the tetrahedral sheet, due to shear forces perpendicular to the uniaxial pressure applied by the anvil. Furthermore, the intensity of a normally very weak transversal optical mode (TO mode) of the inner surface hydroxyls (3684 cm(-1)) remarkably increased with increasing contact pressure, while the longitudinal optical mode (LO mode) at 3694 cm(-1) strongly decreased its intensity. This possibly is determined by a strong alignment of the platy kaolinite particles along their ab-planes due to the applied pressure.


Biomineralization in bryozoans: present, past and future.
Many animal phyla have the physiological ability to produce biomineralized skeletons with functional roles that have been shaped by natural selection for more than 500 million years. Among these are bryozoans, a moderately diverse phylum of aquatic invertebrates with a rich fossil record and importance today as bioconstructors in some shallow-water marine habitats. Biomineralizational patterns and, especially, processes are poorly understood in bryozoans but are conventionally believed to be similar to those of the related lophotrochozoan phyla Brachiopoda and Mollusca. However, bryozoan skeletons are more intricate than those of these two phyla. Calcareous skeletons have been acquired independently in two bryozoan clades - Stenolaemata in the Ordovician and Cheilostomata in the Jurassic - providing an evolutionary replicate. This review aims to highlight the importance of biomineralization in bryozoans and focuses on their skeletal ultrastructures, mineralogy and chemistry, the roles of organic components, the evolutionary history of bimineralization in bryozoans with respect to changes in seawater chemistry, and the impact of contemporary global changes, especially ocean acidification, on bryozoan skeletons. Bryozoan skeletons are constructed from three different wall types (exterior, interior and compound) differing in the presence/absence and location of organic cuticular layers. Skeletal ultrastructures can be classified into wall-parallel (i.e. laminated) and wall-perpendicular (i.e. prismatic) fabrics, the latter apparently found in only one of the two biomineralizing clades (Cheilostomata), which is also the only clade to biomineralize aragonite. A plethora of ultrastructural fabrics can be recognized and most occur in combination with other fabrics to constitute a fabric suite. The proportion of aragonitic and bimineralic bryozoans, as well as the Mg content of bryozoan skeletons, show a latitudinal increase into the warmer waters of the tropics. Responses of bryozoan mineralogy and skeletal thickness to oscillations between calcite and aragonite seas through geological time are equivocal. Field and laboratory studies of living bryozoans have shown that predicted future changes in pH (ocean acidification) combined with global warming are likely to have detrimental effects on calcification, growth rate and production of polymorphic zooids for defence and reproduction, although some species exhibit reasonable levels of resilience. Some key questions about bryozoan biomineralization that need to be addressed are identified.


Progress toward Equitably Managed Protected Areas in Aichi Target 11: A Global Survey.
The Convention on Biological Diversity Aichi Target 11 requires its 193 signatory parties to incorporate social equity into protected area (PA) management by 2020. However, there is limited evidence of progress toward this commitment. We surveyed PA managers, staff, and community representatives involved in the management of 225 PAs worldwide to gather information against 10 equity criteria, including the distribution of benefits and burdens, recognition of rights, diversity of cultural and knowledge systems, and processes of participation in decision-making. Our results show that more than half of the respondents indicated that there are still significant challenges to be addressed in achieving equitably managed PAs, particularly in ensuring effective participation in decision-making, transparent procedures, access to justice in conflicting situations, and the recognition of the rights and diversity of local people. Our findings are a first and fundamental contribution toward a global assessment of equitable management in PAs to report on Aichi Target 11 in 2020 and help define the next set of PA targets from 2020-2030.


Noscapine, a Non-addictive Opioid and Microtubule-Inhibitor in Potential Treatment of Glioblastoma.
Noscapine is a phthalide isoquinoline alkaloid that easily traverses the blood brain barrier and has been used for years as an antitussive agent with high safety. Despite binding opioid receptors, noscapine lacks significant hypnotic and euphoric effects rendering it safe in terms of addictive potential. In 1954, Hans Lettré first described noscapine as a mitotic poison. The drug was later tested for cancer treatment in the early 1960's, yet no effect was observed likely as a result of its short biological half-life and limited water solubility. Since 1998, it has regained interest thanks to studies from Emory University, which showed its anticancer activity in animal models with negligible toxicity. In contrast to other microtubule-inhibitors, noscapine does not affect the total intracellular tubulin polymer mass. Instead, it forces the microtubules to spend an increased amount of time in a paused state leading to arrest in mitosis and subsequently inducing mitotic slippage/mitotic catastrophe/apoptosis. In experimental models, noscapine does not induce peripheral neuropathy, which is common with other microtubule inhibitors. Noscapine also inhibits tumor growth and enhances cancer chemosensitivity via selective blockage of NF-κB, an important transcription factor in glioblastoma pathogenesis. Due to their anticancer activities and high penetration through the blood-brain barrier, noscapine analogues strongly deserve further study in various animal models of glioblastoma as potential candidates for future patient therapy.


Performance amelioration of single basin solar still integrated with V- type concentrator: Energy, exergy, and economic analysis.
Solar desalination is one of the most sustainable solutions to produce freshwater from brackish water. The present research work aims to experimentally investigate the effect of a V-shape concentrator integrated with solar still (SS). The V-shape concentrator integrated with the conventional solar still (CSS) is used to supply the saline water at elevated temperature to the basin of SS, which augments the freshwater yield compared to CSS. The experimental investigation was performed at different brackish water depths of 0.01, 0.02, and 0.03 m, respectively. The SS system was evaluated based on water yield, energy, exergy, concentrator efficiency, and economic analysis. The freshwater yield of the solar still integrated with V-shape concentrator (SSVC) was found to be 5.47, 5.10, and 4.89 L/m2.day, whereas the yield of the CSS was 3.73, 3.27, and 2.91 L/m2 .day at the water depths of 0.01, 0.02, and 0.03 m, respectively. The daily energy and exergy efficiency of CSS were 38.5, 33.5, and 29.4% and 1.9, 1.5, and 0.97 % in the case of 0.01, 0.02, and 0.03m water depth , respectively. However, the integration of concentrator significantly augmented the energy efficiency to 57.4, 51.7, and 44.9% and exergy efficiency to 3.8, 3.3, and 2.8% for the respective water depths . Life cycle studies demonstrated that the freshwater cost per liter for CSS and SSVC were 0.0102 $ and 0.0117 $ respectively, at a water depth of 0.01 m. It was concluded that the addition of V-shape concentrator and minimum water depth is useful to augment the energy efficiency, exergy efficiency, and yield of the SS in the very economical way.


Complementary strategies for the management of radiation therapy side effects.
Patients with cancer utilize complementary and alternative medicine (CAM) for a variety of purposes, one of which is the reduction of side effects of conventional treatment. With a large number of their patients using CAM, it is important for advanced practitioners in oncology to have an understanding of these therapies to better guide their patients. Side effects of radiation therapy that may have dose-limiting poten-tial include diarrhea, mucositis, skin toxicity, and xerostomia. A com-mon side effect that is not necessarily dose-limiting but considerably troublesome to patients is cancer- and treatment-related fatigue. The CAM therapies that may alleviate some of the side effects of radiation therapy include probiotics, psyllium, exercise, melatonin, honey, acu-puncture, and calendula. Therapies that require more research or have been shown to be ineffective include aloe vera, glutamine, and deglyc-yrrhizinated licorice. This article provides an overview of these thera-pies as well as related research and analysis.


Real-time 4D signal processing and visualization using graphics processing unit on a regular nonlinear-k Fourier-domain OCT system.
We realized graphics processing unit (GPU) based real-time 4D (3D+time) signal processing and visualization on a regular Fourier-domain optical coherence tomography (FD-OCT) system with a nonlinear k-space spectrometer. An ultra-high speed linear spline interpolation (LSI) method for lambda-to-k spectral re-sampling is implemented in the GPU architecture, which gives average interpolation speeds of >3,000,000 line/s for 1024-pixel OCT (1024-OCT) and >1,400,000 line/s for 2048-pixel OCT (2048-OCT). The complete FD-OCT signal processing including lambda-to-k spectral re-sampling, fast Fourier transform (FFT) and post-FFT processing have all been implemented on a GPU. The maximum complete A-scan processing speeds are investigated to be 680,000 line/s for 1024-OCT and 320,000 line/s for 2048-OCT, which correspond to 1GByte processing bandwidth. In our experiment, a 2048-pixel CMOS camera running up to 70 kHz is used as an acquisition device. Therefore the actual imaging speed is camera- limited to 128,000 line/s for 1024-OCT or 70,000 line/s for 2048-OCT. 3D Data sets are continuously acquired in real time at 1024-OCT mode, immediately processed and visualized as high as 10 volumes/second (12,500 A-scans/volume) by either en face slice extraction or ray-casting based volume rendering from 3D texture mapped in graphics memory. For standard FD-OCT systems, a GPU is the only additional hardware needed to realize this improvement and no optical modification is needed. This technique is highly cost-effective and can be easily integrated into most ultrahigh speed FD-OCT systems to overcome the 3D data processing and visualization bottlenecks.


Effect of dietary intake of omega-3 and omega-6 fatty acids on severity of asthma in children.
We assessed the clinical and biochemical effects in asthmatic children of fish oil supplementation and a diet that increases omega-3 and reduces omega-6 fatty acids. Thirty nine asthmatic children aged 8-12 yrs participated in a double-blind, randomized, controlled trial for 6 months during which they received fish oil capsules plus canola oil and margarine (omega-3 group) or safflower oil capsules plus sunflower oil and margarine (omega-6 group). Plasma fatty acids, stimulated tumour necrosis factor alpha (TNFalpha) production, circulating eosinophil numbers and lung function were measured at baseline and after 3 and 6 months of dietary modification. Day and night symptoms, peak flow rates and medication use were recorded for 1 week prior to laboratory visits. Plasma phospholipid omega-3 fatty acids were significantly greater in the omega-3 group at 3 and 6 months compared to the omega-6 group (p<0.001). In the omega-3 group TNFalpha production fell significantly compared with baseline (p=0.026), but the magnitude of change between groups did not reach significance (p=0.075). There were no significant changes in clinical outcome measures. Dietary enrichment of omega-3 fatty acids over 6 months increased plasma levels of these fatty acids, reduced stimulated tumour necrosis factor alpha production, but had no effect on the clinical severity of asthma in these children.


Review of statistical methods for analysing healthcare resources and costs.
We review statistical methods for analysing healthcare resource use and costs, their ability to address skewness, excess zeros, multimodality and heavy right tails, and their ease for general use. We aim to provide guidance on analysing resource use and costs focusing on randomised trials, although methods often have wider applicability. Twelve broad categories of methods were identified: (I) methods based on the normal distribution, (II) methods following transformation of data, (III) single-distribution generalized linear models (GLMs), (IV) parametric models based on skewed distributions outside the GLM family, (V) models based on mixtures of parametric distributions, (VI) two (or multi)-part and Tobit models, (VII) survival methods, (VIII) non-parametric methods, (IX) methods based on truncation or trimming of data, (X) data components models, (XI) methods based on averaging across models, and (XII) Markov chain methods. Based on this review, our recommendations are that, first, simple methods are preferred in large samples where the near-normality of sample means is assured. Second, in somewhat smaller samples, relatively simple methods, able to deal with one or two of above data characteristics, may be preferable but checking sensitivity to assumptions is necessary. Finally, some more complex methods hold promise, but are relatively untried; their implementation requires substantial expertise and they are not currently recommended for wider applied work.


Fungaemia in haematological malignancies: SEIFEM-2015 survey.
Fungal infections are still a relevant challenge for clinicians involved in the cure of patients with cancer. We retrospectively reviewed charts of hospitalized patients with haematological malignancies (HMs), in which a documented fungaemia was diagnosed between January 2011 and December 2015 at 28 adult and 6 paediatric Italian Hematology Departments. During the study period, we recorded 215 fungal bloodstream infections (BSI). Microbiological analyses documented that BSI was due to moulds in 17 patients (8%) and yeasts in 198 patients (92%), being Candida spp identified in 174 patients (81%). Mortality rates were 70% and 39% for mould and yeast infections, respectively. Infection was the main cause of death in 53% of the mould and 18% of the yeast groups. At the multivariate analysis, ECOG ≥ 2 and septic shock were significantly associated with increased mortality, and removal of central venous catheter (CVC) survival was found to be protective. When considering patients with candidemia only, ECOG ≥ 2 and removal of CVC were statistically associated with overall mortality. Although candidemia represents a group of BSI with a good prognosis, its risk factors largely overlap with those identified for all fungaemias, even though the candidemia-related mortality is lower when compared to other fungal BSI. Management of fungal BSI is still a complex issue, in which both patients and disease characteristics should be focused to address a personalized approach.


Risk Factors for Necrotizing Enterocolitis: A Prospective Multicenter Case-Control Study.
The identification of independent clinical risk factors for necrotizing enterocolitis (NEC) may contribute to early selection of infants at risk, allowing for the development of targeted strategies aimed at the prevention of NEC. The objective of this study was to identify independent risk factors contributing to the development of NEC in a large multicenter cohort. This prospective cohort study was performed in 9 neonatal intensive care units. Infants born at a gestational age ≤30 weeks were included. Demographic and clinical data were collected daily until day 28 postnatally. Factors predictive of the development of NEC were identified using univariate and multivariable analyses in a 1: 5 matched case-control cohort. In total, 843 infants (56 NEC cases) were included in this study. In the case-control cohort, univariate analysis identified sepsis prior to the onset of NEC and formula feeding to be associated with an increased risk of developing NEC, whereas the administration of antibiotics directly postpartum was inversely associated with NEC. In a multivariable logistic regression model, enteral feeding type and the number of days parenterally fed remained statistically significantly associated with NEC, whereas the administration of antibiotics directly after birth was associated with a lower risk of developing NEC. Formula feeding and prolonged (duration of) parenteral feeding were associated with an increased risk of NEC. Contrary to expectations, the initiation of treatment with antibiotics within 24 h after birth was inversely associated with NEC.


A population-based assessment of primary care visits during adjuvant chemotherapy for breast cancer.
We used administrative health data to explore the impact of primary care physician (pcp) visits on acute-care service utilization by women receiving adjuvant chemotherapy for early-stage breast cancer (ebc). Our population-based retrospective cohort study examined pcp visits and acute-care use [defined as an emergency room (er) visit or hospitalization] by women diagnosed with ebc between 2007 and 2009 and treated with adjuvant chemotherapy. Multivariate regression analysis was used to identify the effect of pcp visits on the likelihood of experiencing an acute-care visit. Patients receiving chemotherapy visited a pcp significantly more frequently than they had before their diagnosis [relative risk (rr): 1.48; 95% confidence interval (ci): 1.44 to 1.53; p < 0.001] and significantly more frequently than control subjects without cancer (rr: 1.51; 95% ci: 1.46 to 1.57; p < 0.001). More than one third of pcp visits by chemotherapy patients were related to breast cancer or chemotherapy-related side effects. In adjusted multivariate analyses, the likelihood of experiencing an er visit or hospitalization increased in the days immediately after a pcp visit (rr: 1.92; 95% ci: 1.76 to 2.10; p < 0.001). During chemotherapy treatment, patients visited their pcp more frequently than control subjects did, and they visited for reasons related to their breast cancer or to chemotherapy-related side effects. Visits to a pcp by patients receiving chemotherapy were associated with an increased frequency of er visits or hospitalizations in the days immediately after the pcp visit. Those results suggest an opportunity to institute measures for early detection and intervention in chemotherapy side effects.


Older patients' attitudes towards and experiences of patient-physician end-of-life communication: a secondary analysis of interviews from British, Dutch and Belgian patients.
Older patients often experience sub-standard communication in the palliative phase of illness. Due to the importance of good communication in patient-centred end-of-life care, it is essential to understand the factors which influence older patients' communication with physicians. This study examines older patients' attitudes towards, and experiences of, patient-physician end-of-life (EoL) communication in three European countries. A secondary analysis of interviews from British, Dutch and Belgian patients over the age of 60 with a progressive terminal illness was conducted. Cross-cutting themes were identified using a thematic approach. Themes from 30 interviews (Male n = 20, Median age 78.5) included: confidence and trust; disclosure and awareness; and participation in decision-making. Confidence and trust were reinforced by physicians' availability, time and genuine attention and hindered by misdiagnoses and poor communication style. Most participants preferred full disclosure, though some remained deliberately ill-informed to avoid distress. Patients expressed a variety of preferences for and experiences of involvement in medical EoL decision-making and a few complained that information was only provided about the physician's preferred treatment. A variety of experiences and attitudes regarding disclosure and participation in decision-making were reported from each country, suggesting that communication preferences are highly individual. It is important that physicians are sensitive to this diversity and avoid stereotyping. In regard to communication style, physicians are advised to provide clear explanations, avoid jargon, and continually check understanding. Both the 'informed' and the 'shared' patient-physician decision-making models assume patients make rational choices based on a clear understanding of treatment options. This idealized situation was often not reflected in patients' experiences.


Association between folate, vitamin B(6) and vitamin B(12) intake and depression in the SUN cohort study.
An association between low blood levels of folate, vitamins B(6) and B(12) and a higher prevalence of depressive symptoms has been reported in several epidemiological studies. The present study aimed to assess the association between folate, vitamins B(6) and B(12) intake and depresion prevalence in the SUN cohort study. The study comprised a cross-sectional analysis of 9670 participants. A validated semi-quantitative food frequency questionnaire was used to ascertain vitamin intake. The association between the baseline intake of folate, vitamins B(6) and B(12) categorised in quintiles and the prevalence of depression was assessed. The analyses were repeated after stratifying by smoking habits, alcohol intake, physical activity and personality traits. Among women, odds ratios (OR) [95% confidence interval (CI)] for the third to fifth quintile for vitamin B(12) intake were 0.58 (0.41-0.84), 0.56 (0.38-0.82) and 0.68 (0.45-1.04), respectively. Among those men with a low level of anxiety and current smokers, a significant positive association between low folate intake and the prevalence of depression was found. The OR (95% CI) for the first quintile of intake was 2.85 (1.49-5.45) and 2.18 (1.08-4.38), respectively, compared to the upper quintiles of intake (Q2-Q5) considered as a group. Low folate intake was associated with depression among currently smoking men and men with low anxiety levels. Low intake of vitamin B(12) was associated with depression among women. No significant associations were found for vitamin B(6) intake.


Action-potential modulation during axonal conduction.
Once initiated near the soma, an action potential (AP) is thought to propagate autoregeneratively and distribute uniformly over axonal arbors. We challenge this classic view by showing that APs are subject to waveform modulation while they travel down axons. Using fluorescent patch-clamp pipettes, we recorded APs from axon branches of hippocampal CA3 pyramidal neurons ex vivo. The waveforms of axonal APs increased in width in response to the local application of glutamate and an adenosine A(1) receptor antagonist to the axon shafts, but not to other unrelated axon branches. Uncaging of calcium in periaxonal astrocytes caused AP broadening through ionotropic glutamate receptor activation. The broadened APs triggered larger calcium elevations in presynaptic boutons and facilitated synaptic transmission to postsynaptic neurons. This local AP modification may enable axonal computation through the geometry of axon wiring.


Colocating buprenorphine with methadone maintenance and outpatient chemical dependency services.
Buprenorphine may be used to treat opioid dependence in office-based settings, but treatment models are needed to ensure access to psychosocial services needed by many patients. We describe a novel buprenorphine treatment program colocated with methadone maintenance and outpatient chemical dependency services. We conducted a retrospective chart review of the first 40 consecutive patients initiating buprenorphine treatment in this program to determine characteristics associated with treatment retention. Exclusion criteria were current alcohol or benzodiazepine dependence. Secondary drug users and patients who were psychiatrically or medically ill were included. At 6 months, 60% (n = 24) were retained, 13% (n = 5) tested positive for opiates, and 25% (n = 10) tested positive for secondary substances. Patients who were older (odds ratio [OR] per year of age = 1.1, confidence interval [CI] = 1.0-1.2) and those who were employed (OR = 9.8, CI = 1.8-53.1) were more likely to remain in treatment, but other variables were not associated with retention. Our experience demonstrates that buprenorphine can be successfully integrated into outpatient substance abuse treatment.


The earliest history of the deuterostomes: the importance of the Chengjiang Fossil-Lagerstatte.
While the broad framework of deuterostome evolution is now clear, the remarkable diversity of extant forms within this group has rendered the nature of the ancestral types problematic: what, for example, does the common ancestor of a sea urchin and lamprey actually look like? The answer to such questions can be addressed on the basis of remarkably well-preserved fossils from Cambrian Lagerstätten, not least the celebrated Chengjiang Lagerstätte (Yunnan, China). This deposit is particularly important because of its rich diversity of deuterostomes. These include some of the earliest known representatives, among which are the first vertebrates, as well as more enigmatic groups, notably the vetulicolians and yunnanozoans. The latter groups, in particular, have been the subject of some radical divergences in opinion as to their exact phylogenetic placements. Here, we both review the known diversity of Chengjiang deuterostomes and in particular argue that the vetulicolians and yunnanozoans represent very primitive deuterostomes. Moreover, in the latter case we present new data to indicate that the yunnanozoans are unlikely to be any sort of chordate.


Research productivity among occupational therapy faculty members in the United States.
The purpose of this study was to examine the current research performance patterns of occupational therapy faculty, identify factors that influence individual faculty members productivity, and compare current faculty research performance with earlier studies in occupational therapy. Survey questionnaires from 158 faculty members were analyzed. Compared to earlier data, the results showed that today's occupational therapy faculty members have obtained higher degrees, published more refereed articles, acquired larger external grants, stayed in academia longer, and developed clinical specialty areas. Tenured senior faculty members spent more time on research-related tasks, produced more publications and grants, and perceived institutional factors as more favorable for research than did untenured faculty in lower ranks. The overall enhancement in productivity among occupational therapy faculty members in the 1990s suggests an increase in academic scholarly activities.


Design of clinical trials in acute kidney injury: report from an NIDDK workshop on trial methodology.
Acute kidney injury (AKI) remains a complex clinical problem associated with significant short-term morbidity and mortality and lacking effective pharmacologic interventions. Patients with AKI experience longer-term risks for progressive chronic ESRD, which diminish patients' health-related quality of life and create a larger burden on the healthcare system. Although experimental models have yielded numerous promising agents, translation into clinical practice has been unsuccessful, possibly because of issues in clinical trial design, such as delayed drug administration, masking of therapeutic benefit by adverse events, and inadequate sample size. To address issues of clinical trial design, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored a workshop titled "Clinical Trials in Acute Kidney Injury: Current Opportunities and Barriers" in December 2010. Workshop participants included representatives from academia, industry, and government agencies whose areas of expertise spanned basic science, clinical nephrology, critical care medicine, biostatistics, pharmacology, and drug development. This document summarizes the discussions of collaborative workgroups that addressed issues related to patient selection, study endpoints, the role of novel biomarkers, sample size and power calculations, and adverse events and pilot/feasibility studies in prevention and treatment of AKI. Companion articles outline the discussions of workgroups for model trials related to prevention or treatment of established AKI in different clinical settings, such as in patients with sepsis.


Structures of Helicobacter pylori shikimate kinase reveal a selective inhibitor-induced-fit mechanism.
Shikimate kinase (SK), which catalyzes the specific phosphorylation of the 3-hydroxyl group of shikimic acid in the presence of ATP, is the enzyme in the fifth step of the shikimate pathway for biosynthesis of aromatic amino acids. This pathway is present in bacteria, fungi, and plants but absent in mammals and therefore represents an attractive target pathway for the development of new antimicrobial agents, herbicides, and antiparasitic agents. Here we investigated the detailed structure-activity relationship of SK from Helicobacter pylori (HpSK). Site-directed mutagenesis and isothermal titration calorimetry studies revealed critical conserved residues (D33, F48, R57, R116, and R132) that interact with shikimate and are therefore involved in catalysis. Crystal structures of HpSK·SO(4), R57A, and HpSK•shikimate-3-phosphate • ADP show a characteristic three-layer architecture and a conformationally elastic region consisting of F48, R57, R116, and R132, occupied by shikimate. The structure of the inhibitor complex, E114A • 162535, was also determined, which revealed a dramatic shift in the elastic LID region and resulted in conformational locking into a distinctive form. These results reveal considerable insight into the active-site chemistry of SKs and a selective inhibitor-induced-fit mechanism.


Systematic Review of Safety and Efficacy of Rituximab in Treating Immune-Mediated Disorders.
Background: During the past years biologic agents (also termed biologicals or biologics) have become a crucial treatment option in immunological diseases. Numerous articles have been published on biologicals, which complicates the decision making process on the use of the most appropriate biologic for a given immune-mediated disease. This systematic review is the first of a series of articles assessing the safety and efficacy of B cell-targeting biologics for the treatment of immune-mediated diseases. Objective: To evaluate rituximab's safety and efficacy for the treatment of immune-mediated disorders compared to placebo, conventional treatment, or other biologics. Methods: The PRISMA checklist guided the reporting of the data. We searched the PubMed database between 4 October 2016 and 26 July 2018 concentrating on immune-mediated disorders. Results: The literature search identified 19,665 articles. After screening titles and abstracts against the inclusion and exclusion criteria and assessing full texts, 105 articles were finally included in a narrative synthesis. Conclusions: Rituximab is both safe and effective for the treatment of acquired angioedema with C1-inhibitor deficiency, ANCA-associated vasculitis, autoimmune hemolytic anemia, Behçet's disease, bullous pemphigoid, Castleman's disease, cryoglobulinemia, Goodpasture's disease, IgG4-related disease, immune thrombocytopenia, juvenile idiopathic arthritis, relapsing-remitting multiple sclerosis, myasthenia gravis, nephrotic syndrome, neuromyelitis optica, pemphigus, rheumatoid arthritis, spondyloarthropathy, and systemic sclerosis. Conversely, rituximab failed to show an effect for antiphospholipid syndrome, autoimmune hepatitis, IgA nephropathy, inflammatory myositis, primary-progressive multiple sclerosis, systemic lupus erythematosus, and ulcerative colitis. Finally, mixed results were reported for membranous nephropathy, primary Sjögren's syndrome and Graves' disease, therefore warranting better quality trials with larger patient numbers.


Antidepressants for smoking cessation.
There are at least three reasons to believe antidepressants might help in smoking cessation. Firstly, nicotine withdrawal may produce depressive symptoms or precipitate a major depressive episode and antidepressants may relieve these. Secondly, nicotine may have antidepressant effects that maintain smoking, and antidepressants may substitute for this effect. Finally, some antidepressants may have a specific effect on neural pathways (e.g. inhibiting monoamine oxidase) or receptors (e.g. blockade of nicotinic-cholinergic receptors) underlying nicotine addiction. The aim of this review is to assess the effect and safety of antidepressant medications to aid long-term smoking cessation. The medications include bupropion; doxepin; fluoxetine; imipramine; lazabemide; moclobemide; nortriptyline; paroxetine; S-Adenosyl-L-Methionine (SAMe); selegiline; sertraline; St. John's wort; tryptophan; venlafaxine; and zimeledine. We searched the Cochrane Tobacco Addiction Group Specialised Register which includes reports of trials indexed in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and PsycINFO, and other reviews and meeting abstracts, in July 2013. We considered randomized trials comparing antidepressant medications to placebo or an alternative pharmacotherapy for smoking cessation. We also included trials comparing different doses, using pharmacotherapy to prevent relapse or re-initiate smoking cessation or to help smokers reduce cigarette consumption. We excluded trials with less than six months follow-up. We extracted data and assessed risk of bias using standard methodological procedures expected by the Cochrane Collaboration.The main outcome measure was abstinence from smoking after at least six months follow-up in patients smoking at baseline, expressed as a risk ratio (RR). We used the most rigorous definition of abstinence available in each trial, and biochemically validated rates if available. Where appropriate, we performed meta-analysis using a fixed-effect model. Twenty-four new trials were identified since the 2009 update, bringing the total number of included trials to 90. There were 65 trials of bupropion and ten trials of nortriptyline, with the majority at low or unclear risk of bias. There was high quality evidence that, when used as the sole pharmacotherapy, bupropion significantly increased long-term cessation (44 trials, N = 13,728, risk ratio [RR] 1.62, 95% confidence interval [CI] 1.49 to 1.76). There was moderate quality evidence, limited by a relatively small number of trials and participants, that nortriptyline also significantly increased long-term cessation when used as the sole pharmacotherapy (six trials, N = 975, RR 2.03, 95% CI 1.48 to 2.78). There is insufficient evidence that adding bupropion (12 trials, N = 3487, RR 1.9, 95% CI 0.94 to 1.51) or nortriptyline (4 trials, N = 1644, RR 1.21, 95% CI 0.94 to 1.55) to nicotine replacement therapy (NRT) provides an additional long-term benefit. Based on a limited amount of data from direct comparisons, bupropion and nortriptyline appear to be equally effective and of similar efficacy to NRT (bupropion versus nortriptyline 3 trials, N = 417, RR 1.30, 95% CI 0.93 to 1.82; bupropion versus NRT 8 trials, N = 4096, RR 0.96, 95% CI 0.85 to 1.09; no direct comparisons between nortriptyline and NRT). Pooled results from four trials comparing bupropion to varenicline showed significantly lower quitting with bupropion than with varenicline (N = 1810, RR 0.68, 95% CI 0.56 to 0.83). Meta-analyses did not detect a significant increase in the rate of serious adverse events amongst participants taking bupropion, though the confidence interval only narrowly missed statistical significance (33 trials, N = 9631, RR 1.30, 95% CI 1.00 to 1.69). There is a risk of about 1 in 1000 of seizures associated with bupropion use. Bupropion has been associated with suicide risk, but whether this is causal is unclear. Nortriptyline has the potential for serious side-effects, but none have been seen in the few small trials for smoking cessation.There was no evidence of a significant effect for selective serotonin reuptake inhibitors on their own (RR 0.93, 95% CI 0.71 to 1.22, N = 1594; 2 trials fluoxetine, 1 paroxetine, 1 sertraline) or as an adjunct to NRT (3 trials of fluoxetine, N = 466, RR 0.70, 95% CI 0.64 to 1.82). Significant effects were also not detected for monoamine oxidase inhibitors (RR 1.29, 95% CI 0.93 to 1.79, N = 827; 1 trial moclobemide, 5 selegiline), the atypical antidepressant venlafaxine (1 trial, N = 147, RR 1.22, 95% CI 0.64 to 2.32), the herbal therapy St John's wort (hypericum) (2 trials, N = 261, RR 0.81, 95% CI 0.26 to 2.53), or the dietary supplement SAMe (1 trial, N = 120, RR 0.70, 95% CI 0.24 to 2.07). The antidepressants bupropion and nortriptyline aid long-term smoking cessation. Adverse events with either medication appear to rarely be serious or lead to stopping medication. Evidence suggests that the mode of action of bupropion and nortriptyline is independent of their antidepressant effect and that they are of similar efficacy to nicotine replacement. Evidence also suggests that bupropion is less effective than varenicline, but further research is needed to confirm this finding. Evidence suggests that neither selective serotonin reuptake inhibitors (e.g. fluoxetine) nor monoamine oxidase inhibitors aid cessation.


GSTM1 null polymorphism at the glutathione S-transferase M1 locus: phenotype and genotype studies in patients with primary biliary cirrhosis.
Studies were carried out to test the hypothesis that the GSTM1 null phenotype at the mu (mu) class glutathione S-transferase 1 locus is associated with an increased predisposition to primary biliary cirrhosis. Starch gel electrophoresis was used to compare the prevalence of GSTM1 null phenotype 0 in patients with end stage primary biliary cirrhosis and a group of controls without evidence of liver disease. The prevalence of GSTM1 null phenotype in the primary biliary cirrhosis and control groups was similar; 39% and 45% respectively. In the primary biliary cirrhosis group all subjects were of the common GSTM1 0, GSTM1 A, GSTM1 B or GSTM1 A, B phenotypes while in the controls, one subject showed an isoform with an anodal mobility compatible with it being a product of the putative GSTM1*3 allele. As the GSTM1 phenotype might be changed by the disease process, the polymerase chain reaction was used to amplify the exon 4-exon 5 region of GSTM1 and show that in 13 control subjects and 11 patients with primary biliary cirrhosis, GSTM1 positive and negative genotypes were associated with corresponding GSTM1 expressing and non-expressing phenotypes respectively. The control subject with GSTM1 3 phenotype showed a positive genotype.


LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8+ T cell tumor-infiltration impairing anti-PD1 therapy.
Cancer response to immunotherapy depends on the infiltration of CD8+ T cells and the presence of tumor-associated macrophages within tumors. Still, little is known about the determinants of these factors. We show that LIF assumes a crucial role in the regulation of CD8+ T cell tumor infiltration, while promoting the presence of protumoral tumor-associated macrophages. We observe that the blockade of LIF in tumors expressing high levels of LIF decreases CD206, CD163 and CCL2 and induces CXCL9 expression in tumor-associated macrophages. The blockade of LIF releases the epigenetic silencing of CXCL9 triggering CD8+ T cell tumor infiltration. The combination of LIF neutralizing antibodies with the inhibition of the PD1 immune checkpoint promotes tumor regression, immunological memory and an increase in overall survival.


Potential protective effects of extra virgin olive oil on the hepatotoxicity induced by co-exposure of adult rats to acrylamide and aluminum.
Extra virgin olive oil has been shown to be effective against oxidative stress associated diseases. In addition to the high quantities of oleic acid, it is rich in phenolic compounds. We investigated the protective efficacy of extra virgin olive oil (EVOO) against the hepatotoxicity induced by both aluminum and acrylamide. Animals were divided into four groups containing six rats each: group 1, serving as controls, received distilled water; group 2 received drinking water containing aluminum chloride (50 mg kg(-1) body weight) and acrylamide (20 mg kg(-1) body weight) by gavage; group 3 received both aluminum and acrylamide in the same ways as well as EVOO (300 μl) by gavage; group 4 received only EVOO by gavage for 3 weeks. The rats exposed to both aluminum and acrylamide exhibited oxidative stress observed by an increase in MDA, AOPP and a decrease in GSH, NPSH and vitamin C levels. The activities of CAT and GPx were decreased, while SOD activity was increased. The liver metallothioneins, such as MT1 and MT2 genes expression, were also increased. EVOO supplementation improved all the parameters mentioned above. The plasma transaminases (AST and ALT), LDH activities, glucose and albumin levels, TC, LDL-C levels, TC/HDL-C and LDL-C/HDL-C ratios were increased, while high density lipoprotein-cholesterol (HDL-C) and TG decreased. The co-administration of EVOO to acrylamide and aluminum treated rats restored their hepatic markers to near-normal values. Liver histological studies confirmed the biochemical parameters and the beneficial role of EVOO. These results suggest that extra virgin olive oil, when added to the diet, may have a beneficial role in decreasing the liver damage induced by both aluminum and acrylamide.


Knowledge-mediated retrieval of laboratory observations.
Intelligent medical applications including agents, clinical decision support systems, and expert systems can benefit from components that expose the meanings of medical concepts. We have endeavored to create an ontology for laboratory observations and to make the ontology accessible in a distributed environment through a knowledge mediator offering several services. To date we have created two such services, one service to mediate the retrieval of laboratory observations and an auxiliary service to facilitate the mapping of units of measure to LOINC property-types. We report progress and insights on the development of our ontology and related knowledge mediator.


How Gen Y and Boomers will reshape your agenda.
When it comes to workplace preferences, Generation Y workers closely resemble Baby Boomers. Because these two huge cohorts now coexist in the workforce, their shared values will hold sway in the companies that hire them. The authors, from the Center for Work-Life Policy, conducted two large-scale surveys that reveal those values. Gen Ys and Boomers are eager to contribute to positive social change, and they seek out workplaces where they can do that. They expect flexibility and the option to work remotely, but they also want to connect deeply with colleagues. They believe in employer loyalty but desire to embark on learning odysseys. Innovative firms are responding by crafting reward packages that benefit both generations of workers--and their employers.


Recombinational repair is critical for survival of Escherichia coli exposed to nitric oxide.
Nitric oxide (NO(.)) is critical to numerous biological processes, including signal transduction and macrophage-mediated immunity. In this study, we have explored the biological effects of NO(.)-induced DNA damage on Escherichia coli. The relative importance of base excision repair, nucleotide excision repair (NER), and recombinational repair in preventing NO(.)-induced toxicity was determined. E. coli strains lacking either NER or DNA glycosylases (including those that repair alkylation damage [alkA tag strain], oxidative damage [fpg nei nth strain], and deaminated cytosine [ung strain]) showed essentially wild-type levels of NO(.) resistance. However, apyrimidinic/apurinic (AP) endonuclease-deficient cells (xth nfo strain) were very sensitive to killing by NO(.), which indicates that normal processing of abasic sites is critical for defense against NO(.). In addition, recA mutant cells were exquisitely sensitive to NO(.)-induced killing. Both SOS-deficient (lexA3) and Holliday junction resolvase-deficient (ruvC) cells were very sensitive to NO(.), indicating that both SOS and recombinational repair play important roles in defense against NO(.). Furthermore, strains specifically lacking double-strand end repair (recBCD strains) were very sensitive to NO(.), which suggests that NO(.) exposure leads to the formation of double-strand ends. One consequence of these double-strand ends is that NO(.) induces homologous recombination at a genetically engineered substrate. Taken together, it is now clear that, in addition to the known point mutagenic effects of NO(.), it is also important to consider recombination events among the spectrum of genetic changes that NO(. ) can induce. Furthermore, the importance of recombinational repair for cellular survival of NO(.) exposure reveals a potential susceptibility factor for invading microbes.


Regulatory roles of RNA modifications in breast cancer.
Collectively referred to as the epitranscriptome, RNA modifications play important roles in gene expression control regulating relevant cellular processes. In the last few decades, growing numbers of RNA modifications have been identified not only in abundant ribosomal (rRNA) and transfer RNA (tRNA) but also in messenger RNA (mRNA). In addition, many writers, erasers and readers that dynamically regulate the chemical marks have also been characterized. Correct deposition of RNA modifications is prerequisite for cellular homeostasis, and its alteration results in aberrant transcriptional programs that dictate human disease, including breast cancer, the most frequent female malignancy, and the leading cause of cancer-related death in women. In this review, we emphasize the major RNA modifications that are present in tRNA, rRNA and mRNA. We have categorized breast cancer-associated chemical marks and summarize their contribution to breast tumorigenesis. In addition, we describe less abundant tRNA modifications with related pathways implicated in breast cancer. Finally, we discuss current limitations and perspectives on epitranscriptomics for use in therapeutic strategies against breast and other cancers.


A statistical method to calculate blood contamination in the measurement of salivary hormones in healthy women.
Previous studies have reported that salivary concentrations of certain hormones correlate with their respective serum levels. However, most of these studies did not control for potential blood contamination in saliva. In the present study we developed a statistical method to test the amount of blood contamination that needs to be avoided in saliva samples for the following hormones: cortisol, estradiol, progesterone, testosterone and oxytocin. Saliva and serum samples were collected from 38 healthy, medication-free women (mean age=33.8±7.3yr.; range=19-45). Serum and salivary hormonal levels and the amount of transferrin in saliva samples were determined using enzyme immunoassays. Salivary transferrin levels did not correlate with salivary cortisol or estradiol (up to 3mg/dl), but they were positively correlated with salivary testosterone, progesterone and oxytocin (p<0.05). After controlling for blood contamination, only cortisol (r=0.65, P<0.001) and progesterone levels (r=0.57, P=0.002) displayed a positive correlation between saliva and serum. Our analyses suggest that transferrin levels higher than 0.80, 0.92 and 0.64mg/dl should be avoided for testosterone, progesterone and oxytocin salivary analyses, respectively. We recommend that salivary transferrin is measured in research involving salivary hormones in order to determine the level of blood contamination that might affect specific hormonal salivary concentrations.


Screening and validation for plasma biomarkers of nephrotoxicity based on metabolomics in male rats.
Currently, drug-induced nephrotoxicity is widespread and seriously affects human health. However, the conventional indexes of renal function lack sensitivity, leading to a delay in the detection of nephrotoxicity. Therefore, we need to identify more sensitive indexes for evaluating nephrotoxicity. In this study, we used gentamicin (100 mg kg-1), etimicin (100 mg kg-1) and amphotericin B (4 mg kg-1) to establish renal injury models in rats, and we collected information using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry in the screening stage. Thirteen nephrotoxicity metabolites were selected after multivariate statistical and integration analyses. Then, we conducted trend analysis to select 5 nephrotoxicity biomarkers [thymidine, LysoPC(16:1), LysoPC(18:4), LysoPC(20:5), and LysoPC(22:5)] whose content changed consistently at different timepoints after drug administration. To verify the sensitivity and specificity of these biomarkers for nephrotoxicity, receiver operating characteristic (ROC) and support vector machine (SVM) analyses were applied. The area under the curve of the 5 biomarkers were 0.806-0.901 at the 95% confidence interval according to the ROC analysis. We used the SVM classified model to verify these biomarkers, and the prediction rate was 95.83%. Therefore, the 5 biomarkers have strong sensitivity and high accuracy; these biomarkers are more sensitive indexes for evaluating renal function to identify nephrotoxicity and initiate prompt treatment.


Are there multiple ways to direct attention in working memory?
In visual working memory tasks, memory for an item is enhanced if participants are told that the item is relatively more valuable than others presented within the same trial. Experiment 1 explored whether these probe value boosts (termed prioritization effects in previous literature) are affected by probe frequency (i.e., how often the more valuable item is tested). Participants were presented with four colored shapes sequentially and asked to recall the color of one probed item following a delay. They were informed that the first item was more valuable (differential probe value) or as valuable as the other items (equal probe value), and that this item would be tested more frequently (differential probe frequency) or as frequently (equal probe frequency) as the other items. Probe value and probe frequency boosts were observed at the first position, though both were accompanied by costs to other items. Probe value and probe frequency boosts were additive, suggesting the manipulations yield independent effects. Further supporting this, experiment 2 revealed that probe frequency boosts are not reliant on executive resources, directly contrasting with previous findings regarding probe value. Taken together, these outcomes suggest there may be several ways in which attention can be directed in working memory.


Cadherin expression is required for the spread of Shigella flexneri between epithelial cells.
Shigella flexneri, a gram-negative pathogen, invades the human colonic epithelium. After entering epithelial cells, bacteria escape into the cytoplasm, move intracellularly, and pass from cell to cell. The bacterium diverts actin and associated actin-binding proteins to generate a cytoskeleton-based motor that pushes forward the bacterium. As the moving bacterium reaches the inner face of the host-cell cytoplasmic membrane, a protrusion forms that allows passage of this bacterium into a neighboring cell. We show here that components of the intermediate junction are used by the bacterium to allow this passage. Using S180, a mouse fibroblastic sarcoma cell line that does not produce cell adhesion molecules (CAM), and S180L and S180cadN, the same cell line transfected with L-CAM and N-cadherin cDNA, respectively, we demonstrate that expression of a cadherin is required for cell-to-cell spread to occur.


Quantitative analysis of in vitro ubiquitinated cyclin B1 reveals complex chain topology.
Protein ubiquitination regulates many cellular processes, including protein degradation, signal transduction, DNA repair and cell division. In the classical model, a uniform polyubiquitin chain that is linked through Lys 48 is required for recognition and degradation by the 26S proteasome. Here, we used a reconstituted system and quantitative mass spectrometry to demonstrate that cyclin B1 is modified by ubiquitin chains of complex topology, rather than by homogeneous Lys 48-linked chains. The anaphase-promoting complex was found to attach monoubiquitin to multiple lysine residues on cyclin B1, followed by poly-ubiquitin chain extensions linked through multiple lysine residues of ubiquitin (Lys 63, Lys 11 and Lys 48). These heterogeneous ubiquitin chains were sufficient for binding to ubiquitin receptors, as well as for degradation by the 26S proteasome, even when they were synthesized with mutant ubiquitin that lacked Lys 48. Together, our observations expand the context of what can be considered to be a sufficient degradation signal and provide unique insights into the mechanisms of substrate ubiquitination.


LIN28A marks the spermatogonial progenitor population and regulates its cyclic expansion.
One of the hallmarks of highly proliferative adult tissues is the presence of a stem cell population that produces progenitor cells bound for differentiation. Progenitor cells undergo multiple transit amplifying (TA) divisions before initiating terminal differentiation. In the adult male germline, daughter cells arising from the spermatogonial stem cells undergo multiple rounds of TA divisions to produce undifferentiated clones of interconnected 2, 4, 8, and 16 cells, collectively termed A(undifferentiated) (A(undiff)) spermatogonia, before entering a stereotypic differentiation cascade. Although the number of TA divisions markedly affects the tissue output both at steady state and during regeneration, mechanisms regulating the expansion of the TA cell population are poorly understood in mammals. Here, we show that mice with a conditional deletion of Lin28a in the adult male germline, display impaired clonal expansion of the progenitor TA A(undiff) spermatogonia. The in vivo proliferative activity of Au(ndiff) spermatogonial cells as indicated by BrdU incorporation during S-phase was reduced in the absence of LIN28A. Thus, contrary to the role of LIN28A as a key determinant of cell fate signals in multiple stem cell lineages, in the adult male germline it functions as an intrinsic regulator of proliferation in the population of A(undiff) TA spermatogonia. In addition, neither precocious differentiation nor diminished capacity for self-renewal potential as assessed by transplantation was observed, suggesting that neither LIN28A itself nor the pool of Aal progenitor cells substantially contribute to the functional stem cell compartment.


Development and validation of an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the quantitative determination of rhamnolipid congeners.
Rhamnolipids (RLs) are synthesised as a complex mixture of congeners comprising either one or two molecules of rhamnose glycosidically linked to a dimer of 3-hydroxy fatty acids varying in chain length and degree of saturation. Currently, HPLC-MS/MS is the most precise and accurate method for RL determination, while accurate quantification is limited. In this study, a rapid ultra pressure liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the rapid and quantification of individual RL congeners. Increased RLs specificity was achieved using tandem mass spectrometry in multiple reaction monitoring (MRM) mode which was used to quantify RL isomer pairs such as Rha-Rha-C8-C10/Rha-Rha-C10-C8 which are difficult to resolve chromatographically. UPLC showed an 18-fold reduction in retention time for Rha-Rha-C10-C10 (1.07 min) and a 17-fold reduction for Rha-C10-C10 (1.36), the major rhamnolipids present, compared to HPLC, with a total run time less than 2.2 min. The results show that the linear range for the main RL congeners (Rha-C10-C10 and Rha-Rha-C10-C10) is 0.1 to 100 μg/mL. The LOD and LOQ for Rha-C10-C10 is 0.05 and 0.1 μg/mL and for Rha-Rha-C10-C10 is 0.1 and 0.5 μg/mL, respectively. The method was validated for linearity, intra- and inter-day precision and accuracy in accordance with FDA guidelines. The method was applied for the quantification of 14 individual RL congeners produced by Pseudomonas aeruginosa ST5 and comparison of RLs composition on four different carbon sources. Quantification of the individual congeners showed a conserved congener distribution irrespective of carbon source with a preferential selection for C10 β-hydroxyacids as the lipid component of RLs. The only statistically significant differences detected were between actual RL yields on the various carbon sources.


Mature myelin maintenance requires Qki to coactivate PPARβ-RXRα-mediated lipid metabolism.
Lipid-rich myelin forms electrically insulating, axon-wrapping multilayers that are essential for neural function, and mature myelin is traditionally considered metabolically inert. Surprisingly, we discovered that mature myelin lipids undergo rapid turnover, and quaking (Qki) is a major regulator of myelin lipid homeostasis. Oligodendrocyte-specific Qki depletion, without affecting oligodendrocyte survival, resulted in rapid demyelination, within 1 week, and gradually neurological deficits in adult mice. Myelin lipids, especially the monounsaturated fatty acids and very-long-chain fatty acids, were dramatically reduced by Qki depletion, whereas the major myelin proteins remained intact, and the demyelinating phenotypes of Qki-depleted mice were alleviated by a high-fat diet. Mechanistically, Qki serves as a coactivator of the PPARβ-RXRα complex, which controls the transcription of lipid-metabolism genes, particularly those involved in fatty acid desaturation and elongation. Treatment of Qki-depleted mice with PPARβ/RXR agonists significantly alleviated neurological disability and extended survival durations. Furthermore, a subset of lesions from patients with primary progressive multiple sclerosis were characterized by preferential reductions in myelin lipid contents, activities of various lipid metabolism pathways, and expression level of QKI-5 in human oligodendrocytes. Together, our results demonstrate that continuous lipid synthesis is indispensable for mature myelin maintenance and highlight an underappreciated role of lipid metabolism in demyelinating diseases.


Meiotic drive changes sperm precedence patterns in house mice: potential for male alternative mating tactics?
With female multiple mating (polyandry), male-male competition extends to after copulation (sperm competition). Males respond to this selective pressure through physiological, morphological and behavioural adaptations. Sperm competitiveness is commonly decreased in heterozygote carriers of male meiotic drivers, selfish genetic elements that manipulate the production of gametes in males. This might give carriers an evolutionary incentive to reduce the risk of sperm competition. Here, we explore this possibility in house mice. Natural populations frequently harbour a well-characterised male driver (t haplotype), which is transmitted to 90 % of heterozygous (+/t) males' offspring. Previous research demonstrated strong detrimental effects on sperm competitiveness, and suggested that +/t males are particularly disadvantaged against wild type males when first-to-mate. Low paternity success in the first-to-mate role is expected to favour male adaptations that decrease the risk of sperm competition by preventing female remating. Genotype-specific paternity patterns (sperm precedence) could lead to genetically determined alternative reproductive tactics that can spread through gene level selection. Here, we seek confirmation that +/t males are generally disadvantaged when first-to-mate and address whether males of different genotypes differ in reproductive tactics (copulatory and morphological) to maximise individual or driver fitness. Finally, we attempt to explain the mechanistic basis for alternative sperm precedence patterns in this species. We confirmed that +/t males are weak sperm competitors when first to mate. When two +/t males competed, the second-to-mate was more successful, which contrasts with first male sperm precedence when wild type males competed. However, we found no differences between male genotypes in reproductive behaviour or morphology that were consistent with alternative reproductive tactics. Sperm of +/+ and +/t males differed with respect to in vitro sperm features. Premature hypermotility in +/t males' sperm can potentially explain why +/t males are very weak sperm competitors when first-to-mate. Our results demonstrate that meiotic drivers can have strong effects on sperm precedence patterns, and may provide a heritable basis for alternative reproductive tactics motivated by reduced sperm competitiveness. We discuss how experimental and evolutionary constraints may help explain why male genotypes did not show the predicted differences.


Familial Risk of Chronic Musculoskeletal Pain and the Importance of Physical Activity and Body Mass Index: Prospective Data from the HUNT Study, Norway.
The main objectives of the current study was i) to prospectively examine if chronic musculoskeletal pain in parents is associated with risk of chronic musculoskeletal pain in their adult offspring, and ii) to assess if these parent-offspring associations are modified by offspring body mass index and leisure time physical activity. We used data on 4,742 adult offspring linked with their parents who participated in the population-based HUNT Study in Norway in 1995-97 and in 2006-08. Family relations were established through the national Family Registry. A Poisson regression model was used to estimate relative risk (RR) with 95% confidence interval (CI). In total, 1,674 offspring (35.3%) developed chronic musculoskeletal pain during the follow-up period of approximately 11 years. Both maternal (RR: 1.26, 95% CI: 1.03, 1.55) and paternal chronic musculoskeletal pain (RR: 1.29, 95% CI: 1.06, 1.57) was associated with increased risk of offspring chronic musculoskeletal pain. Compared to offspring of parents without chronic musculoskeletal pain, the adverse effect of parental pain was somewhat stronger among offspring who reported a low (RR: 1.82, 95% CI: 1.32, 2.52) versus high (RR: 1.32, 95% CI: 0.95, 1.84) level of leisure time physical activity. Offspring of parents with chronic musculoskeletal pain and who were classified as obese had more than twofold increased risk (RR: 2.33, 95% CI: 1.68, 3.24) of chronic musculoskeletal pain compared to normal weight offspring of parents without pain. In conclusion, parental chronic musculoskeletal pain is positively associated with risk of chronic musculoskeletal pain in their adult offspring. Maintenance of normal body weight may reduce the risk of chronic musculoskeletal pain in offspring of pain-afflicted parents.


Cannibalism by damselflies increases with rising temperature.
Trophic interactions are likely to change under climate warming. These interactions can be altered directly by changing consumption rates, or indirectly by altering growth rates and size asymmetries among individuals that in turn affect feeding. Understanding these processes is particularly important for intraspecific interactions, as direct and indirect changes may exacerbate antagonistic interactions. We examined the effect of temperature on activity rate, growth and intraspecific size asymmetries, and how these temperature dependencies affected cannibalism in Lestes congener, a damselfly with marked intraspecific variation in size. Temperature increased activity rates and exacerbated differences in body size by increasing growth rates. Increased activity and changes in body size interacted to increase cannibalism at higher temperatures. We argue that our results are likely to be general to species with life-history stages that vary in their temperature dependencies, and that the effects of climate change on communities may depend on the temperature dependencies of intraspecific interactions.


The Role of Communication with Friends in Sexual Initiation.
This study identifies a theoretical mechanism through which communication with friends about sex influences sexual initiation in a sample of adolescents. The Integrative Model was used to assess the effect of attitudes, normative pressure and self efficacy on intentions to have sex in a sample of virgin adolescents. Results show that the constructs of the theory partially mediated the effect of communication with friends on subsequent sexual initiation. The effect of communication with friends on sexual initiation was not different for males and females. Overall, the results suggest how conversations with friends about sex influence adolescents' intentions to initiate sexual intercourse, which in turn influence subsequent sexual initiation.


Development and evaluation of a social cognitive theory-based instrument to assess correlations for physical activity among people with spinal cord injury.
People with spinal cord injury (SCI) are more susceptible to sedentary lifestyles because of the displacement of physical functioning and the copious barriers. Benefits of physical activity for people with SCI include physical fitness, functional capacity, social integration and psychological well-being. The purpose of this study was to develop and test a social cognitive theory-based instrument aimed to predict physical activity among people with SCI. An instrument was developed through the utilization and modification of previous items from the literature, an expert panel review, and cognitive interviewing, and tested among a sample of the SCI population using a cross-sectional design. Statistical analysis included descriptives, correlations, multiple regression, and exploratory factor analysis. The physical activity outcome variable was significantly and positively correlated with self-regulatory efficacy (r = 0.575), task self-efficacy (r = 0.491), self-regulation (r = 0.432), social support (r = 0.284), and outcome expectations (r = 0.247). Internal consistency for the constructs ranged from 0.82 to 0.96. Construct reliability values for the self-regulation (0.95), self-regulatory efficacy (0.96), task self-efficacy (0.94), social support (0.84), and outcome expectations (0.92) each exceeded the 0.70 a priori criteria. The factor analysis was conducted to seek modifications of current instrument to improve validity and reliability. The data provided support for the convergent validity of the five-factor SCT model. This study provides direction for further development of a valid and reliable instrument for predicting physical activity among people with SCI.


Childhood obesity prevention studies: lessons learned and to be learned.
To provide an overview of methodological issues in the design, delivery and evaluation of childhood obesity prevention programmes. Review of existing literature. International. Interventions have varied considerably with regard to their design, subject selection criteria, sample size, attrition rates, intervention components and duration of both the intervention and the follow-up phases. However, overall, there is only a limited body of consistent, high-quality evidence on which valid and generalisable conclusions can be drawn about best practices for the prevention of childhood obesity. Although the rationale for targeting children and adolescents through primary prevention is now compelling, effective obesity prevention remains elusive. There is increasing consensus that prevention of childhood obesity necessitates multifaceted health promotion interventions based on population health principles. By definition, such interventions should have a range of outcome indicators of effectiveness, generalisability and sustainability, not just the traditional ones focused on individual lifestyle behaviour change. Given the complexity and intricacy of population-based intervention programmes, multiple methods of data collection which combine both qualitative and quantitative approaches will need to be fully exploited in order to move towards evidence-based practice in the future.


Nonparametric Independence Screening in Sparse Ultra-High Dimensional Additive Models.
A variable screening procedure via correlation learning was proposed in Fan and Lv (2008) to reduce dimensionality in sparse ultra-high dimensional models. Even when the true model is linear, the marginal regression can be highly nonlinear. To address this issue, we further extend the correlation learning to marginal nonparametric learning. Our nonparametric independence screening is called NIS, a specific member of the sure independence screening. Several closely related variable screening procedures are proposed. Under general nonparametric models, it is shown that under some mild technical conditions, the proposed independence screening methods enjoy a sure screening property. The extent to which the dimensionality can be reduced by independence screening is also explicitly quantified. As a methodological extension, a data-driven thresholding and an iterative nonparametric independence screening (INIS) are also proposed to enhance the finite sample performance for fitting sparse additive models. The simulation results and a real data analysis demonstrate that the proposed procedure works well with moderate sample size and large dimension and performs better than competing methods.


Measurement of body condition in a common carabid beetle, Poecilus cupreus: a comparison of fresh weight, dry weight, and fat content.
Because of its direct consequences on reproductive success, body condition is an often-studied individual trait in insects. Various studies on insects use disparate methods to assess "body condition." However, it is doubtful that the results obtained by disparate methods are comparable. In this study, the body conditions of Poecilus cupreus (Linnaeus) (Coleoptera: Carabidae) from eight sites were compared based on the following commonly used variables: (i) fresh weight, (ii) dry weight, and (iii) fat content. All of these variables were corrected for structural body size. Moreover, the effects of using the following ways of assessing structural body size were examined: (a) one size measurement (length of elytron, which is commonly used in beetles), and (b) three size measurements (length of elytron, width of pronotum and length of hind femur). The results obtained using the various estimations of body condition (i, ii, iii) varied significantly. Therefore, studies employing distinct body measurements to assess body condition are not comparable to each other. Using multiple structural size measurements in body condition analyses is better than the common practice of using only one size measurement. However, in the present study, results provided by both methods differ only slightly. A recommendation on the use of terminology in studies on body condition is introduced.


Aging, mobility impairments and subjective wellbeing.
Wellbeing is often described as U-shaped over the life course, suggesting an apparent paradox that wellbeing remains high at older ages despite increases in impairments. We explore associations among age, lower body impairments-one of the most common late-life impairments-and three measures of wellbeing: life satisfaction, emotional wellbeing and somatic wellbeing. We hypothesize that age effects are positive, become stronger once lower body impairments are controlled, and are concentrated among those who have maintained their mobility. Net of confounding factors, we hypothesize that lower body impairments are associated with worse wellbeing and these effects diminish with advancing age. We analyze the 2013 Disability and Use of Time supplement to the Panel Study of Income Dynamics (N = 1607 adults ages 60 and older). We estimate nested regression models that include age, severity of lower body impairments and confounding demographic, psychological, and socioeconomic factors and activities; test age-impairment interactions; and estimate age- and impairment-stratified models. Positive age effects were observed after controlling for lower body impairments for life satisfaction (β = 0.90; p < 0.05), although statistical significance weakened (p = 0.07) in fully adjusted models. For emotional wellbeing, adjusted age effects were negative (β = -0.05; p < 0.05) and were concentrated among those with limitations (β = -0.14; p < 0.01). For all three outcomes, severity of impairments reduced wellbeing in adjusted models. These effects were strongest for somatic wellbeing, especially for 65-74 year olds. Our study challenges the notion that wellbeing is U-shaped throughout the life course and underscores the critical role of mobility across wellbeing domains in later life.


Prevalence and prediction of obstructive coronary artery disease in patients referred for valvular heart surgery.
Current guidelines recommend a coronary evaluation before valvular heart surgery (VHS). Diagnostic coronary angiography is recommended in patients with known coronary artery disease (CAD) and those with high pretest probability of CAD. In patients with low or intermediate pretest probability of CAD, the guidelines recommend coronary computed tomographic angiography. However, there are no tools available to objectively assess a patient's risk for obstructive CAD before VHS. To address this deficit, 5,360 patients without histories of CAD who underwent diagnostic coronary angiography as part of preoperative evaluation for VHS were identified. Obstructive CAD was defined as ≥50% stenosis in ≥1 artery. Of the patients assessed, 1,035 (19.3%) were found to have obstructive CAD. Through multivariate analysis, age, gender, diabetes, renal dysfunction, hyperlipidemia, and a family history of premature CAD were found to be associated with the presence of obstructive CAD (p <0.001 for all). After adjustment, the specific dysfunctional valve was not associated with the presence of obstructive CAD. Patients were then randomly split into derivation and validation cohorts. Within the derivation cohort, using only age, gender, and the presence or absence of risk factors, a model was constructed to predict the risk for obstructive CAD (C statistic 0.766, 95% confidence interval 0.750 to 0.783). The risk prediction model performed well within the validation cohort (C statistic 0.767, 95% confidence interval 0.751 to 0.784, optimism 0.004). The bias-corrected C statistic for the model was 0.765 (95% confidence interval 0.748 to 0.782). In conclusion, this novel risk prediction tool can be used to objectively risk-stratify patients who undergo preoperative evaluation before VHS and to facilitate appropriate triage to computed tomographic angiography or diagnostic coronary angiography.


Relationship Between Seizure Frequency and Functional Abnormalities in Limbic Network of Medial Temporal Lobe Epilepsy.
Background: We compared resting-state functional connectivity (RSFC) among limbic and temporal lobe regions between patients with medial temporal lobe epilepsy (mTLE) and healthy control subjects to identify imaging evidence of functional networks related to seizure frequency, age of seizure onset, and duration of epilepsy. Methods: Twelve patients with drug-resistant, unilateral medial temporal lobe epilepsy and 12 healthy control subjects matched for age, sex, and handedness participated in the imaging experiments. We used network-based statistics to compare functional connectivity graphs in patients with mTLE and healthy controls to investigate the relationship between functional connectivity abnormalities and seizure frequency. Results: Among mTLE patients, we found functional network abnormalities throughout the limbic system, but primarily in the hemisphere ipsilateral to the seizure focus. The RSFCs between ipsilateral hypothalamus and ventral anterior cingulate cortex and between ipsilateral subiculum and contralateral posterior cingulate cortex were highly correlated with seizure frequency. Discussion: These findings suggest that in mTLE, changes in limbic networks ipsilateral to the epileptic focus are common. The pathological changes in connectivity between cingulate cortex, hypothalamus and subiculum ipsilateral to the seizure focus were correlated with increased seizure frequency.


Perceived job stress and mental health in precision machine workers of Japan: a 2 year cohort study.
To determine whether perceived job stress affects mental health in occupational settings. A 2 year cohort study was conducted. Initially, a survey including the general health questionnaire (GHQ) and a questionnaire about perceived job stress was carried out. Of 462 workers who initially showed a GHQ score of < or = 7,310 were successfully followed up for 2 years. The 2 year risks of developing mental ill health (a GHQ score > or = 8) were assessed relative to perceived job stress. To control for potential confounding factors, multiple logistic regression analyses were conducted. The overall 2 year risk for developing mental ill health was high at 57.7%. Workers who reported aspects of perceived job stress showed a greater 2 year risk than those without stress. Multiple logistic regression analyses showed that some components of perceived job stress were associated with a higher 2 year risk, among which "not allowed to make mistakes" showed the largest adjusted odds ratio (OR) (95% confidence interval (95% CI) of 2.37 (1.32 to 4.29). "Poor relationship with superior" had a significant effect on mental health only in women, with an adjusted OR (95% CI) of 3.79 (1.65 to 8.73). Certain specific items of perceived job stress seem to be associated with mental ill health in workers. These could broadly be described as job strain, or job demand items. The type of job stress that predicts mental health may be dependent on the characteristics of the workplace investigated.