Bioactive LbL-assembled multilayer nanofilms upregulate tenogenesis and angiogenesis enabling robust healing of degenerative rotator cuff tendons in vivo.
Degenerative changes to rotator cuff tendons are often diagnosed in elderly patients. Spontaneous healing of degenerative tendons is rather inefficient as a result of the lack of a suitable microenvironment for tendon stem cell differentiation and vascularization. Herein, multilayer hyaluronic acid/chitosan (HA/CS) nanofilms were assembled by a layer-by-layer assembly method onto aligned poly(ε-caprolactone) (PCL) nanofibers for use in healing degenerative tendons. Materials testing showed that the number of layers of HA/CS nanofilms could adjust the hydrophilicity and wettability of the nanofibrous membranes. In vitro, the optimal 8-layer (termed as 8LP) membrane afforded aligned morphology of tendon stem/progenitor cells (TSPCs) and up-regulated mRNA expression of tenogenic markers (SCX, BGN). In a rabbit model with disorganized rotator cuff tendons, the 8LP group up-regulated mRNA levels of collagen I/III and tenascin (TNC) at 6 weeks, but not 12 weeks, post-surgery as compared to the native PCL group. Next, vascular endothelial growth factor-loaded 8LP (termed as 8LP-V) was prepared. Compared to 8LP, 8LP-V produced higher levels of angiogenesis in the tendons at 6 or 12 weeks post-surgery, thus supplying endogenous pre-tendon growth factors (TGF-β, IGF-1) to further enhance tenogenic transcriptional factors. As a result, 8LP-V yielded thicker collagen fibers and/or higher tendon stiffness as compared to the 8LP and clinical pericardial patch groups. This study highlights the rational design of LbL-assembled multilayer HA/CS films to upregulate tenogenesis for robust healing of degenerative rotator cuff tendons.


At the Margins: Comparing School Experiences of Nonbinary and Binary-Identified Transgender Youth.
Transgender, nonbinary, and gender nonconforming (TNG) young people are a diverse group, including young people with gender identities beyond the gender binary. Whereas nonbinary youth experience disparities in victimization and mental health, school belonging, support, and resources have not been well described. We conducted an online survey of TNG young people (ages 12-22) in Wisconsin to assess school belonging, safety, support, and resources. We compared responses among participants with nonbinary versus binary identities using mulvariate analysis of variance, multivariate analysis of covariance, chi-square and logistic regression analysis. A total of 287 TNG young people met inclusion criteria (average age 18.2 ± 2.5 years). More than 40% of participants identified as nonbinary. Nonbinary participants were less likely to be out to teachers, but more likely to utilize supportive staff as a resource compared to binary-identified TNG peers. There were no significant differences in school safety and belonging. Most school experiences do not vary significantly between TNG young people with binary versus nonbinary gender identities, though nonbinary young people are less likely to be out at school. Future research should examine factors that impact whether nonbinary young people share their gender identity and access school support services.


Evaluation of housing adaptation interventions: integrating the economic perspective into occupational therapy practice.
The home environment is a key determinant of health, quality of life, and well-being. Given its relevance for such aspects, the scarcity of evaluations of housing adaptation (HA) interventions aimed at removing environmental barriers and accessibility problems in the homes of people with disabilities is surprising. This article aims to contribute to the development of strategies for economic evaluations of HA interventions, by stimulating the dissemination and application of the concepts of effectiveness, cost, and cost-effectiveness as used within health economics. The focus is limited to three overarching questions for the evaluation of HA interventions. Considering X and Y as two hypothetical interventions for the same individual case, the article asks: (i) Will X be more effective than Y?; (ii) Will X cost more than Y?, and (iii) Will X be more cost-effective than Y? Vignette-like descriptions of fictional cases are used to exemplify the economic concepts explained in the article. In the conclusion, the need is stressed for new experimental data regarding both costs and outcomes of HA interventions, in order to realize sound evaluations with the potential to inform policy and professionals in this field. Given the heterogeneity among national contexts, systematic approaches applied in a coherent manner could strengthen cross-national research and collaborations.


The eIF2alpha kinases inhibit vesicular stomatitis virus replication independently of eIF2alpha phosphorylation.
The eIF2alpha kinases have been involved in the inhibition of vesicular stomatatis virus replication but the contribution of each kinase to this process has not been fully investigated. Using mouse embryonic fibroblasts (MEFs) from knock-out mice we show that PKR and HRI have no effects on VSV replication as opposed to PERK and GCN2, which exhibit strong inhibitory effects. When MEFs containing the serine 51 to alanine mutation of eIF2alpha were used, we found that VSV replication is independent of eIF2alpha phosphorylation. Nevertheless, the kinase domain of the eIF2alpha kinases is both necessary and sufficient to inhibit VSV replication in cultured cells. Induction of PI3K-Akt/PKB pathway by eIF2alpha kinase activation plays no role in the inhibition of VSV replication. Our data provide strong evidence that VSV replication is not affected by eIF2alpha phosphorylation or downstream effector pathways such as the PI3K-Akt/PKB pathway. Thus, the anti-viral properties of eIF2alpha kinases are not always related to their inhibitory effects on host protein synthesis as previously thought and are possibly mediated by phosphorylation of proteins other than eIF2alpha.


Trust-region algorithm for the inversion of molecular diffusion NMR data.
Diffusion NMR experiments are very useful in studying structural and dynamical properties of molecules and in sorting out components from mixtures. A number of numerical approaches have been developed for the processing of diffusion NMR data. In this paper, numerical problems of the direct regularization methods such as CONTIN, MaxEnt, and the newly proposed ITAMeD approach are illustrated by analyzing simulated and experimental data. It allows us to further develop a new method to calculate the distribution of diffusion coefficients. Therefore, we present here an iterative regularization method based on the Trust-Region Algorithm for the Inversion (TRAIn) of molecular diffusion NMR data. It is demonstrated in this paper that our approach overcomes major numerical difficulties of the direct regularization methods mentioned above. Besides, this method reconstructs more reliable diffusion coefficient distributions, especially for real world samples of which the diffusion coefficients are nonsymmetrically distributed.


Expression in Escherichia coli of BCY1, the regulatory subunit of cyclic AMP-dependent protein kinase from Saccharomyces cerevisiae. Purification and characterization.
The regulatory (R) subunit of cAMP-dependent protein kinase from the yeast Saccharomyces cerevisiae was expressed in Escherichia coli by engineering the gene for yeast R, BCY1, into an E. coli expression vector that contained a promoter from phage T7. Oligonucleotide-directed mutagenesis was used to create an NdeI restriction site at the natural ATG of the yeast R. This facilitated construction of the T7 expression vector so that the sequence of the protein produced was identical to the natural R subunit. Yeast R was highly expressed in a soluble form. 20 mg of purified yeast R was obtained from 4 liters of E. coli. N-terminal amino acid sequencing revealed that the expressed protein began with the natural sequence. 60% of the molecules contained an N-terminal methionine, and 40% initiated with valine, the second amino acid of yeast R. The protein produced in E. coli migrated on a sodium dodecyl sulfate-polyacrylamide gel with an Mr of 52,000. The yeast R bound 2 mol of cAMP/mol of R monomer with a Kd of 76 nM. The protein was treated with urea to remove bound cAMP. Sedimentation values before and after the urea treatment were identical (s20,w = 5.1). Addition of purified R subunit to a preparation of yeast C subunit (TPK1) rendered catalytic activity cAMP-dependent with an activity ratio of 4.6. The yeast R was autophosphorylated by yeast C to a level of 0.8 mol of phosphate/mol of R monomer. By these criteria, the R subunit produced in E. coli was structurally and functionally identical to the natural yeast R subunit and similar to mammalian type II R subunits.


Development and Validation of a Score to Predict Mortality in Children Undergoing Extracorporeal Membrane Oxygenation for Respiratory Failure: Pediatric Pulmonary Rescue With Extracorporeal Membrane Oxygenation Prediction Score.
Our objective was to develop and validate a prognostic score for predicting mortality at the time of extracorporeal membrane oxygenation initiation for children with respiratory failure. Preextracorporeal membrane oxygenation mortality prediction is important for determining center-specific risk-adjusted outcomes and counseling families. Multivariable logistic regression of a large international cohort of pediatric extracorporeal membrane oxygenation patients. Multi-institutional data. Prognostic score development: A total of 4,352 children more than 7 days to less than 18 years old, with an initial extracorporeal membrane oxygenation run for respiratory failure reported to the Extracorporeal Life Support Organization's data registry during 2001-2013 were used for derivation (70%) and validation (30%). Bidirectional stepwise logistic regression was used to identify factors associated with mortality. Retained variables were assigned a score based on the odds of mortality with higher scores indicating greater mortality. External validation was accomplished using 2,007 patients from the Pediatric Health Information System dataset. None. The Pediatric Pulmonary Rescue with Extracorporeal Membrane Oxygenation Prediction score included mode of extracorporeal membrane oxygenation; preextracorporeal membrane oxygenation mechanical ventilation more than 14 days; preextracorporeal membrane oxygenation severity of hypoxia; primary pulmonary diagnostic categories including, asthma, aspiration, respiratory syncytial virus, sepsis-induced respiratory failure, pertussis, and "other"; and preextracorporeal membrane oxygenation comorbid conditions of cardiac arrest, cancer, renal and liver dysfunction. The area under the receiver operating characteristic curve for internal and external validation datasets were 0.69 (95% CI, 0.67-0.71) and 0.66 (95% CI, 0.63-0.69). Pediatric Pulmonary Rescue with Extracorporeal Membrane Oxygenation Prediction is a validated tool for predicting in-hospital mortality among children with respiratory failure receiving extracorporeal membrane oxygenation support.


The layer-wise method and the backpropagation hybrid approach to learning a feedforward neural network.
Feedforward neural networks (FNN's) have been proposed to solve complex problems in pattern recognition and classification and function approximation. Despite the general success of learning methods for FNN's, such as the backpropagation (BP) algorithm, second-order optimization algorithms and layer-wise learning algorithms, several drawbacks remain to be overcome. In particular, two major drawbacks are convergence to a local minima and long learning time. In this paper we propose an efficient learning method for a FNN that combines the BP strategy and optimization layer by layer. More precisely, we construct the layer-wise optimization method using the Taylor series expansion of nonlinear operators describing a FNN and propose to update weights of each layer by the BP-based Kaczmarz iterative procedure. The experimental results show that the new learning algorithm is stable, it reduces the learning time and demonstrates improvement of generalization results in comparison with other well-known methods.


Validation of SmartPill® wireless motility capsule for gastrointestinal transit time: Intra-subject variability, software accuracy and comparison with video capsule endoscopy.
There is interest in ultimately combining endoscopy and motility assessments. Gastric emptying (GET), small bowel (SBTT), colon (CTT) and whole gut transit (WGTT) times are conveniently obtained by SmartPill® wireless motility capsule (WMC) that records luminal pH, temperature and pressure. Reproducibility within same subjects and accuracy of software derived times (MotiliGI® ) were investigated for diagnostic application. GET and SBTT were separately measured using video capsule endoscopy (VCE). The aim of this investigation was to assess same subject reproducibility of WMC, accuracy of software derived transit times and relate to Pillcam® SB (small bowel) VCE motility data. Seventy three healthy adults ingested a 260 kcal mixed meal followed by WMC tests. Food intake was permitted after 6 hours. Regional transit data was obtained for GET, SBTT and CTT, the sum yielding WGTT. Nineteen subjects repeated WMC tests 2 or 4 weeks later; a separate 70 underwent VCE while fasted. Visually derived data from WMC yielded GET 3.46±0.27, SBTT 5.15±0.21, CTT 20.76±1.19 and WGTT 29.53±1.28 hours (mean±SEM). Pearson's correlation coefficients (r) against software derived results were: GET 0.78 (P<.0001), SBTT 0.28 (P<.05), CTT 0.96 (P<.0001), WGTT 0.99 (P<.0001). VCE yielded lower GET (0.71±0.08 hours) and SBTT (4.15±0.13 hours). GET, SBTT, CTT and WGTT obtained by WMC are commensurate with literature values, including by other methods. Visually and software derived transit times have strongest correlations for CTT and WGTT. WMC yields longer GET and SBTT than VCE, perhaps due to meal related effects on motility.


Three-dimensional micro-level computational study of Wolff's law via trabecular bone remodeling in the human proximal femur using design space topology optimization.
The law of bone remodeling, commonly referred to as Wolff's Law, asserts that the internal trabecular bone adapts to external loadings, reorienting with the principal stress trajectories to maximize mechanical efficiency creating a naturally optimum structure. The goal of the current study was to utilize an advanced structural optimization algorithm, called design space optimization (DSO), to perform a micro-level three-dimensional finite element bone remodeling simulation on the human proximal femur and analyse the results to determine the validity of Wolff's hypothesis. DSO optimizes the layout of material by iteratively distributing it into the areas of highest loading, while simultaneously changing the design domain to increase computational efficiency. The result is a "fully stressed" structure with minimized compliance and increased stiffness. The large-scale computational simulation utilized a 175 μm mesh resolution and the routine daily loading activities of walking and stair climbing. The resulting anisotropic trabecular architecture was compared to both Wolff's trajectory hypothesis and natural femur samples from literature using a variety of visualization techniques, including radiography and computed tomography (CT). The results qualitatively revealed several anisotropic trabecular regions, that were comparable to the natural human femurs. Quantitatively, the various regional bone volume fractions from the computational results were consistent with quantitative CT analyses. The global strain energy proceeded to become more uniform during optimization; implying increased mechanical efficiency was achieved. The realistic simulated trabecular geometry suggests that the DSO method can accurately predict bone adaptation due to mechanical loading and that the proximal femur is an optimum structure as the Wolff hypothesized.


Sensory-specific satiety is intact in amnesics who eat multiple meals.
What is the relationship between memory and appetite? We explored this question by examining preferences for recently consumed food in patients with amnesia. Although the patients were unable to remember having eaten, and were inclined to eat multiple meals, we found that sensory-specific satiety was intact in these patients. The data suggest that sensory-specific satiety can occur in the absence of explicit memory for having eaten and that impaired sensory-specific satiety does not underlie the phenomenon of multiple-meal eating in amnesia. Overeating in amnesia may be due to disruption of learned control by physiological aftereffects of a recent meal or to problems utilizing internal cues relating to nutritional state.


Nano biomaterials based strategies for enhanced brain targeting in the treatment of neurodegenerative diseases: an up-to-date perspective.
Neurons and their connecting axons gradually degenerate in neurodegenerative diseases (NDs), leading to dysfunctionality of the neuronal cells and eventually their death. Drug delivery for the treatment of effected nervous system is notoriously complicated because of the presence of natural barriers, i.e., the blood-brain barrier and the blood cerebrospinal fluid barrier. Palliative care is currently the standard care for many diseases. Therefore, treatment programs that target the disease's origin rather than its symptoms are recommended. Nanotechnology-based drug delivery platforms offer an innovative way to circumvent these obstacles and deliver medications directly to the central nervous system, thereby enabling treatment of several common neurological problems, i.e., Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. Interestingly, the combination of nanomedicine and gene therapy enables targeting of selective mutant genes responsible for the progression of NDs, which may provide a much-needed boost in the struggle against these diseases. Herein, we discussed various central nervous system delivery obstacles, followed by a detailed insight into the recently developed techniques to restore neurological function via the differentiation of neural stem cells. Moreover, a comprehensive background on the role of nanomedicine in controlling neurogenesis via differentiation of neural stem cells is explained. Additionally, numerous phytoconstituents with their neuroprotective properties and molecular targets in the identification and management of NDs are also deliberated. Furthermore, a detailed insight of the ongoing clinical trials and currently marketed products for the treatment of NDs is provided in this manuscript.


Thoracic complications in solid organ transplantation.
Thoracic complications of solid organ transplantation are common and can arise from the implantation surgical procedure or can be secondary to the need for lifelong immunosuppression. Problems that arise can be general to cardiothoracic surgery or unique to transplant patients. This article provides an overview of these complications and some approaches to their avoidance and management.


Phytochemical Content, Antioxidant and Cytotoxic Activities of Sedum spurium.
Sedum L. species are used for their hemostatic, antidiarrheal, antifungal, diuretic and wound healing properties, and there is growing interest in these species because of their usage in folk medicine. DPPH, SO, NO, and ABTS radical scavenging activities and protective effects against H(2)(02) induced cytotoxicity, as well as cytotoxic activities against the Hep-2 cell line of various extracts from Sedum spurium Bieb. were investigated. Besides, the total phenol, flavonoid, and flavonol contents of the extracts were determined to clarify their biological and phytochemical properties. Chromatographic studies on the most active extract led to the isolation of the major compound, identified as 2-methyl-erythritol by (1)H and (13)C NMR techniques. The EtOAc extract is found to be the most active extract in all tests. However, major compound of EtOAc extract did not possess tested activities. The EtOAC extract of S. spurium could be effective to improve antihemolytic defences of erythrocytes, and radical scavenging potential of the antioxidant mechanism. The extracts should be investigated in detail for their cytotoxic activities because of their possible pro-oxidant effects at high concentrations.


Lesions of the anteroventral third ventricle region exaggerate neuroendocrine and thermogenic but not behavioral responses to a novel environment.
Mild psychological stressors provoke an acute rise in core temperature (T(C)), stimulate the hypothalamo-pituitary-adrenocortical (HPA) axis, and induce various stress-related behaviors. In the present study, we examined the effect of ablation of the anteroventral third ventricle region (AV3V) on both physiological and behavioral responses to a novel environment. T(C) was monitored in male Sprague-Dawley rats, with either sham or AV3V lesions, during a 5-h exposure to a novel environment. Trunk blood was collected, in a second group of rats, for the assessment of plasma levels of ACTH and corticosterone. Novelty-induced grooming and rearing behaviors were assessed in a third group of animals. T(C) was elevated in all animals after 30 min in the novel environment, but the rise was exaggerated in rats with AV3V lesions ( approximately 0.5 degrees C). AV3V-lesion rats maintained a higher core temperature for 2 h before it returned to the same level as the control group. Plasma levels of ACTH and corticosterone were also exaggerated in the AV3V lesion group after 30 min in a novel environment. In contrast to the physiological responses, the behavioral measures of grooming and rearing revealed no differences between the groups. The results from the current study suggest that neurons within the AV3V region exert an inhibitory influence on the HPA axis and fever developed in response to stressful psychological stimuli. They also confirm that the physiological and hormonal components of the stress response are independent of certain behavioral measures of stress.


HMOC, a chrysin derivative, induces tolerogenic properties in lipopolysaccharide-stimulated dendritic cells.
Although we previously identified a new hydroxymethoxyl chrysin derivative (HMOC) using ionizing radiation, the anti-inflammatory mechanism of HMOC in dendritic cells remains unclear. In this study, we investigate the effects of HMOC on phenotypic and functional changes in activated bone marrow-derived dendritic cells (BMDCs). In lipopolysaccharide (LPS)-stimulated BMDCs, HMOC treatment inhibited pro-inflammatory cytokines (TNF-α, IL-12p70, and IL-1β), surface molecules (CD80, CD86, MHC-I, and MHC-II), and antigen-presentation to MHC-I and II without a decrease in IL-10. Furthermore, HMOC increased indoleamine 2,3-dioxygenase-1 (IDO1) activity via activation of JNK and p38 signaling in the presence of LPS. Interestingly, LPS-stimulated DCs treated with HMOC inhibited the proliferation and activation of CD4+ and CD8+ T cells, as well as differentiation of CD4+ T cells into Th1-, Th2- and Th17 cells. In addition, LPS-stimulated DCs treated with HMOC induced an increase in CD4+CD25+Foxp3+ regulatory T cells (Tregs). Collectively, our results suggest that HMOC confers tolerogenic properties in BMDCs, which are responsible for inducing Th cell differentiation to Tregs. Our findings provide a better understanding of the anti-inflammatory mechanism of HMOC in DCs and may contribute to development of a valuable therapeutic candidate for atopic dermatitis.


Parallel In Vivo Assessment of Drug Phenotypes at Various Time Points during Systemic BRAF Inhibition Reveals Tumor Adaptation and Altered Treatment Vulnerabilities.
Treatment of BRAF-mutated melanoma tumors with BRAF inhibitor-based therapy produces high response rates, but of limited duration in the vast majority of patients. Published investigations of resistance mechanisms suggest numerous examples of tumor adaptation and signal transduction bypass mechanisms, but without insight into biomarkers that would predict which mechanism will predominate. Monitoring phenotypic response of multiple adaptive mechanisms simultaneously within the same tumor as it adapts during treatment has been elusive. This study reports on a method to provide a more complete understanding of adaptive tumor responses. We simultaneously measured in vivo antitumor activity of 12 classes of inhibitors, which are suspected of enabling adaptive escape mechanisms, at various time points during systemic BRAF inhibition. We used implantable microdevices to release multiple compounds into distinct regions of a tumor to measure the efficacy of each compound independently and repeated these measurements as tumors progressed on systemic BRAF treatment. We observed varying phenotypic responses to specific inhibitors before, during, and after prolonged systemic treatment with BRAF inhibitors. Our results specifically identify PI3K, PDGFR, EGFR, and HDAC inhibitors as becoming significantly more efficacious during systemic BRAF inhibition. The sensitivity to other targeted inhibitors remained mostly unchanged, whereas local incremental sensitivity to PLX4720 declined sharply. These findings suggest redundancy of several resistance mechanisms and may help identify optimal constituents of more effective combination therapy in BRAF-mutant melanoma. They also represent a new paradigm for dynamic measurement of adaptive signaling mechanisms within the same tumor during therapy. Clin Cancer Res; 22(24); 6031-8. ©2016 AACR.


Non-surgical factors in the correction of aphakia.
72 unselected patients wearing aphakic spectacle correction were examined more than 6 months postoperatively. Approximately one third had poor adaptation in spite of satisfactory acuity. No correlation with age was found in the 60-85 year range. Binocularity appeared to play no part in adaptation but a significant sex difference was found, females predominating in the non-adapted group. Tests of eye movements showed defects in vestibulo-ocular suppression, smooth pursuit, and saccadic accuracy in the non-adapted group. This may indicate floccular dysfunction as a reason for failure to adapt to aphakic spectacles. This suggests the possibility of a useful preoperative assessment test to predict adaptation difficulties.


The molecular cues regulating immune cell trafficking.
Lymphocyte recirculation between the blood and the lymphoid/non-lymphoid tissues is an essential homeostatic mechanism that regulates humoral and cellular immune responses in vivo. This system promotes the encounter of naïve T and B cells with their specific cognate antigen presented by dendritic cells, and with the regulatory cells with which they need to interact to initiate, maintain, and terminate immune responses. The constitutive lymphocyte trafficking is mediated by particular types of blood vessels, including the high endothelial venules (HEVs) in lymph nodes and Peyer's patches, and the flat-walled venules in non-lymphoid tissues including the skin. The lymphocyte migration across HEVs involves tethering/rolling, arrest/firm adhesion/intraluminal crawling, and transendothelial migration. On the other hand, relatively little is known about how lymphocytes and other types of cells migrate across the venules of non-lymphoid tissues. Here we summarize recent findings about the molecular mechanisms that govern immune cell trafficking, including the roles of chemokines and lysophospholipids in regulating immune cell motility and endothelial permeability.


100 YEARS OF VITAMIN D: Effect of serum vitamin D level before ovarian stimulation on the cumulative live birth rate of women undergoing in vitro fertilization: a retrospective analysis.
Vitamin D receptors are present in the female reproductive tract. Studies on the association between serum vitamin D level and pregnancy rate of in vitro fertilization (IVF) showed inconsistent results and focused on a single fresh or frozen embryo transfer cycle. The objective of our study was to evaluate if serum vitamin D level before ovarian stimulation was associated with the cumulative live birth rate (CLBR) of the first IVF cycle. Retrospective cohort study. Women who underwent the first IVF cycle from 2012 to 2016 at a university-affiliated reproductive medicine center were included. Archived serum samples taken before ovarian stimulation were analyzed for 25(OH)D levels using liquid chromatography-mass spectrometry. In total, 1113 had pregnancy outcome from the completed IVF cycle. The median age (25th-75th percentile) of the women was 36 (34-38) years and serum 25(OH)D level was 53.4 (41.9-66.6) nmol/L. The prevalence of vitamin D deficiency (less than 50 nmol/L) was 42.2%. The CLBR in the vitamin D-deficient group was significantly lower compared to the non-deficient group (43.9%, 208/474 vs 50.9%, 325/639, P = 0.021, unadjusted), and after controlling for women's age, BMI, antral follicle count, type and duration of infertility. There were no differences in the clinical/ongoing pregnancy rate, live birth rate and miscarriage rate in the fresh cycle between the vitamin D deficient and non-deficient groups. Vitamin D deficiency was prevalent in infertile women in subtropical Hong Kong. The CLBR of the first IVF cycle in the vitamin D-deficient group was significantly lower compared to the non-deficient group.


Automated assignment and 3D structure calculations using combinations of 2D homonuclear and 3D heteronuclear NOESY spectra.
The NOAH/DIAMOD suite uses feedback filtering and self-correcting distance geometry to generate 3D structures from unassigned NOESY spectra. In this study we determined the minimum set of experiments needed to generate a high quality structure bundle. Different combinations of 3D 15N-edited, 13C-edited HSQC-NOESY and 2D homonuclear 1H-1H NOESY spectra of the 77 amino acid protein, myeloid progenitor inhibitory factor-1 (MPIF-1) were used as input for NOAH/DIAMOD calculations. The quality of the assignments of NOESY cross peaks and the accuracy of the automatically generated 3D structures were compared to those obtained with a conventional manual procedure. Combining data from two types of experiments synergistically increased the number of peaks assigned unambiguously in both individual spectra. As a general trend for the accuracy of the structures we observed structural variations in the backbone fold of the final structures of about 2 A for single spectral data, of 1 A to 1.5 A for double spectral data, and of 0.6 A for triple spectral data sets. The quality of the assignments and 3D structures from the optimal data using all three spectra were similar to those obtained from traditional assignment methods with structural variations within the bundle of 0.6 A and 1.3 A for backbone and heavy atoms, respectively. Almost all constraints (97%) of the automatic NOESY cross peak assignments were cross compatible with the structures from the conventional manual assignment procedure, and an even larger proportion (99%) of the manually derived constraints were compatible with the automatically determined 3D structures. The two mean structures determined by both methods differed only by 1.3 A rmsd for the backbone atoms in the well-defined regions of the protein. Thus NOAD/DIAMOD analysis of spectra from labeled proteins provides a reliable method for high throughput analysis of genomic targets.


Safety and efficacy of remimazolam in induction and maintenance of general anesthesia in high-risk surgical patients (ASA Class III): results of a multicenter, randomized, double-blind, parallel-group comparative trial.
Remimazolam, an ultra-short-acting benzodiazepine sedative is equally effective as propofol in induction and maintenance of general anesthesia with improved hemodynamic stability in American Society of Anesthesiologists (ASA) Class I and II patients. This trial investigated remimazolam's efficacy and safety in vulnerable patients (ASA Class III) undergoing elective general surgery. A multicenter, randomized, double-blind, parallel-group trial in 67 adult surgical patients undergoing general anesthesia with two remimazolam induction doses (6 mg kg-1 h-1-group A and 12 mg kg-1 h-1-group B) has been conducted in 6 trials sites in Japan. Remimazolam was infused up to 2 mg kg-1 h-1 for maintenance of anesthesia in both groups. The functional anesthetic capability of the investigated drug was 100% in both arms. The mean time to loss of consciousness (LoC) was significantly shorter in group B (81.7 s) compared to group A (97.2 s), p = 0.0139. The mean bispectral index (BIS) value during maintenance of anesthesia ranged from 46.0 to 68.0 and from 44.7 to 67.5 in group A and B, respectively. There was no statistically significant difference between the remimazolam arms concerning the incidence of blood pressure (BP) decrease (67.7% in group B vs. 54.8% in group A), recovery profile or the incidence or severity of adverse events (AEs) or adverse drug reactions (ADRs). Both induction regimens (6 and 12 mg kg-1 h-1) were equally efficacious and safe in surgical patients ASA Class III. A significantly shorter time to LoC was observed with the higher remimazolam dosage. Clinical trial registration This trial is registered with the Japan Pharmaceutical Information Center-Clinical Trials Information (JapicCTI). JapicCTI number: 121977.


Membrane lipid from deep-sea hydrothermal vent methanogen: a new macrocyclic glycerol diether.
The membrane lipid of a new deep-sea hydrothermal vent methanogen, Methanococcus jannaschii, has been structurally characterized. The hydrolyzed polar lipid of this archaebacterium is primarily (95 percent) a macrocyclic glycerol diether, which has not been described previously. The structure was elucidated by a combination of chemical and spectroscopic techniques. An initial survey of selected methanogens failed to indicate the presence of this membrane lipid in any microorganism other than Methanococcus jannaschii.


Imaging findings of recurrent tumors after orbital exenteration and free flap reconstruction.
Tumors that recur following orbital exenteration may not be evident on clinical examination, highlighting the need for imaging surveillance. The goal of this study was to report the imaging characteristics of recurrent tumors following orbital exenteration and free flap reconstruction. The authors retrospectively reviewed the records of 48 patients who underwent orbital exenteration for the treatment of orbital malignancy and identified 17 recurrent tumors in 17 patients. The lesions were assessed for the presence of a soft tissue mass, imaging characteristics, and fluorodeoxyglucose avidity. The recurrent tumors were detected 1 month to 6 years 10 months (median, 1 year 3 month) after orbital exenteration. On both CT and MRI, all 17 lesions were soft tissue masses at presentation. On CT, the lesions demonstrated heterogeneous to homogeneous to centrally necrotic enhancement; on MRI, the lesions were T1 hypointense to isointense and T2 hypointense to hyperintense. Twelve of the 15 recurrent tumors with available preoperative imaging had an enhancing appearance similar to that of the original tumor. Thirteen of the 17 recurrent tumors were at the margin of a flap placed for reconstruction; the other 4 lesions were remote from the operative site. Recurrent tumors following orbital exenteration and free flap reconstruction demonstrate a wide range of imaging appearances but most often appear as a soft tissue masses often similar in appearance to the primary tumor and arising near the flap margin. Awareness of the imaging features of recurrent disease is important because failure to diagnose recurrence can delay appropriate treatment.


Acute Effects of Different Set Configurations on Neuromuscular, Metabolic, and Perceptual Responses in Young Women.
We compared neuromuscular, metabolic, and perceptual responses between different resistance training configurations in young women. In a counterbalanced randomized order, 13 young women performed the following protocols in separate sessions (sets x repetitions): traditional (TRAD): 5x10, 90-s of rest interval between sets; more frequent and shorter total rest (FSR): 10x5, 30-s of rest interval between sets. The sessions were composed of leg press exercise with the same intensity. Force (maximum voluntary isometric contraction [MVIC]) and metabolic (lactate concentration) responses were measured pre- and post-resistance training sessions. The rating of perceived exertion (RPE) was measured after each set. The internal training load was calculated using the session-RPE method. There was a significant reduction in the MVIC only after TRAD configuration (Effect size [ES] = 0.36). The lactate concentration increased in both conditions but was higher after TRAD (ES = 2.81) than FSR (ES = 1.23). The RPE has progressively increased in both configurations. On the other hand, the internal training load was lower in the FSR configuration. From our findings, we suggest that more frequent and shorter total rest is an effective strategy for maintaining the ability to produce force, generating less metabolic stress and lower perceived internal load in young women.


The contribution of media analysis to the evaluation of environmental interventions: the commuting and health in Cambridge study.
Media content can increase awareness of, and shape interactions with, public health interventions. As part of a natural experimental evaluation of the travel, physical activity and health impacts of the Cambridgeshire Guided Busway, we analysed print and social media discourse and interview data to understand the nature of new transport infrastructure and how it was experienced. Newspaper articles were systematically retrieved from the LexisNexis database and tweets were identified from an online archive. Interviews were conducted as part of the larger evaluation study with 38 adults. Inductive thematic analysis was performed and comparisons were drawn between datasets. The findings are discussed in relation to five themes. First, an understanding of the intervention context and how the intervention was experienced was developed through accounts of events occurring pre and post the busway's opening. Second, the media captured the dynamic nature of the intervention. Third, the media constructed idealised portrayals of the anticipated busway which in some cases were contradicted by the impact of the busway on the existing context and people's lived experiences. Fourth, differential media coverage of the intervention components suggested that a lesser value was placed on promoting active travel compared with public transport. Lastly, interview data provided support for the hypothesis that the media increased awareness of the busway and served as a frame of reference for constructing expectations and comparing experiences. This analysis has contributed to the wider evaluation of the busway, helping to understand its nature and implementation and informing hypotheses about how the local population interact with the infrastructure by attending to the significance of representations in the media.


Stress fracture of the first metatarsal after total knee arthroplasty: two case reports using gait analysis.
Stress fractures after total knee arthroplasty (TKA) occur mainly in patients with considerable deformity of the knee. In addition, the majority of these fractures after TKA involve the hip joint. We present two cases of stress fractures of the first metatarsal after TKA in patients with severe varus deformity. Correction of leg alignment and pain reduction obtained by TKA lead to stress fracture of the bone. Gait analysis was carried out for both cases in order to clarify the gait characteristics of the stress fracture. As a result, side-to-side differences of the distance between first metatarsal and foot center of pressure in the coronal plane were observed using gait analysis in these patients. Fortunately, conservative treatment was successful for these patients. Stress fractures should be considered when a patient who had a considerable severe deformity of the knee preoperatively complains of foot pain on the affected side. Contrary to stress fractures at the hip joint, patients with the fracture of the first metatarsal can be treated without surgery.


Recent advances in granulosa cell tumor ovary: a review.
Granulosa cell tumors constitute less than 5 % of all ovarian tumors. Unlike epithelial ovarian tumors, they occur in a younger age group, are usually detected in an early stage and often have features of hyperestrogenism. The presenting symptoms are usually nonspecific with abdominal pain or distension. They follow an indolent course and are characterized by a long natural history. Mutation of FOXL2 (402C->G) seen in 97 % of adult GCT may be pathognomonic for adult GCT. Only stage of the disease has been consistently shown in various studies to affect survival of patients with GCT. The initial management of patients, for whom fertility is not an issue, is total abdominal hysterectomy, bilateral salpingo-oophorectomy and removal of all gross disease. Nodal dissection is not a significant factor for survival and is not recommended in surgical staging of GCT. Fertility preserving surgery with unilateral salpingo-oophorectomy is feasible in young patients with stage Ia GCT. Patients with early stage disease (stage I and II) have a very good prognosis with 5 year DFS and OS of 89 % and 99 % respectively and these groups of patients usually don't require any postoperative treatment. Patients with stage Ic disease associated with poor prognostic factors like large tumor size or high mitotic index and stage II, have a higher chance of relapse, and may benefit with postoperative treatment but role of chemotherapy is still debatable. In advanced stage disease (stage III and IV) the 5 year DFS and OS disease was 72 % and 80 % respectively hence the option of postoperative treatment with 6 cycles of BEP should be considered in this group. Recently paclitaxel is being investigated as an effective tool in GCT. The efficacy of radiation in GCT is not well defined but in optimally debulked cases postoperative radiation is a viable option. Due to high chance of recurrence even years after apparent clinical cure of the primary tumor, lifelong follow up with clinical examination and tumor markers like inhibin B is recommended. About 25 % GCT develop recurrence and the median time to recur is usually 4-5 years. Most recurrences are intraperitoneal and usually a complete debulking of the disease is feasible even in the recurrent setting. Postoperative chemotherapy (platinum based) is usually given after surgery more so in cases with widespread disease or after suboptimal cytoreduction. Recurrent chemoresistant, progressive non-responding GCT or patients with high surgical risk are ideal candidates for targeted therapy.


Biochemical and physiological adaptations in the estuarine crab Neohelice granulata during salinity acclimation.
Neohelice granulata (Chasmagnathus granulatus) is an intertidal crab species living in salt marshes from estuaries and lagoons along the Atlantic coast of South America. It is a key species in these environments because it is responsible for energy transfer from producers to consumers. In order to deal with the extremely marked environmental salinity changes occurring in salt marshes, N. granulata shows important and interesting structural, biochemical, and physiological adaptations at the gills level. These adaptations characterize this crab as a euryhaline species, tolerating environmental salinities ranging from very diluted media to concentrated seawater. These characteristics had led to its use as an animal model to study estuarine adaptations in crustaceans. Therefore, the present review focuses on the influence of environmental salinity on N. granulata responses at the ecological, organismic and molecular levels. Aspects covered include salinity tolerance, osmo- and ionoregulatory patterns, morphological and structural adaptations at the gills, and mechanisms of ion transport and their regulation at the gills level during environmental salinity acclimation. Finally, this review compiles information on the effects of some environmental pollutants on iono- and osmoregulatory adaptations showed by N. granulata.


Selective stimulation of a cAMP-specific phosphodiesterase (PDE4A5) isoform by phosphatidic acid molecular species endogenously formed in rat thymocytes.
We have previously reported that concanavalin A (ConA) stimulation of rat thymocytes induces an increase in the cellular phosphatidic acid mass as well as a change in its fatty acid composition. An increase in phosphodiesterase (PDE) activity, mostly due to cAMP-specific (PDE4) isoforms, has also been observed in thymocytes stimulated by ConA. Furthermore, phosphatidic acid was able to stimulate PDE4 activity in vitro. In the present study, cAMP levels have been shown to decrease upon ConA stimulation of thymocytes. Decreasing phosphatidic acid level using diacylglycerol kinase inhibitors induced a parallel decrease of the ConA-stimulated cAMP-specific PDE activity in these cells. Analyses of phosphatidic acid molecular species in cells stimulated for 5 min by ConA revealed a significant increase in 1-stearoyl-2-arachidonoyl-sn-glycerol-3-phosphate and a relative decrease in the other molecular species of phosphatidic acid, mainly species containing palmitate. On the other hand, phosphatidic acid extracted from ConA-stimulated cells activated more efficiently the recombinant PDE4A5 isoform in vitro, as compared to phosphatidic acid extracted from unstimulated cells. In addition, phosphatidic acid species containing unsaturated fatty acids were stimulatory, while those containing two saturated fatty acids had only a marginal effect on the enzyme activity. Taken together, these data suggest that the mitogenic stimulation of thymocytes is accompanied by the synthesis of peculiar phosphatidic acid molecular species able to activate a PDE4 isoform. This activation might be of physiological relevance since cAMP is a major negative effector of the mitogenic response.


Clinical performance and chemical-physical properties of bulk fill composites resin -a systematic review and meta-analysis.
The objective of this study was to perform a meta-analysis of clinical and laboratory studies to compare the performance of bulk-fill and conventional composite resins in terms of polymerization shrinkage, polymerization stress, cusp deflection, marginal quality, degree of conversion, microhardness, flexural strength, fracture strength and clinical performance. One hundred three articles were included in this study, and the Peto method was used to compare the bulk-fill and conventional composites using the RevMan software. Searches were performed in the PubMed and Scopus databases. Laboratory studies and randomized clinical trials comparing one of the previous detailed outcomes between bulk-fill and control composites were included. The bulk-fill composite resins showed less shrinkage, polymerization stress, cusp deflection and microhardness than conventional composites, while both materials presented a similar marginal quality, flexural strength and fracture strength. Also, bulk-fill materials with regular viscosity showed similar shrinkage. The conversion of bulk-fill materials with flowable consistency were similar to conventional composite resins with a thickness of up to 2mm and greater than conventional composites with a thickness greater than 2mm. Despite these in vitro differences, the clinical performance of bulk-fill and conventional composite resins was similar in randomized clinical trials, with one to ten years of follow up. In conclusion, the bulk-fill materials show better or similar performance to the conventional materials in clinical trials and laboratory studies in terms of volumetric shrinkage, polymerization stress, cusps deflection and marginal quality, with the only exception being the lower level of microhardness observed for bulk-fill composites with thickness up to 2mm.


Ketoconazole treatment of nonprimary coccidioidomycosis. Evaluation of 60 patients during three years of study.
Sixty patients with coccidioidomycosis were treated with ketoconazole rather than with another antifungal agent, and their responses were evaluated in relation to the predominant site of involvement. For the three main groups, improvement occurred in 12 of 19 patients with chronic pulmonary infections, in 20 of 23 with soft tissue lesions and in six of 11 with skeletal involvement. Infections in soft tissues improved most rapidly (average of 34 days) and often with 200 mg per day, whereas pulmonary and skeletal infections improved more slowly (63 and 165 days, respectively), usually requiring 400 mg per day. Of 12 patients with response in whom therapy has been discontinued, seven have had relapses. Recurrence was apparent usually within the first month and after six months or less of treatment. Patients in remission had received ketoconazole for six to 17 months. Untoward drug effects included abdominal complaints (23 percent) and gynecomastia (8 percent). Therapy was discontinued in only three patients for side effects. Our findings support the use of ketoconazole in the treatment of certain forms of chronic coccidioidal infections.


Apropos Data Sharing: Abandon the Distrust and Embrace the Opportunity.
In this commentary, we focus on the ethical challenges of data sharing and its potential in supporting biomedical research. Taking human genomics (HG) and European governance for sharing genomic data as a case study, we consider how to balance competing rights and interests-balancing protection of the privacy of data subjects and data security, with scientific progress and the need to promote public health. This is of particular relevancy in light of the current pandemic, which stresses the urgent need for international collaborations to promote health for all. We draw from existing ethical codes for data sharing in HG to offer recommendations as to how to protect rights while fostering scientific research and open science.


Generation of two iPSC lines (MHHi001-A-12 and MHHi001-A-13) carrying biallelic truncating mutations at the 3'-end of SRCAP using CRISPR/Cas9.
Non-Floating Harbour Syndrome (FLHS) neurodevelopmental disorder (NDD) is a recently described disorder caused by mutations in certain regions of the SRCAP gene. We generated two iPSC lines that contain truncating mutation on both alleles at the 3'-end of SRCAP using CRISPR/Cas9 technology. Both cell lines are pluripotent, differentiate into the 3 germ layers and contain no genomic aberrations or off-target modifications. The cell lines form part of a human disease model to investigate the effects of truncating mutations in different regions of SRCAP.


Invasive mold sinusitis: 17 cases in immunocompromised patients and review of the literature.
A 10-year retrospective analysis of invasive mold infections in hospitalized patients was performed to characterize the epidemiology and clinical features of invasive fungal sinusitis. Seventeen cases of invasive mold sinusitis were identified. Eleven cases were caused by Aspergillus flavus, three were caused by unspecified species, and one each was caused by Aspergillus fumigatus, Rhizopus species, and Alternaria species, respectively. Fifteen patients had hematologic malignancies, and two had end-stage liver disease. The most common presenting symptom was periorbital swelling (seven patients). Sinusitis was diagnosed a median of 19 days after admission. Eight patients (47%) survived; six of these patients were treated with both amphotericin B and surgery. Postmortem examination of six patients showed evidence of disseminated disease; the brain was the most common extrapulmonary site (four patients). To our knowledge, this is the largest currently reported series on invasive mold sinusitis; our report extends the information on invasive mold sinusitis and shows that aggressive therapeutic and surgical interventions are needed to prevent rapid progression of disease in immunocompromised patients.


Treatment outcomes by tumor histology in Eastern Cooperative Group Study E4599 of bevacizumab with paclitaxel/carboplatin for advanced non-small cell lung cancer.
The combination of paclitaxel/carboplatin (PC) and bevacizumab (B) was previously shown to extend overall survival (OS) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC). An analysis of survival and safety outcomes based on histology is presented here. Patients with cytologically or histologically confirmed metastatic NSCLC were treated with PC + B (PCB) or PC. Median OS for all patients was determined using Kaplan-Meier methodology. Hazard ratios (HRs) and 95% confidence intervals (CIs) were obtained using an unstratified Cox proportional hazards model. Histology-by-treatment interaction was tested with an unstratified multivariate Cox regression model. A total of 444 patients were randomized to PC, and 434 patients were randomized to PCB (the intent-to-treat population). Median OS times were 10.3 and 12.3 months for PC and PCB, respectively, with an HR for PCB of 0.80 (95% CI: 0.69-0.93). A total of 68.8% of patients had adenocarcinoma histology; 18.9% had "not otherwise specified"; 5.5% had large cell undifferentiated; 2.6% had bronchoalveolar carcinoma; and 3.9% "other." For adenocarcinoma, median OS was 10.3 months for PC treatment (n = 302) and 14.2 months for PCB (n = 300), HR 0.69 (95%CI: 0.58-0.83). Sample sizes for other specific histologic subtypes were too small for meaningful comparisons. Safety profiles among histologies were consistent with the overall safety profile, and there were no unexpected adverse event trends. Addition of B to PC is associated with increased survival in previously untreated patients with nonsquamous NSCLC. Adenocarcinoma was associated with an increased survival benefit of PCB treatment. Data for other histologies are inconclusive, primarily because of small patient sample sizes and large CIs.


Assessing outcomes in body contouring.
Patient-reported outcome (PRO) instruments are questionnaires designed to measure outcomes of importance to patients from their perspective. This article describes the methods used to develop a new PRO instrument for obese patients and patients having bariatric and cosmetic body contouring surgery. The BODY-Q is composed of 19 newly designed scales that measure: (1) appearance; (2) health-related quality of life; and (3) process of care. Recommended guidelines for PRO instrument development were followed to ensure that the BODY-Q meets requirements of regulatory bodies. The BODY-Q is currently being field-tested in an international study.


Enhanced sperm production in bulls following transient induction of hypothyroidism during prepubertal development.
Male reproductive capacity is a critical component of cattle production and the majority of genetic gain is made via selective utilization of gametes from desirable sires. Thus, strategies that enhance sperm production increase the availability of elite genetics for use in improving production characteristics of populations on a worldwide scale. In all mammals, the amount of sperm produced is strongly correlated to the number of Sertoli cells in testes. Studies with rodents showed that the size of the Sertoli cell population is set during prepubertal development via signaling from thyroid hormones. Here, we devised a strategy to increase Sertoli cell number in bulls via induction of a transient hypothyroidic state just prior to and extending beyond the period of Sertoli cell proliferation that we found to normally cease between 4.5 and 5 mo of age. In adulthood, these bulls produced a significantly greater number of sperm compared to age-matched controls and their testes contained nearly 2 times more Sertoli cells. Importantly, sperm motility, morphology, fertilizing ability, and viability after cryopreservation were found to be no different for treated bulls compared to untreated control bulls. This strategy of transient induction of hypothyroidism during a defined period of prepubertal development in bulls could prove to be an efficacious approach for enhancing daily sperm production in genetically desirable sires that will, in turn, provide an avenue for improving the efficiency of commercial cattle production.


A blaVIM-1 positive Aeromonas hydrophila strain in a near-drowning patient: evidence for interspecies plasmid transfer within the patient.
Aim: To show that a strain of Aeromonas hydrophila became resistant to carbapenems by interspecies transfer of a plasmid using long-read sequencing. Material & methods: Whole genome sequencing of the four isolates was done using Illumina Hiseq, while the plasmid was reconstructed using the MinION sequencer. The resistome was identified with ResFinder. Results: Whole genome sequencing and long-read sequencing showed that all isolates carried a blaVIM-1 gene located on a 165 kb incA/C plasmid. ResFinder confirmed that the resistome of the plasmid, comprising 13 resistance genes, was identical within all isolates. Discussion: Long-read sequencing using the MinION successfully reconstructed a plasmid that was identical in all isolates, providing evidence for horizontal gene transfer of this blaVIM-1 gene carrying plasmid within the patient.


The origin of allometric scaling laws in biology from genomes to ecosystems: towards a quantitative unifying theory of biological structure and organization.
Life is the most complex physical phenomenon in the Universe, manifesting an extraordinary diversity of form and function over an enormous scale from the largest animals and plants to the smallest microbes and subcellular units. Despite this many of its most fundamental and complex phenomena scale with size in a surprisingly simple fashion. For example, metabolic rate scales as the 3/4-power of mass over 27 orders of magnitude, from molecular and intracellular levels up to the largest organisms. Similarly, time-scales (such as lifespans and growth rates) and sizes (such as bacterial genome lengths, tree heights and mitochondrial densities) scale with exponents that are typically simple powers of 1/4. The universality and simplicity of these relationships suggest that fundamental universal principles underly much of the coarse-grained generic structure and organisation of living systems. We have proposed a set of principles based on the observation that almost all life is sustained by hierarchical branching networks, which we assume have invariant terminal units, are space-filling and are optimised by the process of natural selection. We show how these general constraints explain quarter power scaling and lead to a quantitative, predictive theory that captures many of the essential features of diverse biological systems. Examples considered include animal circulatory systems, plant vascular systems, growth, mitochondrial densities, and the concept of a universal molecular clock. Temperature considerations, dimensionality and the role of invariants are discussed. Criticisms and controversies associated with this approach are also addressed.


Midwives' views on alcohol guidelines: A qualitative study of barriers and facilitators to implementation in UK antenatal care.
Midwives play an important role in health promotion and prevention of alcohol-related harm, but previous research has suggested that although most midwives report advising on abstinence, evidence exist that women are informed that "some" alcohol is not harmful. The aim of this qualitative study was to explore midwives' views on implementation of the 2016 Chief Medical Officers' alcohol guidelines in antenatal care in the UK. Focus groups and individual interviews with 22 midwives working in maternity and educational settings in the UK were conducted either in person or over telephone. Data were subjected to thematic analysis. Conflict between guidelines from different sources and lack of knowledge of the abstinence advice issued in the Guidelines were barriers to discussing abstinence. Communication with women and building relationships were key facilitators supporting alcohol discussions. How alcohol was addressed appeared to vary across the UK with no uniform approach. Building a trusted relationship was believed to be the way in which women can disclose alcohol use, though the first antenatal contact was not always viewed as the best time to discuss what was considered a personal matter. Despite the release of new guidance in 2016, there was little recognition and awareness of these among midwives. Midwives were by default guided by other national clinical sources or guidelines. Future research should explore how practice-based interventions can address systemic and interpersonal factors to support health professionals to implement the Guidelines, and ensure that women are provided support to change unhealthy behaviours.


Optofluidic differential colorimetry for rapid nitrite determination.
Nitrite detection plays a very important role in environmental monitoring and for industrial purposes. The commonly used colorimetric analysis requires the measurement of a system's calibration curve by asynchronously preparing and detecting a dozen standard samples, leading to time-consuming, slow and cumbersome procedures. Here, we present a differential colorimetry method that determines the nitrite level based on the paired chromaticity gradient, formed by coupling the colour reaction into the microfluidic network. The two gradients reshape each other and contain enough information for the quantitative analysis of the sample being tested, without the need for a calibration curve. The independence of the two gradients of the absorbance change caused by the detecting system and water quality results in a high stability and anti-interference performance, with the assistance of its self-correcting ability. This differential colorimetry method requires little time and energy consumption as only one sample is needed. Standard nitrite solutions of 0.50 mM and 0.33 mM have been determined with an error of 1.16% and 0.50%, respectively. These measurements are advantageous in terms of greater stability by up to 10 times and accuracy by 6 times, compared with the calibration curve approaches. It is foreseeable that this differential colorimetry method will find a wide range of applications in the field of chemical detection.


Characterization of Two Mouse Chd7 Heterozygous Loss-of-Function Models Shows Dysgenesis of the Corpus Callosum and Previously Unreported Features of CHARGE Syndrome.
CHARGE syndrome is a rare congenital disorder frequently caused by mutations in the chromodomain helicase DNA-binding protein-7 CHD7. Here, we developed and systematically characterized two genetic mouse models with identical, heterozygous loss-of-function mutation of the Chd7 gene engineered on inbred and outbred genetic backgrounds. We found that both models showed consistent phenotypes with the core clinical manifestations seen in CHARGE syndrome, but the phenotypes in the inbred Chd7 model were more severe, sometimes having reduced penetrance and included dysgenesis of the corpus callosum, hypoplasia of the hippocampus, abnormal retrosplenial granular cortex, ventriculomegaly, hyperactivity, growth delays, impaired grip strength and repetitive behaviors. Interestingly, we also identified previously unreported features including reduced levels of basal insulin and reduced blood lipids. We suggest that the phenotypic variation reported in individuals diagnosed with CHARGE syndrome is likely due to the genetic background and modifiers. Finally, our study provides a valuable resource, making it possible for mouse biologists interested in Chd7 to make informed choices on which mouse model they should use to study phenotypes of interest and investigate in more depth the underlying cellular and molecular mechanisms.


A Comparison of the Storage-Only Deficit and Joint Mechanism Deficit Hypotheses of the Verbal Working Memory Storage Capacity Limitation of Children With Developmental Language Disorder.
Purpose The storage-only deficit and joint mechanism deficit hypotheses are 2 possible explanations of the verbal working memory (vWM) storage capacity limitation of school-age children with developmental language disorder (DLD). We assessed the merits of each hypothesis in a large group of children with DLD and a group of same-age typically developing (TD) children. Method Participants were 117 children with DLD and 117 propensity-matched TD children 7-11 years of age. Children completed tasks indexing vWM capacity, verbal short-term storage, sustained attention, attention switching, and lexical long-term memory (LTM). Results For the DLD group, all of the mechanisms jointly explained 26.5% of total variance. Storage accounted for the greatest portion (13.7%), followed by controlled attention (primarily sustained attention; 6.5%) and then lexical LTM (5.6%). For the TD group, all 3 mechanisms together explained 43.9% of total variance. Storage accounted for the most variance (19.6%), followed by lexical LTM (16.0%), sustained attention (5.4%), and attention switching (3.0%). There was a significant LTM × Group interaction, in which stronger LTM scores were associated with significantly higher vWM capacity scores for the TD group as compared to the DLD group. Conclusions Results support a joint mechanism deficit account of the vWM capacity limitation of children with DLD. Results provide substantively new insights into the underlying factors of the vWM capacity limitation in DLD. Supplemental Material https://doi.org/10.23641/asha.9932312.


Performance of normative and approximate evidence accumulation on the dynamic clicks task.
The aim of a number of psychophysics tasks is to uncover how mammals make decisions in a world that is in flux. Here we examine the characteristics of ideal and near-ideal observers in a task of this type. We ask when and how performance depends on task parameters and design, and, in turn, what observer performance tells us about their decision-making process. In the dynamic clicks task subjects hear two streams (left and right) of Poisson clicks with different rates. Subjects are rewarded when they correctly identify the side with the higher rate, as this side switches unpredictably. We show that a reduced set of task parameters defines regions in parameter space in which optimal, but not near-optimal observers, maintain constant response accuracy. We also show that for a range of task parameters an approximate normative model must be finely tuned to reach near-optimal performance, illustrating a potential way to distinguish between normative models and their approximations. In addition, we show that using the negative log-likelihood and the 0/1-loss functions to fit these types of models is not equivalent: the 0/1-loss leads to a bias in parameter recovery that increases with sensory noise. These findings suggest ways to tease apart models that are hard to distinguish when tuned exactly, and point to general pitfalls in experimental design, model fitting, and interpretation of the resulting data.


Influence of the Fabrication Accuracy of Hot-Embossed PCL Scaffolds on Cell Growths.
Polycaprolactone (PCL) is a biocompatible and biodegradable polymer widely used for the realization of 3D scaffold for tissue engineering applications. The hot embossing technique (HE) allows the obtainment of PCL scaffolds with a regular array of micro pillars on their surface. The main drawback affecting this kind of micro fabrication process is that such structural superficial details can be damaged when detaching the replica from the mold. Therefore, the present study has focused on the optimization of the HE processes through the development of an analytical model for the prediction of the demolding force as a function of temperature. This model allowed calculating the minimum demolding force to obtain regular micropillars without defects. We demonstrated that the results obtained by the analytical model agree with the experimental data. To address the importance of controlling accurately the fabricated microstructures, we seeded on the PCL scaffolds human stromal cell line (HS-5) and monocytic leukemia cell line (THP-1) to evaluate how the presence of regular or deformed pillars affect cells viability. In vitro viability results, scanning electron and fluorescence microscope imaging analysis show that the HS-5 preferentially grows on regular microstructured surfaces, while the THP-1 on irregular microstructured ones.


MTSTR: Multi-task learning for low-resolution scene text recognition via dual attention mechanism and its application in logistics industry.
Recognizing texts in images plays an important role in many applications, such as industrial intelligence, robot vision, automatic driving, command assistance, and scene understanding. Although great progress has been achieved in various fields, research on complex systems modeling using text recognition technology requires further attention. To address this, we propose a new end-to-end multi-task learning method, which includes a super-resolution branch (SRB) and a recognition branch. To effectively learn the semantic information of images, we utilize the feature pyramid network (FPN) to fuse high- and low-level semantic information. The feature map generated by FPN is then delivered separately to the super-resolution branch and the recognition branch. We introduce a novel super-resolution branch, the SRB based on the proposed dual attention mechanism (DAM), designed to enhance the capability of learning low-resolution text features. The DAM incorporates the residual channel attention to enhance channel dependencies and the character attention module to focus on context information. For the recognition branch, the feature map generated by FPN is fed into an RNN sequence module, and an attention-based decoder is constructed to predict the results. To address the issue of low-resolution text recognition in numerous Chinese scenes, we propose the Chinese super-resolution datasets instead of relying on traditional down-sampling techniques to generate training datasets. Experiments demonstrate that the proposed method performs robustly on low-resolution text images and achieves competitive results on benchmark datasets.


Worksite health promotion programs with environmental changes: a systematic review.
It is now widely believed that health promotion strategies should go beyond education or communication to achieve significant behavioral changes among the target population. Environmental modifications are thought to be an important addition to a worksite health promotion program (WHPP). This review aimed to systematically assess the effectiveness of WHPPs with environmental modifications, on physical activity, dietary intake, and health risk indicators. Online searches were performed for articles published up to January 2004 using the following inclusion criteria: (1) (randomized) controlled trial (RCT/CT); (2) intervention should include environmental modifications; (3) main outcome must include physical activity, dietary intake, and health risk indicators; and (4) healthy working population. Methodologic quality was assessed using a checklist derived from the methodologic guidelines for systematic reviews (Cochrane Back Review Group), and conclusions on the effectiveness were based on a rating system of five levels of evidence. Thirteen relevant, mostly multicenter, trials were included. All studies aimed to stimulate healthy dietary intake, and three trials focused on physical activity. Follow-up measurements of most studies took place after an average 1-year period. Methodologic quality of most included trials was rated as poor. However, strong evidence was found for an effect on dietary intake, inconclusive evidence for an effect on physical activity, and no evidence for an effect on health risk indicators. It is difficult to draw general conclusions based on the small number of studies included in this review. However, evidence exists that WHPPs that include environmental modifications can influence dietary intake. More controlled studies of high methodologic quality need to be initiated that investigate the effects of environmental interventions on dietary intake and especially on physical activity in an occupational setting.


Mesostructured Materials with Controllable Long-Range Orientational Ordering and Anisotropic Properties.
Inorganic-organic mesophase materials provide a wide range of tunable properties, which are often highly dependent on their nano-, micro-, or meso-scale compositions and structures. Among these are macroscopic orientational order and corresponding anisotropic material properties, the adjustability of which are difficult to achieve. This is due to the complicated transient and coupled transport, chemical reaction, and surface processes that occur during material syntheses. By understanding such processes, general criteria are established and used to prepare diverse mesostructured materials with highly aligned channels with uniform nanometer dimensions and controllable directionalities over macroscopic dimensions and thicknesses. This is achieved by using a micropatterned semipermeable poly(dimethylsiloxane) stamp to manage the rates, directions, and surfaces at which self-assembling phases nucleate and the directions that they grow. This enables mesostructured surfactant-directed silica and titania composites, including with functional guest species, and mesoporous carbons to be prepared with high degrees of hexagonal order, as well as controllable orthogonal macroscopic orientational order. The resulting materials exhibit novel anisotropic properties, as demonstrated by the example of direction-dependent photocurrent generation, and are promising for enhancing the functionality of inorganic-organic nanocomposite materials in separations, catalysis, and energy conversion applications.


Employing the biology of successful fracture repair to heal critical size bone defects.
Bone has the natural ability to remodel and repair. Fractures and small noncritical size bone defects undergo regenerative healing via coordinated concurrent development of skeletal and vascular elements in a soft cartilage callus environment. Within this environment bone regeneration recapitulates many of the same cellular and molecular mechanisms that form embryonic bone. Angiogenesis is intimately involved with embryonic bone formation and with both endochondral and intramembranous bone formation in differentiated bone. During bone regeneration osteogenic cells are first associated with vascular tissue in the adjacent periosteal space or the adjacent injured marrow cavity that houses endosteal blood vessels. Critical size bone defects cannot heal without the assistance of therapeutic aids or materials designed to encourage bone regeneration. We discuss the prospects for using synthetic hydrogels in a bioengineering approach to repair critical size bone defects. Hydrogel scaffolds can be designed and fabricated to potentially trigger the same bone morphogenetic cascade that heals bone fractures and noncritical size defects naturally. Lastly, we introduce adult Xenopus laevis hind limb as a novel small animal model system for bone regeneration research. Xenopus hind limbs have been used successfully to screen promising scaffolds designed to heal critical size bone defects.


Entomopathogenic nematodes for control of insect pests above and below ground with comments on commercial production.
Entomopathogenic nematodes (EPNs) have been utilized in classical, conservation, and augmentative biological control programs. The vast majority of applied research has focused on their potential as inundatively applied augmentative biological control agents. Extensive research over the past three decades has demonstrated both their successes and failures for control of insect pests of crops, ornamental plants, trees and lawn and turf. In this paper we present highlights of their development for control of insect pests above and below ground. The target insects include those from foliar, soil surface, cryptic and subterranean habitats. Advances in mass-production and formulation technology of EPNs, the discovery of numerous efficacious isolates/strains, and the desirability of reducing pesticide usage have resulted in a surge of commercial use and development of EPNs. Commercially produced EPNs are currently in use for control of scarab larvae in lawns and turf, fungus gnats in mushroom production, invasive mole crickets in lawn and turf, black vine weevil in nursery plants, and Diaprepes root weevil in citrus in addition to other pest insects. However, demonstrated successful control of several other insects, often has not lead to capture of a significant share of the pesticide market for these pests.


Treatment of mandible fractures using bioabsorbable plates.
This study evaluated the short-term outcome of treating fractures of the mandible with bioabsorbable plates. Sixty-nine fractures of the mandible in 49 patients were treated by open reduction and internal fixation using bioabsorbable plates and 2.4-mm, 2.0-mm, and 1.5-mm pretapped screws. The duration of intermaxillary fixation ranged from 0 to 23 days, with a mean of 4.6 days. Patients were evaluated for complications during the follow-up period, which ranged from 1 to 18 months. Six patients (12.2 percent) experienced complications. These included infection (four patients), premature occlusal contact (one patient), and temporomandibular disorder (one patient). Except for one case, all complications were minor and adequately managed with incision and drainage, elastic traction, physical therapy, and medication. Delayed infection (osteomyelitis) developed in a symphysis fracture and was treated by saucerization and antibiotics. The fracture line subsequently showed complete consolidation. Bioabsorbable plates can be selectively used for internal fixation in mandibular fractures, with the advantage that they do not need to be removed.


Tumour necrosis factor alpha binding to human and mouse trophoblast.
Tumour necrosis factor alpha (TNF-alpha) is a cytokine with pleiotropic effects, modulating cell growth, differentiation, and synthesis of various substances. Recent demonstration of TNF-alpha mRNA and protein in the uteroplacental unit suggests that this cytokine may be involved in the development of the embryo. To determine whether the embryo itself binds TNF-alpha, mouse blastocyst outgrowths and human first trimester villous trophoblast were analysed for TNF-alpha binding. Our experiments revealed that binding of TNF-alpha could be specifically detected on the trophectoderm of the outgrowing mouse embryos. They also show a complete disappearance of the colony-stimulating factor 1 (CSF-1) receptor that occurs shortly after the binding of TNF-alpha by the trophectoderm. In human first trimester villous trophoblast, TNF-alpha binding was found to be predominantly detectable on the syncytiotrophoblast and to a lesser extent on the cytotrophoblastic cells. Binding was not observed on adjacent embryonic or maternal cells. Our results further support the idea that TNF-alpha as well as other cytokines may modulate early embryonic development and implantation.


Transient response of piles-bridge under horizontal excitation.
Moving ships and other objects drifting on water often impact a bridge's pile foundations. The mechanical model of the piles-bridge structure under horizontal forcing was established, and a time-domain approach based on Finite-difference Method was developed for analyzing the dynamic response of the piles-bridge structure. For a single pile, good agreement between two computed results validated the present approach. The slenderness ratio of the pile, the pile-soil stiffness ratio and the type of the structure influence the dynamic response of the piles-bridge structure. The computed results showed that the stiffness of the structure determines the dynamic response of the piles-bridge structure under horizontal forcing.


Diabetes mellitus after GDM.
The impact of factors that influence diabetes mellitus (DM) and impaired glucose tolerance (IGT) incidence rates among former gestation diabetes mellitus (GDM) patients undermine attempts at interstudy comparisons. The recommended diagnostic standards for GDM by oral glucose tolerance test (OGTT) are the O'Sullivan and Mahan criteria and the World Health Organization (WHO) criteria for IGT, which result in prevalence rates of 2.5 and 7.2%, respectively, when applied to 752 unselected pregnant women. In applying the O'Sullivan and Mahan criteria, the current open-ended definition of GDM without rules either to exclude overt diabetes uncovered by pregnancy or to require a return to a normal OGTT after pregnancy is shown to be a major source of differences in subsequent incidence rates of diabetes. For subsequent nonpregnant diagnoses, the differences between WHO and National Diabetes Data Group criteria and the allowable modifications within each of the diagnostic standards all result in different incidence rates of diabetes. Review of 12 worldwide studies of diabetes among former GDM patients indicated a wide range of incidence rates, from 19 to 87% for combined DM and IGT and 6 to 62% for DM. In applying WHO DM criteria to GDM patients and control subjects, the excess risk of diabetes among GDM patients was 18% in Copenhagen and 30.9% in Boston, MA. The potential impact of varying observation periods within studies was seen when the application of an actuarial method added a further 50% to the Boston incidence rates of both GDM patients and control subjects. Although the variability in diabetes incidence rates is wide, there is broad general agreement on the predictive nature of gestational blood glucose levels.


What's up in heart failure care in the Netherlands?
To provide an overview of heart failure management programmes in the Netherlands. A descriptive study was performed consisting of two phases, a screening phase in which all hospitals (n=109) and 105 home care organisations were approached by telephone to assess availability of heart failure management programmes. In phase 2, content and organisation of the programmes were described by a questionnaire. At the moment, the majority of hospitals (75%) have a heart failure management programme or are developing such a programme. In 19 home care organisations (18%) a programme was available and three organisations had concrete plans to start one in the short term. Components of heart failure programmes differ considerably, with a follow-up after discharge from hospital as the most often reported component. Other components of programmes include patient education, increased access to healthcare professionals and adjusting medication. Exercise programmes are not often available. Organisational aspects with regard to setting, financing and staffing also differ between various programmes. There is a considerable increase in the number of heart failure management programmes in the Netherlands, both hospital based and home based. Many questions regarding the most optimal content and organisation of heart failure management programmes remain unanswered.


Quantification of dissolved organic carbon at very low levels in natural ice samples by a UV-induced oxidation method.
The study of chemical impurities trapped in solid precipitation and accumulated in polar ice sheets and high-elevation, midlatitude cold glaciers over the last several hundreds of years provides a unique way to reconstruct our changing atmosphere from the preindustrial era to the present day. Numerous ice core studies of inorganic species have already evaluated the effects of growing anthropogenic emissions of SO(2) or NO(x) on the chemical composition of the atmosphere in various regions of the world. While it was recently shown that organic species dominate the atmospheric aerosol mass, the contribution of anthropogenic emissions to their budget remains poorly understood. The study of organics in ice is at the infancy stage, and it still is difficult to draw a consistent picture of the organic content of polar ice from sparse available data. A UV oxidation method and IR quantification of CO(2) was optimized to obtain measurements of dissolved organic carbon content as low as a few ppbC. Stringent working conditions were defined to prevent contamination during the cleaning of ice. Measurements in various ice cores corresponding to preindustrial times revealed dissolved organic carbon content of less than 10 ppbC in Antarctica and up to 75 ppbC in alpine ice.


Expanding Bicycle Infrastructure to Promote Physical Activity in Hidalgo County, Texas.
The role of the built environment as both an asset and a barrier in promoting physical activity is well documented. However, literature on the role of communities in catalyzing policy, systems, and environmental (PSE) change to address gaps in the built environment is scant. We describe a community-driven PSE intervention, resulting in expanded bicycle infrastructure and physical activity opportunities in a South Texas border community. Funded through the Centers for Disease Control and Prevention, the Working on Wellness project engaged community-based coalitions in efforts to increase opportunities for physical activity in Hidalgo County, Texas. Coalitions collaborated with the city of Weslaco to install bicycle lanes and with the Hidalgo County Metropolitan Planning Organization to establish a countywide Bicycle Friendly Business program. Community-driven PSE interventions can be effective public health strategies in creating long-term sustainable solutions that address environmental determinants of obesity.


Harnessing Metabolic Regulation to Increase Hfq-Dependent Antibiotic Susceptibility in Pseudomonas aeruginosa.
The opportunistic human pathogen Pseudomonas aeruginosa is responsible for ~ 10% of hospital-acquired infections worldwide. It is notorious for its high level resistance toward many antibiotics, and the number of multi-drug resistant clinical isolates is steadily increasing. A better understanding of the molecular mechanisms underlying drug resistance is crucial for the development of novel antimicrobials and alternative strategies such as enhanced sensitization of bacteria to antibiotics in use. In P. aeruginosa several uptake channels for amino-acids and carbon sources can serve simultaneously as entry ports for antibiotics. The respective genes are often controlled by carbon catabolite repression (CCR). We have recently shown that Hfq in concert with Crc acts as a translational repressor during CCR. This function is counteracted by the regulatory RNA CrcZ, which functions as a decoy to abrogate Hfq-mediated translational repression of catabolic genes. Here, we report an increased susceptibility of P. aeruginosa hfq deletion strains to different classes of antibiotics. Transcriptome analyses indicated that Hfq impacts on different mechanisms known to be involved in antibiotic susceptibility, viz import and efflux, energy metabolism, cell wall and LPS composition as well as on the c-di-GMP levels. Furthermore, we show that sequestration of Hfq by CrcZ, which was over-produced or induced by non-preferred carbon-sources, enhances the sensitivity toward antibiotics. Thus, controlled synthesis of CrcZ could provide a means to (re)sensitize P. aeruginosa to different classes of antibiotics.


Technology insight: water diffusion MRI--a potential new biomarker of response to cancer therapy.
Diffusion-weighted MRI (DW-MRI) is a functional imaging technique that displays information about the extent and direction of random water motion in tissues. Water movement in tissues is modified by interactions with hydrophobic cellular membranes, intracellular organelles and macromolecules. DW-MRI provides information on extracellular-space tortuosity, tissue cellularity and the integrity of cellular membranes. Images can be sensitive to large or small displacements of water, therefore, macroscopic water flows and microscopic water displacements in the extracellular space can be depicted. Preclinical and clinical data indicate a number of potential roles of DW-MRI in the characterization of malignancy, including determination of lesion aggressiveness and monitoring response to therapy. This Review outlines the biological basis of observations made on DW-MRI and describes how measurements are acquired and quantified, and discusses the interpretation of images and limitations of the technique. The strength of evidence for adoption of DW-MRI as a biomarker for the assessment of tumor response is presented.


Problems in the detection of carriers of haemophilia A.
Factor VIII activity and factor VIII related--or Willebrand--antigen were studied in 49 known carriers of haemophilia A and 31 normal women, and the data were analysed by four statistical approaches. Sixteen per cent of normals and 18% of carriers were misclassified, overlapping with the other group. Although the percentage of carriers detected is higher when taking into account the results of both biological and immunological factor VIII, it is lower than others recently reported, and the discrepancies between the results obtained are discussed.


Potential Dose to Nuclear Medicine Technologists from 99mTc-DTPA Aerosol Lung Studies.
Air sampling performed during 190 Tc-labeled DTPA aerosol lung ventilation studies indicated that the maximum airborne concentration to which the nuclear medicine technologists might be exposed was 7.1 × 10 Bq mL (1.9 × 10 μCi mL). If a single technologist performed ALL the aerosol studies, at this maximum airborne concentration, based on the Annual Limit on Intake (ALI), the resulting dose equivalents could be either 1 mSv (100 mrem) to the lungs or 0.1 mSv (10 mrem) to the total body. However, the procedures are shared by the technical staff, the times of exposure are represented by only a fraction of the overall procedure time, and the average airborne concentrations were found to be more than an order of magnitude lower than the maximum. This resulted in a projected average annual dose equivalent of 7.0 × 10 mSv (0.7 mrem) to the lungs or 7.0 × 10 mSv (0.07 mrem) to the whole body from the performance of these procedures.


Vascular accumulation of a novel photosensitizer, MV6401, causes selective thrombosis in tumor vessels after photodynamic therapy.
The antivascular effects of photodynamic therapy (PDT) and their mechanisms are not clearly understood. Here, we examined the effects of PDT with a novel photosensitizer MV6401 on the microvasculature in a mammary tumor (MCaIV) grown in a murine dorsal skinfold chamber and in normal tissue controls. The mice were irradiated with light 15 min after i.v. administration of MV6401 when the drug was localized only in the vascular compartment, as shown by fluorescence microscopy and immunohistochemistry. PDT with MV6401 caused a dose-dependent biphasic blood flow stasis and vascular hyperpermeability, as determined by intravital microscopy. This biphasic response was classified into two components: (a) an acute response observed immediately after PDT; and (b) a long-term response observed at times greater than 3 h after PDT. The acute temporal vascular effects were characteristic of vasoconstriction but not of thrombus formation. However, the long-term vascular shutdown was mediated by thrombus formation, as evidenced by histological evaluation and inhibition with heparin. Minimal effects were observed in normal vessels after antivascular doses used against the tumor, but there was no long-term vascular damage. In concert with the stasis, a dose-dependent tumor growth delay was observed. This study provides mechanistic insights into antitumor vascular effects of PDT and suggests novel strategies for tumor treatment with PDT.


Molecular mechanism of viscoelastic polymer enhanced oil recovery in nanopores.
Polymer flooding is a promising chemical enhanced oil recovery (EOR) method, which realizes more efficient extraction in porous formations characterized with nanoscale porosity and complicated interfaces. Understanding the molecular mechanism of viscoelastic polymer EOR in nanopores is of great significance for the advancement of oil exploitation. Using molecular dynamics simulations, we investigated the detailed process of a viscoelastic polymer displacing oil at the atomic scale. We found that the interactions between polymer chains and oil provide an additional pulling effect on extracting the residual oil trapped in dead-end nanopores, which plays a key role in increasing the oil displacement efficiency. Our results also demonstrate that the oil displacement ability of polymer can be reinforced with the increasing chain length and viscoelasticity. In particular, a polymer with longer chain length exhibits stronger elastic property, which enhances the foregoing pulling effect. These findings can help to enrich our understanding on the molecular mechanism of polymer enhanced oil recovery and provide guidance for oil extraction engineering.


National adverse drug reaction surveillance: 1985.
The Food and Drug Administration received about 37,000 adverse drug reaction reports in 1985. Seventy-one percent of the reports involved toxic reactions to usual doses of drugs and were sent by medical care professionals directly to the Food and Drug Administration or to pharmaceutical manufacturers. In terms of severity, 2% of reports involved death while 21% involved hospitalization. The highest proportions of hospitalization or death were found for reports describing cardiovascular, hematologic, or respiratory effects. Nearly half of the reported deaths were in patients more than 59 years of age. The majority of reports described an adverse drug reaction occurring within two weeks of initial exposure to the suspected drug. Adverse drug reaction reporting by physicians is crucial to ensuring that pharmaceutical products are used appropriately.


Knowns and unknowns in the future of multiple sclerosis treatment.
Multiple sclerosis is a chronic disease confined to the central nervous system. Its pathological hallmarks are neuroinflammation, de- and re-myelination, neurodegeneration and astrogliosis. The aetiology of multiple sclerosis is unknown, although a growing body of evidence supports an autoimmune pathogenesis triggered by environmental factors in genetically susceptible individuals. It is therefore perhaps unsurprising that immunomodulatory therapies have now been the mainstay of pharmacotherapy and the focus for the search for a cure for many decades. Currently, clinicians have access to two distinct treatment strategies, namely general immunomodulation or immunosuppression. During the last two decades, several immunomodulatory agents and one immunosuppressant drug have been shown to be effective in clinical trials and have been approved on this basis for the treatment of multiple sclerosis. Current drugs offer well-established safe and effective therapeutic agents for multiple sclerosis in both the short and long term. More recently, growing knowledge of specific anatomical, cellular and molecular targets that play critical roles in the inflammatory cascade of multiple sclerosis have shifted the focus of drug development towards specific targets. Future multiple sclerosis therapies arising from this research may offer better suppression of disease activity, but may be associated with potentially severe side-effects in some patients that may be difficult to manage. In the near future, better understanding of the pathogenesis of multiple sclerosis will probably allow the development of even more effective agents for all clinical phenotypes of the disease. Future therapeutic agents will also have to be designed to address the neurodegenerative component of the physiopathology of multiple sclerosis.


Humoral immune response of the duck to duck hepatitis virus: virus-neutralizing vs. virus-precipitating antibodies.
Ducks were induced to develop high-level duck hepatitis virus (DHV)-neutralizing antibodies by inculation with a chicken-embryo-adapted DHV via subcutaneous, intramuscular, and intratracheal routes. Administration of the DHV orally in a gelatin capsule failed to stimulate immune response in the ducks. Contact controls of these ducks also remained negative for anti-DHV antibodies. These observations indicated that the DHV administered orally, in gelatin capsule, failed to infect the ducks. None of numerous duck anti-DHV immune sera, with virus-neutralizing activity in the range of 1.8 to 5.57 log10 median- embryo-infective-dose (EID50) neutralization index, developed precipitin lines against a variety of DHV preparations tested in low- and high-ionic-strength agar. The results suggest that the agar-gel immunodiffusion test is unsuitable for serologic testing of duck sera for anti-DHV antibody activity. Virus-neutralizing activity was revealed in both immunoglobulin M (IgM) and IgG classes of sera of actively immunized ducks. Immunodiffusion tests of Sephadex G-200 fractions of 1-day-old duckling sera with monospecific rabbit anti-duck IgM (DIgM) serum failed to detect DIgM. These results demonstrated that the IgM is not being transferred from the dam to the newly hatched ducklings. Seven- and 14-day-old ducks had DIgM in their sera. However, this IgM had no DHV-neutralizing activity, indicating that it was newly developed by the ducklings, which had no active DHV immune response, not having been exposed to DHV.