Air pollution threatens the health of children in China.
. China's rapid economic development has come at the cost of severe environmental degradation, most notably from coal combustion. Outdoor air pollution is associated with >300000 deaths, 20 million cases of respiratory illness, and a health cost of >500 billion renminbi (>3% of gross domestic product) annually. The young are particularly susceptible to air pollution, yet there has been only limited recognition of its effects on children's health and development. DATA SOURCES/DATA EXTRACTION: To fill this gap, we reviewed relevant published environmental studies, biomedical and molecular/epidemiologic research, and economic and policy analyses. China relies on coal for approximately 70% to 75% of its energy needs, consuming 1.9 billion tons of coal each year. In addition to CO(2), the major greenhouse gas, coal burning in China emits vast quantities of particulate matter, polycyclic aromatic hydrocarbons, sulfur dioxide, arsenic, and mercury. Automobiles emit nitrogen dioxide and benzene in addition to particulate matter and polycyclic aromatic hydrocarbons. Seventy percent of Chinese households burn coal or biomass for cooking and heating, which contaminates indoor air. Adverse effects of combustion-related air pollution include reduced fetal and child growth, pulmonary disease including asthma, developmental impairment, and increased risk of cancer. A prospective molecular epidemiologic study of newborns in Chongqing has demonstrated direct benefits to children's health and development from the elimination of a coal-burning plant. Recognition of the full health and economic cost of air pollution to Chinese children and the benefits of pollution reduction should spur increased use of renewable energy, energy efficiency, and clean-fuel vehicles. This is a necessary investment for China's future.


Updated Survey of Social Media Use by Members of the American Urological Association.
We performed a more detailed, updated analysis of social media use by AUA members. Specifically we sought to characterize the frequency of and reason for using different social media platforms as well as barriers to social media use. From November to December 2013 we sent a 21-item survey on social media use to 16,376 AUA members with a valid email address. A total of 1,114 members (6.8%) completed the survey. Responses were tallied and statistical analysis was performed to evaluate use patterns based on demographic characteristics. Overall 71% of AUA members who responded to the survey currently had a social media account. The most popular social media platform was Facebook® (89% of respondents), followed by LinkedIn® (59%), YouTube™ (54%), Twitter® (48%) and Google+™ (35%). All platforms except LinkedIn were used primarily for personal reasons. Fewer than a third of respondents had viewed an AUA social media site and 35% of physician respondents participated in a physician-only social media community. Among respondents who did not use social media the most common reasons were no perception of added value and privacy concerns. Although most AUA respondents are involved in social media, they primarily use social media for personal reasons. There remains significant potential for growth and education on the usefulness of social media for urologists in the professional setting.


Comparative reliability analyses of zirconium oxide and lithium disilicate restorations in vitro and in vivo.
The authors analyzed the in vitro and in vivo performance of lithium disilicate glass-ceramic (LDGC) restorations and yttria-stabilized tetragonal zirconia polycrystalline (Y-TZP) (that is, zirconium oxide) restorations with regard to reliability, clinical performance and abrasion resistance. In the in vitro study, four authors subjected samples of LDGC, Y-TZP and metal-ceramic crowns to step-stress fatigue testing. Four investigators assessed the in vivo clinical performance of LDGC and zirconium oxide-based restorations at four and seven years, respectively. In addition, one author conducted a randomized, controlled clinical trial to analyze the volumetric loss of enamel and ceramic antagonist surfaces. The LDGC crowns exhibited the highest fatigue load-to-failure values in the in vitro analysis. The results of the in vivo assessment showed that the clinical performance of the LDGC restorations at four years was comparable to that of the zirconium oxide-based crowns at seven years. The results of the in vivo, randomized, controlled clinical trial showed that LDGC crowns were not only resistant to wear, but also were wear friendly to enamel antagonist surfaces. The LDGC crowns in the in vitro and in vivo studies exhibited high durability, and they were wear friendly to opposing natural dentition. LDGC and zirconium oxide-based crowns are a clinically acceptable means of treating teeth that require full-coverage restorations. In addition, LDGC materials exhibit excellent clinical performance, as well as demonstrate acceptable abrasion compatibility with the opposing natural dentition.


Causal relationship between the loss of RUNX3 expression and gastric cancer.
Runx3/Pebp2alphaC null mouse gastric mucosa exhibits hyperplasias due to stimulated proliferation and suppressed apoptosis in epithelial cells, and the cells are resistant to growth-inhibitory and apoptosis-inducing action of TGF-beta, indicating that Runx3 is a major growth regulator of gastric epithelial cells. Between 45% and 60% of human gastric cancer cells do not significantly express RUNX3 due to hemizygous deletion and hypermethylation of the RUNX3 promoter region. Tumorigenicity of human gastric cancer cell lines in nude mice was inversely related to their level of RUNX3 expression, and a mutation (R122C) occurring within the conserved Runt domain abolished the tumor-suppressive effect of RUNX3, suggesting that a lack of RUNX3 function is causally related to the genesis and progression of human gastric cancer.


Bioavailability and catalytic properties of copper and iron for Fenton chemistry in human cerebrospinal fluid.
A breakdown in homeostasis of redox-active metals represents an important factor for neurodegeneration. We have used EPR spectroscopy and BMPO spin-trap to investigate the catalytic properties and ligand modulation of redox activity of copper and iron in human cerebrospinal fluid (CSF). In contrast to iron, copper supplementation provoked a statistically significant increase in hydroxyl free radical generation in CSF treated with H(2)O(2). However, in a binary copper/iron containing Fenton system, iron catalytically activated copper. The chelator EDTA, which represents a model of physiological metal ligands, completely prevented copper's redox activity in CSF, while iron chelation led to a significant increase in hydroxyl radical generation, indicating that copper and iron do not only have diverse catalytic properties in the CSF but also that their redox activities are differently modulated by ligands. The application of DDC reduced hydroxyl radical generation in the CSF containing catalytically active metals (free Cu(2+) or Fe(3+)-EDTA complex). We conclude that chelators, such as DDC, are capable of preventing the prooxidative activity of both metals and may be suitable for reducing hydroxyl radical formation in certain pathophysiological settings.


Quantifying the use of connected digital products in clinical research.
Over recent years, the adoption of connected technologies has grown dramatically, with potential for improving health care delivery, research, and patient experience. Yet, little has been documented about the prevalence and use of connected digital products (e.g., products that capture physiological and behavioral metrics) in formal clinical research. Using 18 years of data from ClinicalTrials.gov, we document substantial growth in the use of connected digital products in clinical trials (~34% CAGR) and show that these products have been used across all phases of research and by a diverse group of trial sponsors. We identify four distinct use cases for how such connected products have been integrated within clinical trial design and suggest implications for various stakeholders engaging in clinical research.


Validation of delayed sentinel lymph node mapping for melanoma.
Sentinel lymph node mapping using radiolabeled tracer and blue dye is widely accepted and applied for staging melanoma. Common practice involves injection of radiolabeled tracer on the morning of surgery. However, optimal timing of radiolabeled colloid injection with respect to surgery remains debated. Injection on the day before surgery would offer the advantages of increased scheduling flexibility and decreased radiation exposure to the patient and operating room staff. We hypothesized that a single injection of radiolabeled colloid given 24 hours before surgery would be sufficient and would possibly improve intraoperative sentinel lymph node identification. Ninety-five patients with newly diagnosed cutaneous melanoma underwent injection of radiolabeled colloid and lymphoscintigraphy 18 to 24 hours before surgery for sentinel lymph node mapping and biopsy. Sixty-three patients underwent repeat imaging immediately before surgery, and the images were compared with those obtained the previous day. Intraoperative mapping utilized a hand-held gamma probe and injection of blue dye to identify sentinel lymph nodes. Two hundred fifty-one sentinel lymph nodes were identified by initial lymphoscintigraphy in 95 patients. Delayed imagingwithout reinjection of radiolabeled tracer compared with the initial lymphoscintigraphy demonstrated no change (71%), clarification of initial ambiguous patterns (10%), or newly identified nodes (19%). Two hundred sixty-one sentinel lymph nodes were resected, of which 79% stained blue. Microscopic metastases were present in 20 sentinel lymph nodes (8%) in 19 patients (20%). All positive nodes contained radioactivity and blue dye. A single injection of radiocolloid 24 hours before surgery combined with intraoperative blue dye injection identified all sentinel lymph nodes and did not miss any metastatic disease. In addition, delayed imaging may clarify initial ambiguous findings and identify additional nodes at risk for metastasis. This technique produces sentinel lymph node identification rates, harvest rates, and rates of positivity comparable to those reported with the use of injection of radiolabeled tracer on the day of surgery and greatly facilitates the technical and administrative aspects of sentinel lymph node mapping.


Central growth hormone signaling is not required for the timing of puberty.
Growth hormone (GH) is a key factor in the regulation of body growth, as well as a variety of other cellular and metabolic processes. Neurons expressing kisspeptin and leptin receptors (LepR) have been shown to modulate the hypothalamic-pituitary-gonadal (HPG) axis and are considered GH-responsive. The presence of functional GH receptors (GHR) in these neural populations suggests that GH may regulate the HPG axis via a central mechanism. However, there have been no studies evaluating whether or not GH-induced intracellular signaling in the brain plays a role in the timing of puberty or mediates the ovulatory cycle. Towards the goal of understanding the influence of GH on the central nervous system as a mediator of reproductive functions, GHR ablation was induced in kisspeptin and LepR expressing cells or in the entire brain. The results demonstrated that GH signaling in specific neural populations can potentially modulate the hypothalamic expression of genes related to the reproductive system or indirectly contribute to the progression of puberty. GH action in kisspeptin cells or in the entire brain was not required for sexual maturation. On the other hand, GHR ablation in LepR cells delayed puberty progression, reduced serum leptin levels, decreased body weight gain and compromised the ovulatory cycle in some individuals, while the lack of GH effects in the entire brain prompted shorter estrous cycles. These findings suggest that GH can modulate brain components of the HPG axis, although central GH signaling is not required for the timing of puberty.


Characterization of pp85, a target of oncogenes and growth factor receptors.
An 85,000-molecular-weight polypeptide (85K polypeptide) has previously been identified as a common substrate for tyrosine phosphorylation upon polyomavirus middle T transformation or upon platelet-derived growth factor stimulation of 3T3 cells. In each case, pp85 has an associated phosphatidylinositol kinase activity. The tissue distribution of pp85 was determined by middle T blotting experiments; the highest levels were found in brain, lung, and spleen tissues. High-resolution examination of 85K by isoelectric focusing demonstrated that there are at least 10 different forms. These were resolved into two families, 85K and 86K; the ratio of the two families changed in different cells. Similar forms were found for pp85 associated with pp60v-src. Individual species within each family differed by phosphorylation. Analysis of pp85 and pp86 by immunoprecipitation with anti-phosphotyrosine antibody showed increasing phosphorylation in response to middle T or pp60v-src transformation. The association of middle T with pp85 and pp60c-src was examined in pulse-chase experiments. Association of middle T with pp60c-src was slow and was accompanied by progressive modification of middle T. pp85 formed a dissociable complex with middle T within 2.5 min.


Effects of deployment on diet quality and nutritional status markers of elite U.S. Army special operations forces soldiers.
Special Operations Forces (SOF) Soldiers deploy frequently and require high levels of physical and cognitive performance. Nutritional status is linked to cognitive and physical performance. Studies evaluating dietary intake and nutritional status in deployed environments are lacking. Therefore, this study assessed the effects of combat deployment on diet quality and serum concentrations of nutritional status markers, including iron, vitamin D, parathyroid hormone (PTH), glucose, and lipids, among elite United States (U.S.) Army SOF Soldiers. Changes from baseline to post-deployment were determined with a repeated measure within-subjects design for Healthy Eating Index-2010 (HEI-2010) scores, intake of foods, food groups, key nutrients, and serum nutritional status markers. Dietary intake was assessed with a Block Food Frequency Questionnaire. The association between post-deployment serum 25-hydroxy vitamin D (25-OH vitamin D) and PTH was determined. Analyses of serum markers were completed on 50 participants and analyses of dietary intake were completed on 33 participants. In response to deployment, HEI-2010 scores decreased for total HEI-2010 (70.3 ± 9.1 vs. 62.9 ± 11.1), total fruit (4.4 ± 1.1 vs. 3.7 ± 1.5), whole fruit (4.6 ± 1.0 vs. 4.2 ± 1.4), dairy (6.2 ± 2.7 vs. 4.8 ± 2.4), and empty calories (14.3 ± 3.2 vs. 11.1 ± 4.5) (P ≤ 0.05). Average daily intakes of foods and food groups that decreased included total dairy (P < 0.01), milk (P < 0.01), and non-juice fruit (P = 0.03). Dietary intake of calcium (P = 0.05) and vitamin D (P = 0.03) decreased. PTH increased from baseline (3.4 ± 1.6 vs. 3.8 ± 1.4 pmol/L, P = 0.04), while there was no change in 25-OH vitamin D. Ferritin decreased (385 ± 173 vs. 354 ± 161 pmol/L, P = 0.03) and soluble transferrin receptor increased (16.3 ± 3.7 vs. 17.1 ± 3.5 nmol/L, P = 0.01). There were no changes in glucose or lipids. Post-deployment, serum 25-OH vitamin D was inversely associated with PTH (r = -0.43, P < 0.01). HEI-2010 scores and dietary intake of milk, calcium, and vitamin D decreased following deployment. Serum PTH increased and iron stores were degraded. No Soldiers were iron deficient. Personnel that deploy frequently should maintain a high diet quality in the U.S. and while deployed by avoiding empty calories and consuming fruits, vegetables, and adequate sources of calcium, vitamin D, and iron. Improving availability and quality of perishable food during deployment may improve diet quality.


Long-term functional outcomes after laparoscopic and open rectopexy for the treatment of rectal prolapse.
Laparoscopic rectopexy to treat full-thickness rectal prolapse has proven short-term benefits, but there is little long-term follow-up and functional outcome data available. Patients who had abdominal surgery for prolapse during a ten-year period were identified and interviewed to ascertain details of prolapse recurrence, constipation, incontinence, cosmesis, and satisfaction. Additional details on recurrences that required surgery and mortality were obtained from chart review and the State Death Registry. Of 321 prolapse operations, laparoscopic rectopexy was performed in 126 patients, open rectopexy in 46, and resection rectopexy in 21 patients. At a median follow-up of five years after laparoscopic rectopexy, there were five (4 percent) confirmed full-thickness recurrences that required surgery. Actuarial recurrence rates of laparoscopic rectopexy were 6.9 percent at five years (95 percent confidence interval, 0.1-13.8 percent) and 10.8 percent at ten years (95 percent confidence interval, 0.9-20.1 percent). Seven patients underwent rubber band ligation for mucosal prolapse and seven required other surgical procedures. There was one recurrence after open rectopexy (2.4 percent) and one after resection rectopexy (4.7 percent), and there was no significant difference between groups. Overall constipation scores were not increased after laparoscopic rectopexy, with no significant difference to open rectopexy or resection rectopexy. This study has demonstrated that laparoscopic rectopexy has reliable long-term results for treating rectal prolapse, including low recurrence rates and no overall change in functional outcomes.


Covalent cross-linking as a strategy to generate novel materials based on layered (2D) and other low D structures.
Covalent linking of 2D structures such as graphene, MoS2 and C3N4 by employing coupling reactions provides a strategy to generate a variety of materials with new or improved properties. These materials in a way provide the counter point based on covalent bonds to the van der Waals heterostructures. In this article, we describe materials obtained by linking graphene, MoS2 and BN with other layered structures and also with one-dimensional nanotubes and zero-dimensional MOFs and MOPs. Novel properties of the materials relate not only to porosity, surface area and gas adsorption, but also to supercapacitor characterstics, mechanical properties and the hydrogen evolution reaction. It should be possible to discover many more interesting structures and materials by employing the cross-linking strategy described here.


Neurokinin receptors subserving bronchoconstriction.
Tachykinin receptor subtypes were initially defined using agonist potency rations for the endogenous ligands substance P (SP), neurokinin (NK) A, and NKB. On this basis it was suggested that there are three tachykinin receptor subtypes. These subtypes were designated NK1, NK2, and NK3, where SP is most potent at NK1 receptors, NKA is most potent at NK2 receptors, and NKB is most potent at NK3 receptors. Recently analogs of the endogenous ligands that show greater selectivity (about 1000-fold) for the different receptor subtype have been developed. In addition selective antagonists, which are either nonpeptides or modified peptides, for the receptor subtypes have been developed. This minireview concentrates on the wealth of new knowledge concerning the tachykinin receptor subtypes subserving bronchoconstriction in several mammalian species, including man, provided by the use of these selective agonists and antagonists.


Radiobiological and dosimetric analysis of daily megavoltage CT registration on adaptive radiotherapy with Helical Tomotherapy.
Pre-treatment patient repositioning in highly conformal image-guided radiation therapy modalities is a prerequisite for reducing setup uncertainties. In Helical Tomotherapy (HT) treatment, a megavoltage CT (MVCT) image is usually acquired to evaluate daily changes in the patient's internal anatomy and setup position. This MVCT image is subsequently compared to the kilovoltage CT (kVCT) study that was used for dosimetric planning, by applying a registration process. This study aims at investigating the expected effect of patient setup correction using the Hi-Art tomotherapy system by employing radiobiological measures such as the biologically effective uniform dose (D) and the complication-free tumor control probability (P(+)). A new module of the Tomotherapy software (TomoTherapy, Inc, Madison, WI) called Planned Adaptive is employed in this study. In this process the delivered dose can be calculated by using the sinogram for each delivered fraction and the registered MVCT image set that corresponds to the patient's position and anatomical distribution for that fraction. In this study, patients treated for lung, pancreas and prostate carcinomas are evaluated by this method. For each cancer type, a Helical Tomotherapy plan was developed. In each cancer case, two dose distributions were calculated using the MVCT image sets before and after the patient setup correction. The fractional dose distributions were added and renormalized to the total number of fractions planned. The dosimetric and radiobiological differences of the dose distributions with and without patient setup correction were calculated. By using common statistical measures of the dose distributions and the P(+) and D concepts and plotting the tissue response probabilities vs. D a more comprehensive comparison was performed based on radiobiological measures. For the lung cancer case, at the clinically prescribed dose levels of the dose distributions, with and without patient setup correction, the complication-free tumor control probabilities, P(+) are 48.5% and 48.9% for a D(ITV) of 53.3 Gy. The respective total control probabilities, P(B) are 56.3% and 56.5%, whereas the corresponding total complication probabilities, P(I) are 7.9% and 7.5%. For the pancreas cancer case, at the prescribed dose levels of the two dose distributions, the P(+) values are 53.7% and 45.7% for a D(ITV) of 54.7 Gy and 53.8 Gy, respectively. The respective P(B) values are 53.7% and 45.8%, whereas the corresponding P(I) values are ~0.0% and 0.1%. For the prostate cancer case, at the prescribed dose levels of the two dose distributions, the P(+) values are 10.9% for a D(ITV) of 75.2 Gy and 11.9% for a D(ITV) of 75.4 Gy, respectively. The respective P(B) values are 14.5% and 15.3%, whereas the corresponding P(I) values are 3.6% and 3.4%. Our analysis showed that the very good daily patient setup and dose delivery were very close to the intended ones. With the exception of the pancreas cancer case, the deviations observed between the dose distributions with and without patient setup correction were within ±2% in terms of P(+). In the radiobiologically optimized dose distributions, the role of patient setup correction using MVCT images could appear to be more important than in the cases of dosimetrically optimized treatment plans were the individual tissue radiosensitivities are not precisely considered.


Lifetime shift work exposure: association with anthropometry, body composition, blood pressure, glucose and heart rate variability.
To evaluate the association between lifetime exposure to shift work and blood pressure, fasting glucose (FG), anthropometric variables, body composition and heart rate variability (HRV). Male shift workers (N=438) were evaluated using principal component (PC) analysis. The variables used were: weight, body mass index (BMI), waist circumference (WC), neck circumference (NC), hip circumference (HC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), body fat mass (BFKg), body fat percentage (BF%), visceral fat area (VFA), FG, systolic (SBP) and diastolic blood pressure (DBP), and HRV variables. ECG was performed, extracting heart rate (HR), root mean square of the successive differences (RMSSD), high frequency (HF), low frequency (LF) and the LF/HF ratio. Using linear regression models, the lifetime shift work exposure was associated with each PC. Five PCs were obtained, which accounted for 79.6% of the total variation of the data. PC1 (weight, BMI, WC, NC, HC, WHR, WHtR, BFKg, BF% and VFA) was designated as body obesity; PC2 (HF, RMSSD and LF) as good cardiac regulation; PC3 (SBP and DBP) as blood pressure; PC4 (LF/HF ratio and HR) as bad cardiac regulation and PC5 (WHR and FG) as insulin resistance. After age adjustment, the regression analysis showed that lifetime shift work was negatively associated with PC2 and positively associated with PC3. The association of lifetime shift work exposure with PC2 and PC3 suggests that shift work promotes unfavourable changes in autonomic cardiac control related to a decrease in parasympathetic modulation and an increase in blood pressure.


Optic nerve head blood speed as a function of age in normal human subjects.
We used the laser Doppler technique to determine the relation between age and the speed of blood cells moving through the capillaries of the optic nerve head. We studied 22 normal human volunteers ranging in age from 16-76 years. The results were best described by a statistically significant quadratic relationship between capillary blood speed and age. Blood speeds were lowest in the youngest and oldest subjects and highest in subjects between 27 and 35 years old. A two-phase linear model showed a statistically significant 20% decrease in blood speed in volunteers between the ages of 31 and 76. The results were not affected by gender, degree of refractive error, systemic blood pressure, intraocular pressure, cup/disc ratio of the optic nerve head, or by site-to-site differences in the light scattering properties of the optic nerve head tissue. Capillary blood speed was, on average, 15% greater from temporal sites than from nasal sites, corresponding to the equally greater distribution of ganglion cell axons within the same area. The results provide a baseline of normal age-controlled data that can be compared to measurements obtained from patients with disorders of the optic nerve head thought to have a vascular etiology.


Detecting signatures of past pathogen selection on human HLA loci: are there needles in the haystack?
Human leucocyte antigens (HLAs) are responsible for the display of peptide fragments for recognition by T-cell receptors. The gene family encoding them is thus integral to human adaptive immunity, and likely to be under strong pathogen selection. Despite this, it has proved difficult to demonstrate specific examples of pathogen-HLA coevolution. Selection from multiple pathogens simultaneously could explain why the evolutionary signatures of particular pathogens on HLAs have proved elusive. Here, we present an individual-based model of HLA evolution in the presence of two mortality-causing pathogens. We demonstrate that it is likely that individual pathogen species causing high mortality have left recognizable signatures on the HLA genomic region, despite more than one pathogen being present. Such signatures are likely to exist at the whole-population level, and involve haplotypic combinations of HLA genes rather than single loci.


Improving transportation networks: Effects of population structure and decision making policies.
Transportation networks are one of the fundamental tools for human society to work, more so in our globalized world. The importance of a correct, efficient design of a transportation network for a given region or country cannot be overstated. We here study how network design is affected by the geography of the towns or nuclei to be connected, and also by the decision process necessary to choose which connections should be improved (in a generic sense) first. We begin by establishing that Delaunay networks provide an efficient starting point for the network design and at the same time allow us to introduce a computationally amenable model. Subsequent improvements lead to decentralized designs in geographies where towns are more or less homogeneously distributed, whereas radial designs arise when there is a core-periphery distribution of nodes. We also show that optimization of Delaunay networks outperforms that of complete networks at a lower cost, by allowing for a proper selection of the links to improve. In closing, we draw conclusions relevant to policy making applied to designing transportation networks and point our how our study can be useful to identify mechanisms relevant to the historical development of a region.


Insulin release from human pancreatic islets in vitro.
Islets of Langerhans were isolated by collagenase digestion from the pancreas of a 39 year-old female renal transplant donor. The islets were subjected to three consecutive periods of tissue culture, after each of which they were incubated in vitro with various agents whose effects on insulin release from islets of laboratory animals have previously been established. After the first culture period, the basal insulin secretion rate of 5.2 microunits/islet/h seen with 2 mmol/l glucose was increased approx. 5-fold on raising the glucose concentration to 20 mmol/l. The islets retained the insulin-secretory response to 20 mmol/l glucose throughout the period of study. Insulin secretion was also stimulated by mannose, leucine, alpha-ketoisocaproate, dihydroxyacetone and 3-hydroxybutyrate, but not by fructose or N-acetyl-glucosamine. Fructose however increased insulin release in the presence of 4 mmol/l glucose. Caffeine elicited insulin release in the absence of glucose and enhanced insulin release in response to 10 mmol/l glucose. Glucose-stimulated insulin release was inhibited by trifluoperazine (25 mumol/l).


Low-intensity pulsed ultrasonography versus electrical stimulation for fracture healing: a systematic review and network meta-analysis.
To best inform evidence-based patient care, it is often desirable to compare competing therapies. We performed a network meta-analysis to indirectly compare low intensity pulsed ultrasonography (LIPUS) with electrical stimulation (ESTIM) for fracture healing. We searched the reference lists of recent reviews evaluating LIPUS and ESTIM that included studies published up to 2011 from 4 electronic databases. We updated the searches of all electronic databases up to April 2012. Eligible trials were those that included patients with a fresh fracture or an existing delayed union or nonunion who were randomized to LIPUS or ESTIM as well as a control group. Two pairs of reviewers, independently and in duplicate, screened titles and abstracts, reviewed the full text of potentially eligible articles, extracted data and assessed study quality. We used standard and network meta-analytic techniques to synthesize the data. Of the 27 eligible trials, 15 provided data for our analyses. In patients with a fresh fracture, there was a suggested benefit of LIPUS at 6 months (risk ratio [RR] 1.17, 95% confidence interval [CI] 0.97-1.41). In patients with an existing nonunion or delayed union, ESTIM had a suggested benefit over standard care on union rates at 3 months (RR 2.05, 95% CI 0.99-4.24). We found very low-quality evidence suggesting a potential benefit of LIPUS versus ESTIM in improving union rates at 6 months (RR 0.76, 95% CI 0.58-1.01) in fresh fracture populations. To support our findings direct comparative trials with safeguards against bias assessing outcomes important to patients, such as functional recovery, are required.


MRI/PET nonrigid breast-image registration using skin fiducial markers.
We propose a finite-element method (FEM) deformable breast model that does not require elastic breast data for nonrigid PET/MRI breast image registration. The model is applicable only if the stress conditions in the imaged breast are virtually the same in PET and MRI. Under these conditions, the observed intermodality displacements are solely due the imaging/reconstruction process. Similar stress conditions are assured by use of an MRI breast-antenna replica for breast support during PET, and use of the same positioning. The tetrahedral volume and triangular surface elements are used to construct the FEM mesh from the MRI image. Our model requires a number of fiducial skin markers (FSM) visible in PET and MRI. The displacement vectors of FSMs are measured followed by the dense displacement field estimation by first distributing the displacement, vectors linearly over the breast surface and then distributing them throughout the volume. Finally, the floating MRI image is warped to a fixed PET image, by using an appropriate shape function in the interpolation from mesh nodes to voxels. We tested our model on an elastic breast phantom with simulated internal lesions and on a small number of patients imaged, with FMS using PET and MRI. Using simulated lesions (in phantom) and real lesions (in patients) visible in both PET and MRI, we established that the target registration error (TRE) is below two pet voxels.


Rev-erbalpha, a heme sensor that coordinates metabolic and circadian pathways.
The circadian clock temporally coordinates metabolic homeostasis in mammals. Central to this is heme, an iron-containing porphyrin that serves as prosthetic group for enzymes involved in oxidative metabolism as well as transcription factors that regulate circadian rhythmicity. The circadian factor that integrates this dual function of heme is not known. We show that heme binds reversibly to the orphan nuclear receptor Rev-erbalpha, a critical negative component of the circadian core clock, and regulates its interaction with a nuclear receptor corepressor complex. Furthermore, heme suppresses hepatic gluconeogenic gene expression and glucose output through Rev-erbalpha-mediated gene repression. Thus, Rev-erbalpha serves as a heme sensor that coordinates the cellular clock, glucose homeostasis, and energy metabolism.


A Meta-Analysis of the Efficacy of Case Management for Substance Use Disorders: A Recovery Perspective.
Background: Case management is a client-centered approach to improve the coordination and continuity of service delivery, especially for persons with substance use disorders (SUD) and multiple and complex support needs. This intervention supports individuals by helping them identify needed services, facilitate linkage with services, and promote participation and retention in services. However, it is questionable whether case management is equally effective in promoting recovery and aspects of personal functioning. The objective was to conduct an updated meta-analysis and to assess whether case management was more effective than treatment as usual (TAU) among persons with SUD for improving treatment-related (e.g., successful linkage with and retention in treatment) as well as personal functioning outcomes (e.g., substance use). Methods: This meta-analysis focuses on randomized controlled trials (RCTs) that included persons with alcohol or drug use disorders and compared case management with TAU. To be eligible, interventions had to meet core case management functions as defined in the literature. We conducted searches of the following databases to May 2017: the Cochrane Drugs and Alcohol Specialized Register, CENTRAL, PubMed, Embase, CINAHL, and Web of Science. Also, reference lists of retrieved publications were scanned for relevant (un)published studies. Results: The overall effect size for case management compared to TAU across all outcome categories and moments was small and positive (SMD = 0.18, 95% CI 0.07-0.28), but statistically significant. Effects were considerably larger for treatment tasks (SMD = 0.33, 95% CI 0.18-0.48) than for personal functioning outcomes (SMD = 0.06, 95% CI -0.02 to 0.15). The largest effect sizes were found for retention in substance abuse treatment and linkage with substance abuse services. Moderator effects of case management models and conditions were assessed, but no significant differences were observed. Conclusions: The primary results from earlier meta-analyses were supported: case management is more effective than TAU conditions for improving outcomes, but this effect is significantly larger for treatment-related tasks than for personal functioning outcomes. Case management can be an important supplement to available services for improving linkage and retention, although further research is needed to assess its potential for supporting recovery from a longitudinal perspective.


Assessment of local pulse wave velocity distribution in mice using k-t BLAST PC-CMR with semi-automatic area segmentation.
Local aortic pulse wave velocity (PWV) is a measure for vascular stiffness and has a predictive value for cardiovascular events. Ultra high field CMR scanners allow the quantification of local PWV in mice, however these systems are yet unable to monitor the distribution of local elasticities. In the present study we provide a new accelerated method to quantify local aortic PWV in mice with phase-contrast cardiovascular magnetic resonance imaging (PC-CMR) at 17.6 T. Based on a k-t BLAST (Broad-use Linear Acquisition Speed-up Technique) undersampling scheme, total measurement time could be reduced by a factor of 6. The fast data acquisition enables to quantify the local PWV at several locations along the aortic blood vessel based on the evaluation of local temporal changes in blood flow and vessel cross sectional area. To speed up post processing and to eliminate operator bias, we introduce a new semi-automatic segmentation algorithm to quantify cross-sectional areas of the aortic vessel. The new methods were applied in 10 eight-month-old mice (4 C57BL/6J-mice and 6 ApoE (-/-)-mice) at 12 adjacent locations along the abdominal aorta. Accelerated data acquisition and semi-automatic post-processing delivered reliable measures for the local PWV, similiar to those obtained with full data sampling and manual segmentation. No statistically significant differences of the mean values could be detected for the different measurement approaches. Mean PWV values were elevated for the ApoE (-/-)-group compared to the C57BL/6J-group (3.5 ± 0.7 m/s vs. 2.2 ± 0.4 m/s, p < 0.01). A more heterogeneous PWV-distribution in the ApoE (-/-)-animals could be observed compared to the C57BL/6J-mice, representing the local character of lesion development in atherosclerosis. In the present work, we showed that k-t BLAST PC-MRI enables the measurement of the local PWV distribution in the mouse aorta. The semi-automatic segmentation method based on PC-CMR data allowed rapid determination of local PWV. The findings of this study demonstrate the ability of the proposed methods to non-invasively quantify the spatial variations in local PWV along the aorta of ApoE (-/-)-mice as a relevant model of atherosclerosis.


Incorporating a quiz into informed consent processes: qualitative study of participants' reactions.
Formal checks of participant understanding are now widely recommended to improve informed consent processes. However, the views of the participants these assessments are designed to protect are rarely considered. In this paper the findings of a qualitative study aimed at documenting community reactions to a semi-structured questionnaire ('quiz') are reported. The quiz was administered to 189 mothers after consenting for their children to participate in a malaria vaccine trial on the Kenyan Coast. Once the malaria vaccine trial was underway, focus group discussions were held with some of these mothers (nine groups; 103 mothers), and with community-based field staff attached to the malaria vaccine trial (two groups of five workers). Individual interviews with other trial staff were also held. The quiz prompted community members to voice concerns about blood sampling and vaccine side-effects, thereby encouraging additional discussions and interactions between the research team and potential study participants. However, it also caused significant upset and concern. Some of the quiz questions, or the way in which they were asked, appeared to fuel misconceptions and fears, with potentially negative consequences for both the study and community members. Formal approaches to checking study understanding should be employed with sensitivity and caution. They are influenced by and impact upon complex social relationships between and among researchers and community members. Adequate consideration of these contexts in assessments of understanding, and in responding to the issues raised, requires strong social science capacity.


Evasion of inflammasome activation by microbial pathogens.
Activation of the inflammasome occurs in response to infection with a wide array of pathogenic microbes. The inflammasome serves as a platform to activate caspase-1, which results in the subsequent processing and secretion of the proinflammatory cytokines IL-1β and IL-18 and the initiation of an inflammatory cell death pathway termed pyroptosis. Effective inflammasome activation is essential in controlling pathogen replication as well as initiating adaptive immune responses against the offending pathogens. However, a number of pathogens have developed strategies to evade inflammasome activation. In this Review, we discuss these pathogen evasion strategies as well as the potential infectious complications of therapeutic blockade of IL-1 pathways.


The association between guideline adherence, age and overall survival among women with non-metastatic breast cancer: A systematic review.
Conformity with treatment guidelines should benefit patients. Studies have reported variation in adherence to breast cancer (BC) guidelines, particularly among older women. This study investigated (i) whether adherence to treatment guideline recommendations for women with non-metastatic BC improves overall survival (OS), (ii) whether that relationship varies by age. MEDLINE and EMBASE were systematically searched for studies on guideline adherence and OS in women with non-metastatic BC, published after January 2000, which examined recommendations on breast surgery, chemotherapy, radiotherapy or endocrine therapy. Study results were summarised using narrative synthesis. Sixteen studies met the inclusion criteria. The recommendations for each treatment covered were similar, but studies differed in their definitions of adherence. 5-year OS rates among patients having compliant treatment ranged from 91.3% to 93.2%, while rates among patients having non-compliant treatment ranged from 75.9% to 83.4%. Six studies reported an adjusted hazard ratio (aHR) for non-compliant treatment compared with compliant treatment; all concluded OS was worse among patients whose overall treatment was non-compliant (aHR range: 1.52 [1.30-1.82] to 2.57 [1.96-3.37]), but adjustment for potential confounders was limited. Worse adherence among older women was reported in 12/16 studies, but they did not provide consistent evidence on whether OS was associated with treatment adherence and age. Individual studies reported that better adherence to guidelines improved OS among women with non-metastatic BC, but the evidence base has weaknesses including inconsistent definitions of adherence. More precise and consistent research designs, including the evaluation of barriers to adherence across the spectrum of healthcare practice, are required to fully understand guideline compliance, as well as the relationship between compliance and OS following a BC diagnosis.


Ontologies relevant to behaviour change interventions: a method for their development.
Background: Behaviour and behaviour change are integral to many aspects of wellbeing and sustainability. However, reporting behaviour change interventions accurately and synthesising evidence about effective interventions is hindered by lacking a shared, scientific terminology to describe intervention characteristics. Ontologies are knowledge structures that provide controlled vocabularies to help unify and connect scientific fields. To date, there is no published guidance on the specific methods required to develop ontologies relevant to behaviour change. We report the creation and refinement of a method for developing ontologies that make up the Behaviour Change Intervention Ontology (BCIO). Aims: (1) To describe the development method of the BCIO and explain its rationale; (2) To provide guidance on implementing the activities within the development method. Method and results: The method for developing ontologies relevant to behaviour change interventions was constructed by considering principles of good practice in ontology development and identifying key activities required to follow those principles. The method's details were refined through application to developing two ontologies. The resulting ontology development method involved: (1) defining the ontology's scope; (2) identifying key entities; (3) refining the ontology through an iterative process of literature annotation, discussion and revision; (4) expert stakeholder review; (5) testing inter-rater reliability; (6) specifying relationships between entities, and; (7) disseminating and maintaining the ontology. Guidance is provided for conducting relevant activities for each step. Conclusions: We have developed a detailed method for creating ontologies relevant to behaviour change interventions, together with practical guidance for each step, reflecting principles of good practice in ontology development. The most novel aspects of the method are the use of formal mechanisms for literature annotation and expert stakeholder review to develop and improve the ontology content. We suggest the mnemonic SELAR3, representing the method's first six steps as Scope, Entities, Literature Annotation, Review, Reliability, Relationships.


Combined intermittent hypoxia and surface muscle electrostimulation as a method to increase peripheral blood progenitor cell concentration.
Our goal was to determine whether short-term intermittent hypoxia exposure, at a level well tolerated by healthy humans and previously shown by our group to increase EPO and erythropoiesis, could mobilize hematopoietic stem cells (HSC) and increase their presence in peripheral circulation. Four healthy male subjects were subjected to three different protocols: one with only a hypoxic stimulus (OH), another with a hypoxic stimulus plus muscle electrostimulation (HME) and the third with only muscle electrostimulation (OME). Intermittent hypobaric hypoxia exposure consisted of only three sessions of three hours at barometric pressure 540 hPa (equivalent to an altitude of 5000 m) for three consecutive days, whereas muscular electrostimulation was performed in two separate periods of 25 min in each session. Blood samples were obtained from an antecubital vein on three consecutive days immediately before the experiment and 24 h, 48 h, 4 days and 7 days after the last day of hypoxic exposure. There was a clear increase in the number of circulating CD34+ cells after combined hypobaric hypoxia and muscular electrostimulation. This response was not observed after the isolated application of the same stimuli. Our results open a new application field for hypobaric systems as a way to increase efficiency in peripheral HSC collection.


Concurrent PEDF deficiency and Kras mutation induce invasive pancreatic cancer and adipose-rich stroma in mice.
Pigment epithelium-derived factor (PEDF), a non-inhibitory SERPIN with potent antiangiogenic activity, has been recently implicated in metabolism and adipogenesis, both of which are known to influence pancreatic cancer progression. Increased pancreatic fat in human pancreatic tumour correlates with greater tumour dissemination while PEDF deficiency in mice promotes pancreatic hyperplasia and visceral obesity. Oncogenic Ras, the most common mutation in pancreatic ductal adenocarcinoma (PDAC), has similarly been shown to promote adipogenesis and premalignant lesions. In order to determine whether concurrent loss of PEDF is sufficient to promote adipogenesis and tumorigenesis in the pancreas, the authors ablated PEDF in an EL-Kras(G12D) mouse model of non-invasive cystic papillary neoplasms. EL-Kras(G12D)/PEDF deficient mice developed invasive PDAC associated with enhanced matrix metalloproteinase (MMP)-2 and MMP-9 expression and increased peripancreatic fat with adipocyte hypertrophy and intrapancreatic adipocyte infiltration (pancreatic steatosis). In support of increased adipogenesis, the stroma of the pancreas of EL-Kras(G12D)/PEDF deficient mice demonstrated higher tissue levels of two lipid droplet associated proteins, tail-interacting protein 47 (TIP47, perilipin 3) and adipose differentiation-related protein (ADRP, Pperilipin 2), while adipose triglyceride lipase, a key factor in lipolysis, was decreased. In patients with PDAC, both tissue and serum levels of PEDF were decreased, stromal TIP47 expression was higher and the tissue VEGF to PEDF ratio was increased (p<0.05). These data highlight the importance of lipid metabolism in the tumour microenvironment and identify PEDF as a critical negative regulator of both adiposity and tumour invasion in the pancreas.


Blood pressure patterns in women with gestational hypertension or mild preeclampsia at term.
Gestational hypertension (GH) and mild preeclampsia (PE) represent the most common medical complications of pregnancy, with the majority of cases developing at or near term. There is little knowledge of the course of blood pressure over time in these women. We explored the pattern of systolic and diastolic blood pressure over time in women with GH or mild PE at term participating in the HYPITAT trial, and we attempted to identify clinical factors influencing these blood pressure patterns and the impact of severe hypertension on clinical management. We used data from the HYPITAT trial, that included women with a singleton pregnancy with a fetus in cephalic position between 36 and 41 weeks of gestation with the diagnosis of GH or mild PE. Blood pressure measurements were performed from randomization or admission until delivery or discharge from the hospital. We included the highest blood pressure of each day. We evaluated systolic and diastolic blood pressure change over time, as well as the influence of clinical characteristics and laboratory findings on the course of blood pressure. We used univariate and multivariate regression analysis with a backward stepwise algorithm for the selection of variables. The model with the best fit (lowest AIC) was selected as the final model. We also compared mode of delivery for women with and without severe hypertension. We studied 1076 women who had 4188 blood pressure measurements done. The systolic blood pressure showed a significant non-linear increase over time and for the diastolic blood pressure the pattern was also non-linear. In the multivariable model of systolic blood pressure change over time, nulliparity, ethnicity, systolic blood pressure (at baseline), BMI and LDH at randomization influenced the course of blood pressure. In the diastolic blood pressure model ALT and the baseline diastolic blood pressure had a significant influence. When we explored the association between blood pressure and mode of delivery, it appeared that development of severe hypertension was a risk factor for Caesarean section. The blood pressure in patients with GH or PE at term showed a non-linear increase with time, which was aggravated by clinical characteristics. Development of severe hypertension was a risk factor for Caesarean section, which may explain the elevated Caesarean section rates in the expectant monitoring group in the HYPITAT trial.


Flavin adenine dinucleotide--dependent monooxygenase: its role in the sulfoxidation of pesticides in mammals.
The flavin adenine dinucleotide--dependent monooxygenase in mammalian hepatic microsomes plays a major role in the oxidative metabolism of thioether-containing pesticides. Thirty-four compounds were tested, and it was determined that organophosphorus insecticides such as disulfoton and phorate are rapidly oxidized by the purified enzyme to their corresponding sulfoxides. The enzyme does not catalyze the oxidation of the thiophosphoryl and thiol sulfur atoms of these or other phosphorothioates and phosphorodithioates, or the oxidation of the sulfoxide to the sulfone. Carbamates aldicarb and Croneton are also oxidized, but at a lower rate.


The secreted antigens of Mycobacterium tuberculosis and their relationship to those recognized by the available antibodies.
Proteins secreted by strains of Mycobacterium tuberculosis during short-term, zinc-sufficient batch culture were identified in order to define antigens likely to be relevant to the pathogenesis of human disease. [35S]Methionine-labelled proteins in supernatants of 4-7 d cultures were separated by PAGE under both denaturing and non-denaturing conditions, and the position of labelled material was determined. Secreted protein patterns of M. tuberculosis were quite similar to those of Bacillus Calmette-Guérin (BCG) but differed by the absence of the 46 kDa dimeric protein specific to BCG and by the presence in large amounts of a 23 kDa protein which, when denatured, gave 13 kDa subunits. This 13 kDa subunit protein constituted up to 20% of secreted proteins in classical strains of M. tuberculosis of phage type B but was not detected in phage type I strains from South India. This may be relevant to the different pathogenicity of these strains. Western blot analysis showed that antigens defined in supernatants of short-term (3 d) cultures of M. tuberculosis constituted a small subset of those seen in supernatants of organisms cultured for longer periods. One of the secreted proteins has the interesting property of binding to fibronectin. The available monoclonal antibodies and antisera have been used to identify lines on immunoblots corresponding to the secreted/released antigens of M. tuberculosis. The present findings suggest that there are major secreted antigens to which antibodies do not yet appear to have been produced experimentally.


The Phosphatidylinositol 3-Kinase Pathway as a Potential Therapeutic Target in Bladder Cancer.
Purpose: Activation of the PI3K pathway occurs in over 40% of bladder urothelial cancers. The aim of this study is to determine the therapeutic potential, the underlying action, and the resistance mechanisms of drugs targeting the PI3K pathway.Experimental Design: Urothelial cancer cell lines and patient-derived xenografts (PDXs) were analyzed for alterations of the PI3K pathway and for their sensitivity to the small-molecule inhibitor pictilisib alone and in combination with cisplatin and/or gemcitabine. Potential predictive biomarkers for pictilisib were evaluated, and RNA sequencing was performed to explore drug resistance mechanisms.Results: The bladder cancer cell line TCCSUP, which harbors a PIK3CA E545K mutation, was sensitive to pictilisib compared to cell lines with wild-type PIK3CA Pictilisib exhibited stronger antitumor activity in bladder cancer PDX models with PI3KCA H1047R mutation or amplification than the control PDX model. Pictilisib synergized with cisplatin and/or gemcitabine in vitro, significantly delayed tumor growth, and prolonged survival compared with single-drug treatment in the PDX models. The phosphorylation of ribosomal protein S6 correlated with response to pictilisib both in vitro and in vivo, and could potentially serve as a biomarker to predict response to pictilisib. Pictilisib activated the compensatory MEK/ERK pathway that likely contributed to pictilisib resistance, which was reversed by cotreatment with the RAF inhibitor sorafenib. RNA sequencing of tumors resistant to treatment suggested that LSP1 downregulation correlated with drug resistance.Conclusions: These preclinical results provide new insights into the therapeutic potential of targeting the PI3K pathway for the treatment of bladder cancer. Clin Cancer Res; 23(21); 6580-91. ©2017 AACR.


Why "good jobs" are good for retailers.
Too many retail managers believe that they must offer bad jobs to keep prices low. As a result, almost one-fifth of American workers suffer low wages, poor benefits, constantly changing schedules, and few opportunitie for advancement. The author's research reveals, however, that the presumed trade-off between investment in employees and low prices is false. To meet short-term performance targets, many retailers cut labor. The unmotivated and poorly trained employees who remain often cannot keep up with their tasks in a complex operating environment. The result is a vicious cycle, in which lower sales and profits tempt managers to cut even more employees. Retailers such as QuikTrip, Mercadona, Trader Joe's, and Costco instead create a virtuous cycle of investment in employees, stellar operational execution, higher sales and profits, and larger labor budgets. They also make work more efficient and fulfilling for employees, improve customer service, and boost sales and profits through four practices: simplify operations by offering fewer products and promotions, train employees to perform multiple tasks, eliminate waste in everything but staffing, and let employees make some decisions.


Effects of publication bias on conservation planning.
Conservation planners need reliable information on spatial patterns of biodiversity. However, existing data sets are skewed because some ecosystems, taxa, and locations are underrepresented. We determined how many articles have been published in recent decades on the biodiversity of different countries and their constituent provinces. We searched the Web of Science catalogues Science Citation Index (SCI) and Social Science Citation Index (SSCI) for biodiversity-related articles published from 1993 to 2016 that included country and province names. We combined data on research publication frequency with other provincial-scale factors hypothesized to affect the likelihood of research activity (i.e., economic development, human presence, infrastructure, and remoteness). Areas that appeared understudied relative to the biodiversity expected based on site climate likely have been inaccessible to researchers for reasons, notably armed conflict. Geographic publication bias is of most concern in the most remote areas of sub-Saharan Africa and South America. Our provincial-scale model may help compensate for publication biases in conservation planning by revealing the spatial extent of research needs and the low cost of redoing this analysis annually.


Urological involvement in renal transplantation.
Historically, urologists were the primary surgeons in renal transplantation. Specialization and increased complexity of the field of transplantation, coupled with a de-emphasis of vascular surgical training in urology, has created a situation where many renal transplants are carried out by surgeons with a general surgery background. Because of its genitourinary nature, however, urological input in renal transplantation is still vital. For living donors, a urologist should be involved to help evaluate and prepare certain patients for eventual donation. This could involve both medical and surgical intervention. Additionally, urologists who carry out living donor nephrectomy maintain a sense of ownership in the renal transplant process and provide a unique opportunity to the trainees of that particular program. For renal transplant recipients, preoperative evaluation of voiding dysfunction and other genitourinary anomalies might be necessary before the transplant. Also, occasional surgical intervention to prepare a patient for renal transplant might be necessary, such as in a patient with a small renal mass that is detected by a screening pretransplant ultrasound. Intraoperatively, for patients with complex urological reconstructions that might be related to the etiology of the renal failure (urinary diversion, bladder augmentation), a urologist who is familiar with the anatomy should be available. Postoperatively, urological evaluation and intervention might be necessary for patients who had a pre-existing urological condition or who might have developed something de novo after the transplant. Although renal transplant programs could consult an on-call urologist for particular issues on an as-needed basis, having a urologist, who has repeated exposure to the particular issues and procedures that are involved with renal transplantation, and who is part of a dedicated multidisciplinary renal transplant team, provides optimal quality of care to these complex patients.


Electrically elicited visual evoked potentials in Argus II retinal implant wearers.
We characterized electrically elicited visual evoked potentials (eVEPs) in Argus II retinal implant wearers. eVEPs were recorded in four subjects, and analyzed by determining amplitude and latency of the first two positive peaks (P1 and P2). Subjects provided subjective feedback by rating the brightness and size of the phosphenes. We established eVEP input-output relationships, eVEP variability between and within subjects, the effect of stimulating different areas of the retina, and the maximal pulse rate to record eVEPs reliably. eVEP waveforms had low signal-to-noise ratios, requiring long recording times and substantial signal processing. Waveforms varied between subjects, but showed good reproducibility and consistent parameter dependence within subjects. P2 amplitude overall was the most robust outcome measure and proved an accurate indicator of subjective threshold. Peak latencies showed small within-subject variability, yet their correlation with stimulus level and subjective rating were more variable than that of peak amplitudes. Pulse rates of up to (2)/3 Hz resulted in reliable eVEP recordings. Perceived phosphene brightness declined over time, as reflected in P1 amplitude, but not in P2 amplitude or peak latencies. Stimulating-electrode location significantly affected P1 and P2 amplitude and latency, but not subjective percepts. While recording times and signal processing are more demanding than for standard visually evoked potential (VEP) recordings, the eVEP has proven to be a reliable tool to verify retinal implant functionality. eVEPs correlated with various stimulus parameters and with perceptual ratings. In view of these findings, eVEPs may become an important tool in functional investigations of retinal prostheses. (ClinicalTrials.gov number NCT00407602.) Dutch Abstract.


Nuclear matrix. Isolation and characterization of a framework structure from rat liver nuclei.
A nuclear framework structure termed the nuclear matrix has been isolated and characterized. This matrix forms the major residual structure of isolated nuclei and consists largely of protein with smaller amounts of RNA, DNA, carbohydrate, and phospholipid. The nuclear matrix can be further resolved by combined treatment with DNase and RNase. The remaining nuclear protein structure, after extraction of 90 percent of the nuclear protein, 99.9 percent of the DNA, and 98 percent of the RNA and phospholipid, is termed the nuclear protein matrix. Electron microscopy of this final nuclear protein matrix reveals an interior framework structure composed of residual nucleolar structures associated with a granular and fibrous internal matrix structure. The internal matrix framework is derived from the interchromatinic structures of the nucleus, and is connected to a surrounding residual nuclear envelope layer containing residual nuclear pore complex structures. Sodium dodecyl sulfate-acrylamide gel electrophoresis of the nuclear matrix proteins demonstrates three major polypeptide fractions, P-1, P-2, and P-3, with average molecular weights of approximately 69,000, 66,000 and 62,000, as well as several minor polypeptides which migrate at approximately 50,000 and at higher molecular weights (>100,000). Polypeptides with molecular weights identical to those of P-1, P-2 and P-3 are also components of isolated nuclear envelopes and nucleoli, whereas isolated chromatin contains no detectable matrix polypeptides. This suggests that the major matrix polypeptides are localized in specific structural regions of the nucleus, i.e., nuclear envelope, nucleoli, and interchromatinic structures. The presence of cytochrome oxidase activity in the isolated nuclear matrix indicates that at least some integral proteins of the nuclear membrane are associated with the matrix.


Oxygenase domain of Drosophila melanogaster nitric oxide synthase: unique kinetic parameters enable a more efficient NO release.
Although nitric oxide (NO) is important for cell signaling and nonspecific immunity in the fruit fly Drosophila melanogaster, little is known about its single NO synthase (dNOS). We expressed the oxygenase domain of dNOS (dNOSoxy), characterized its spectroscopic, kinetic, and catalytic properties, and interpreted them in light of a global kinetic model for NO synthesis. Single turnover reactions with ferrous dNOSoxy showed it could convert Arg to N'omega-hydroxy-l-arginine (NOHA), or NOHA to citrulline and NO, when it was given 6R-tetrahydrobiopterin and O2. The dNOSoxy catalyzed Arg hydroxylation and NOHA oxidation at rates that matched or exceeded the rates catalyzed by the three mammalian NOSoxy enzymes. Consecutive heme-dioxy, ferric heme-NO, and ferric heme species were observed in the NOHA reaction of dNOSoxy, indicating that its catalytic mechanism is the same as in the mammalian NOS. However, NO dissociation from dNOSoxy was 4 to 9 times faster than that from the mammalian NOS enzymes. In contrast, the dNOSoxy ferrous heme-NO complex was relatively unreactive toward O2 and in this way was equivalent to the mammalian neuronal NOS. Our data show that dNOSoxy has unique settings for the kinetic parameters that determine its NO synthesis. Computer simulations reveal that these unique settings should enable dNOS to be a more efficient and active NO synthase than the mammalian NOS enzymes, which may allow it to function more broadly in cell signaling and immune functions in the fruit fly.


Layering, freezing, and re-entrant melting of hard spheres in soft confinement.
Confinement can have a dramatic effect on the behavior of all sorts of particulate systems, and it therefore is an important phenomenon in many different areas of physics and technology. Here, we investigate the role played by the softness of the confining potential. Using grand canonical Monte Carlo simulations, we determine the phase diagram of three-dimensional hard spheres that in one dimension are constrained to a plane by a harmonic potential. The phase behavior depends strongly on the density and on the stiffness of the harmonic confinement. While we find the familiar sequence of confined hexagonal and square-symmetric packings, we do not observe any of the usual intervening ordered phases. Instead, the system phase separates under strong confinement, or forms a layered re-entrant liquid phase under weaker confinement. It is plausible that this behavior is due to the larger positional freedom in a soft confining potential and to the contribution that the confinement energy makes to the total free energy. The fact that specific structures can be induced or suppressed by simply changing the confinement conditions (e.g., in a dielectrophoretic trap) is important for applications that involve self-assembled structures of colloidal particles.


A Novel Blended Curriculum for Communication of Informed Consent With Surgical Interns.
Interns often conduct procedural informed consent discussions (ICDs), identified as a core entrustable professional activity. Deficiencies in the training process for ICDs span across specialties. We provide evidence for a curriculum and assessment designed to standardize the training process and ensure ICD competency in surgical interns. In March 2019, PowerPoint educational materials were emailed to one academic institution's new surgical interns, who in June participated in an onsite 1-hour role-play "hot seat" group activity (GA) with an untrained simulated patient, and in October completed a single trained simulated patient (real-time raters) verification of proficiency (VOP) assessment. Curriculum evaluation was measured through intern pre-/post-confidence (5-point scale), and the VOP's Cronbach's alpha and test-retest were examined. Data were analyzed with descriptive statistics, paired t tests, and 2-way random effects models. Of 44 new interns, 40 (91%) participated in the remote teaching and live GA and were assessed by the VOP. Pre-/post-GA confidence increased a mean difference of 1.3 (SD = 0.63, P < .001). The VOP's Cronbach's alpha was 0.88 and test-retest was 0.84 (95% CI 0.67-0.93, P < .001), with a 95% pass rate. The 2 first-time fail students required remediation. Time commitment included 1 hour maximum for individual training and implementation and 30 minutes for assessment. The use of volunteers and donated space mitigated additional costs. Remote asynchronous and group skills teaching for new general surgical interns improved their confidence in conducting procedural ICDs. A patient-simulation verification process appeared feasible with preliminary evidence of retest and internal consistency.


Meta-analysis of randomized controlled trials of cranial electrostimulation. Efficacy in treating selected psychological and physiological conditions.
To clarify the diverse published results of cranial electrostimulation (CES) efficacy, we conducted an extensive literature review that identified 18 of the most carefully conducted randomized controlled trials of CES versus sham treatment. For the 14 trials that had sufficient data, we used the techniques of meta-analysis to pool the published results of treating each of four conditions: anxiety (eight trials), brain dysfunction (two trials), headache (two trials), and insomnia (two trials). Because studies utilized different outcome measures, we used an effect size method to normalize measures which we then pooled across studies within each condition. The meta-analysis of anxiety showed CES to be significantly more effective than sham treatment (p < .05). Pooling did not affect results that were individually positive (headache and pain under anesthesia) or negative (brain dysfunction and insomnia). Most studies failed to report all data necessary for meta-analysis. Moreover, in all but two trials, the therapist was not blinded and knew which patients were receiving CES or sham treatment. We strongly recommend that future trials of CES report complete data and incorporate therapist blinding to avoid possible bias.


Timolol and epinephrine in primary open angle glaucoma. Transient additive effect.
A randomized, double-blind clinical study was conducted on patients with primary open angle glaucoma to determine whether timolol and epinephrine have an additive effect in lowering intraocular pressure. Sixteen patients were randomly assigned to one of two treatment sequences (timolol alone, supplemented after two weeks with epinephrine, and vice versa). An initial additive effect in lowering IOP was found in both sequences. However, after several weeks of combined therapy, complete loss of additive effect was found. Patients who were treated first with epinephrine for two weeks and then supplemented with timolol had significantly lower IOPs, for at least two weeks, than patients in the reverse treatment sequence. Epinephrine treatment alone caused a significant increase in facility of outflow, but this effect did not occur with simultaneous timolol treatment. The results are discussed in terms of possible fundamental beta- and alpha-adrenergic influences on aqueous dynamics and their potential clinical relevance.


Risk factors for second screen-detected or interval breast cancers in women with a personal history of breast cancer participating in mammography screening.
Women with a personal history of breast cancer (PHBC) have increased risk of an interval cancer. We aimed to identify risk factors for second (ipsilateral or contralateral) screen-detected or interval breast cancer within 1 year of screening in PHBC women. Screening mammograms from women with history of early-stage breast cancer at Breast Cancer Surveillance Consortium-affiliated facilities (1996-2008) were examined. Associations between woman-level, screen-level, and first cancer variables and the probability of a second breast cancer were modeled using multinomial logistic regression for three outcomes [screen-detected invasive breast cancer, interval invasive breast cancer, or ductal carcinoma in situ (DCIS)] relative to no second breast cancer. There were 697 second breast cancers, of these 240 were interval cancers, among 67,819 screens in 20,941 women. In separate models for women with DCIS or invasive first cancer, first breast cancer surgery predicted all three second breast cancer outcomes (P < 0.001), and high ORs for second breast cancers (between 1.95 and 4.82) were estimated for breast conservation without radiation (relative to mastectomy). In women with invasive first breast cancer, additional variables predicted risk (P < 0.05) for at least one of the three outcomes: first-degree family history, dense breasts, longer time between mammograms, young age at first breast cancer, first breast cancer stage, and adjuvant systemic therapy for first breast cancer; and risk of interval invasive breast cancer was highest in women <40 years at first breast cancer (OR, 3.41; 1.34-8.70), those with extremely dense breasts (OR, 2.55; 1.4-4.67), and those treated with breast conservation without radiation (OR, 2.67; 1.53-4.65). Although the risk of a second breast cancer is modest, our models identify risk factors for interval second breast cancer in PHBC women. Our findings may guide discussion and evaluations of tailored breast screening in PHBC women, and incorporating this information into clinical decision-making warrants further research.


Resistance to Cucumber mosaic virus in Cowpea and Implications for Control of Cowpea Stunt Disease.
Cucumber mosaic virus (CMV) and Blackeye cowpea mosaic virus (BlCMV) interact synergistically in dually infected plants of cowpea (Vigna unguiculata subsp. unguiculata) to cause cowpea stunt disease, the most damaging viral disease of this crop in the U.S. Sources of resistance to BlCMV are known and are present in cultivars of cowpea such as Pinkeye Purple Hull-BVR. However, no sources of CMV resistance have been found previously in cowpea. In 1998, PI 441918, a cowpea line growing in regeneration plots, was observed to have few viral symptoms, was not infected with BlCMV, and had a low titer of CMV when tested using direct antigen coating-enzyme-linked immunosorbent assay (DAC-ELISA). In greenhouse tests, infection of PI 441918 with CMV resulted in a lower titer of virus if the inoculated plants were from white seeds of PI 441918 than if the plants were from tan seeds of this PI, and a lower titer of virus than plants of the susceptible cultivar Coronet. In the field, with CMV- and BlCMV-infected plants of Coronet in spreader rows, plants from white seed of PI 441918 had no infection with BlCMV and a low infection rate with CMV. PI 441918 offers a high level of resistance to BlCMV and moderate resistance to CMV, which are important characteristics in a parental line to develop cultivars of cowpea resistant to cowpea stunt disease.


Hypothalamic-pituitary-adrenal axis and bipolar disorder.
There is robust evidence demonstrating abnormalities of the HPA axis in bipolar disorder. Hypercortisolism may be central to the pathogenesis of depressive symptoms and cognitive deficits, which may in turn result from neurocytotoxic effects of raised cortisol levels. Manic episodes may be preceded by increased ACTH and cortisol levels, leading to cognitive problems and functional impairments. Identification and effective treatment of mood and cognitive symptoms of mood disorders are clinical goals, but currently available treatments may fall short of this ideal. Manipulation of the HPA axis has been shown to have therapeutic effects in preclinical and clinical studies, and recent data suggest that direct antagonism of GRs maybe a future therapeutic strategy in the treatment of mood disorders.


The role of van der Waals and exchange interactions in high-pressure solid hydrogen.
We investigate the van der Waals interactions in solid molecular hydrogen structures. We calculate enthalpy and the Gibbs free energy to obtain zero and finite temperature phase diagrams, respectively. We employ density functional theory (DFT) to calculate the electronic structure and density functional perturbation theory (DFPT) with van der Waals (vdW) functionals to obtain phonon spectra. We focus on the solid molecular C2/c, Cmca-12, P63/m, Cmca, and Pbcn structures within the pressure range of 200 < P < 450 GPa. We propose two structures of the C2/c and Pbcn for phase III which are stabilized within different pressure range above 200 GPa. We find that vdW functionals have a big effect on vibrations and finite-temperature phase stability, however, different vdW functionals have different effects. We conclude that, in addition to the vdW interaction, a correct treatment of the high charge gradient limit is essential. We show that the dependence of molecular bond-lengths on exchange-correlation also has a considerable influence on the calculated metallization pressure, introducing errors of up to 100 GPa.


Extracellular calcium regulates postsynaptic efficacy through group 1 metabotropic glutamate receptors.
Bursts of synaptic transmission are known to induce transient depletion of Ca2+ within the synaptic cleft. Although Ca2+ depletion has been shown to lower presynaptic release probability, effects on the postsynaptic cell have not been reported. In this study, we show that physiologically relevant reductions in extracellular Ca2+ lead to a decrease in synaptic strength between synaptically coupled layer 2/3 cortical pyramidal neurons. Using quantal analysis and mEPSP analysis, we demonstrate that a lowered extracellular Ca2+ produces a reduction in the postsynaptic quantal size in addition to its known effect on release probability. An elevated Mg2+ level can prevent this reduction in postsynaptic efficacy at subphysiological Ca2+ levels. We show that the calcium-dependent effect on postsynaptic quantal size is mediated by group 1 metabotropic glutamate receptors, acting via CaMKII (Ca2+/calmodulin-dependent protein kinase II) and PKC. Therefore, physiologically relevant changes in extracellular Ca2+ can regulate information transfer at cortical synapses via both presynaptic and postsynaptic mechanisms.


The urological complications of renal transplantation: a series of 1535 patients.
To determine the incidence of urological complications of renal transplantation at one institution, and relate this to donor and recipient factors. A consecutive series of 1535 renal transplants were audited, and a database of donor and recipient characteristics created for risk-factor analysis. An unstented Leadbetter-Politano anastomosis was the preferred method of ureteric reimplantation. There were 45 urinary leaks, 54 primary ureteric obstructions, nine cases of ureteric calculi, three bladder stones and 19 cases of bladder outlet obstruction at some time after transplantation. The overall incidence of urological complications was 9.2%, with that for urinary leak or primary ureteric obstruction being 6.5%. One graft was lost because of complications, and there were three deaths associated directly or indirectly with urological complications. There was no association with recipient age, cadaveric vs living-donor transplants, or cold ischaemic times before organ reimplantation, although the donor age was slightly higher in cases of urinary leak. There was no association with kidneys imported via the UK national organ-sharing scheme vs the use of local kidneys. The management of these complications is discussed. The incidence of urological complications in this series has remained essentially unchanged for 20 years. The causes of these complications and techniques for their prevention are discussed.


V-ATPase V0 sector subunit a1 in neurons is a target of calmodulin.
The V(0) complex forms the proteolipid pore of a vesicular ATPase that acidifies vesicles. In addition, an independent function in membrane fusion has been suggested in vacuolar fusion in yeast and synaptic vesicle exocytosis in fly neurons. Evidence for a direct role in secretion has also recently been presented in mouse and worm. The molecular mechanisms of how the V(0) components might act or are regulated are largely unknown. Here we report the identification and characterization of a calmodulin-binding site in the large cytosolic N-terminal region of the Drosophila protein V100, the neuron-specific V(0) subunit a1. V100 forms a tight complex with calmodulin in a Ca(2+)-dependent manner. Mutations in the calmodulin-binding site in Drosophila lead to a loss of calmodulin recruitment to synapses. Neuronal expression of a calmodulin-binding deficient V100 uncovers an incomplete rescue at low levels and cellular toxicity at high levels. Our results suggest a vesicular ATPase V(0)-dependent function of calmodulin at synapses.


A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma.
Tumors are capable of coopting hematopoietic cells to create a suitable microenvironment to support malignant growth. Here, we have demonstrated that upregulation of kinase insert domain receptor (KDR), also known as VEGFR2, in a myeloid cell sublineage is necessary for malignant progression of gliomas in transgenic murine models and is associated with high-grade tumors in patients. KDR expression increased in myeloid cells as myeloid-derived suppressor cells (MDSCs) accumulated, which was associated with the transformation and progression of low-grade fibrillary astrocytoma to high-grade anaplastic gliomas. KDR deficiency in murine BM-derived cells (BMDCs) suppressed the differentiation of myeloid lineages and reduced granulocytic/monocytic populations. The depletion of myeloid-derived KDR compromised its proangiogenic function, which inhibited the angiogenic switch necessary for malignant progression of low-grade to high-grade tumors. We also identified inhibitor of DNA binding protein 2 (ID2) as a key upstream regulator of KDR activation during myeloid differentiation. Deficiency of ID2 in BMDCs led to downregulation of KDR, suppression of proangiogenic myeloid cells, and prevention of low-grade to high-grade transition. Tumor-secreted TGF-β and granulocyte-macrophage CSF (GM-CSF) enhanced the KDR/ID2 signaling axis in BMDCs. Our results suggest that modulation of KDR/ID2 signaling may restrict tumor-associated myeloid cells and could potentially be a therapeutic strategy for preventing transformation of premalignant gliomas.


Contaminants of emerging concern in tributaries to the Laurentian Great Lakes: II. Biological consequences of exposure.
The Laurentian Great Lakes contain one fifth of the world's surface freshwater and have been impacted by human activity since the Industrial Revolution. In addition to legacy contaminants, nitrification and invasive species, this aquatic ecosystem is also the recipient of Contaminants of Emerging Concern (CECs) with poorly understood biological consequences. In the current study, we documented the presence, concentrations, and biological effects of CECs across 27 field sites in six Great Lakes tributaries by examining over 2250 resident and caged sunfish (Lepomis ssp.) for a variety of morphological and physiological endpoints and related these results to CEC occurrence. CEC were ubiquitous across studies sites and their presence and concentrations in water and sediment were highest in effluent dominated rivers and downstream of municipal wastewater treatment plant discharges. However, even putative upstream reference sites were not free of CEC presence and fish at these sites exhibited biological effects consistent with CEC exposure. Only the Fox River exhibited consistent adverse biological effects, including increased relative liver size, greater prominence of hepatocyte vacuoles and increased plasma glucose concentrations. Canonical Redundancy Analysis revealed consistent patterns of biological consequences of CEC exposure across all six tributaries. Increasing plasma glucose concentrations, likely as a result of pollutant-induced metabolic stress, were associated with increased relative liver size and greater prominence of hepatocyte vacuoles. These indicators of pollutant exposure were inversely correlated with indicators of reproductive potential including smaller gonad size and less mature gametes. The current study highlights the need for greater integration of chemical and biological studies and suggests that CECs in the Laurentian Great Lakes Basin may adversely affect the reproductive potential of exposed fish populations.


Urinary homocysteic acid levels correlate with mini-mental state examination scores in Alzheimer's disease patients.
Homocysteic acid (HA) has been suggested as a pathogen in a mouse model of Alzheimer's disease (AD), 3xTg-AD. However, it is not established whether HA is involved in humans. We investigated the relationship between urinary HA levels and Mini-Mental State Examination (MMSE) scores in AD patients (n = 70) and non-AD controls (n = 34). We found a positive, statistically significant relationship between the two variables (the urinary HA level and MMSE score) (r = 0.31, p = 0.0008, n = 70). This relationship was stronger in females than males (r = 0.43, p = 0.005, n = 44 in females; r = 0.48, p = 0.02, n = 22 in males). The urinary HA levels were significantly different in AD patients than controls (AD: 8.7 ± 7.5, n = 70; non-dementia control: 13.3 ± 9.4, n = 34, p < 0.01). In addition, aging and smoking were found as lowering factors for urinary HA levels. Our preliminary study showed a negative, statistically significant relationship between blood HA (micromole) and urine HA levels (r = -0.6, p = 0.007, n = 19), and between blood HA levels and MMSE scores (r = -0.79, p = 0.0000518, n = 19). On the basis of these results, we speculate that reduced urinary excretion induces elevated HA levels in blood, resulting in cognitive dysfunctions. This study also suggests that HA may be a candidate of neurotoxins for uremic encephalopathy. Since amyloid-β increases HA toxicity and HA is an agonist of N-methyl-D-aspartic acid (NMDA) receptor, we speculate that elevated blood HA affects the brain cognitive function through NMDA receptor-mediated toxicity in AD.


Autoimmune Diseases in Patients With Cutaneous Lupus Erythematosus.
Increased rates of autoimmune conditions have been reported in association with systemic lupus erythematosus (SLE). Little is known about coexisting autoimmune conditions in patients with cutaneous lupus erythematosus (CLE) without SLE. To determine the prevalence and risk factors of having coexisting autoimmune conditions in patients with CLE. This cross-sectional study was performed from November 2008 to February 2017 at the University of Texas Southwestern Medical Center (UTSW) and Parkland Health and Hospital System, Dallas, Texas. Participants were identified through the UTSW Cutaneous Lupus Registry. All participants had a dermatologist-confirmed diagnosis of CLE using clinicopathological correlation. Exclusion criteria included age younger than 18 years, and meeting at least 4 American College of Rheumatology diagnostic criteria for SLE. Participants with CLE and without concomitant autoimmune diseases were compared by demographic and disease characteristics. The primary and secondary outcomes were presence of coexisting autoimmune condition(s) and individual autoimmune diseases, respectively. Predictor variables significantly associated with coexisting autoimmune diseases were identified by univariate and multivariable logistic regression analyses. Among the 285 participants initially screened, 129 participants with CLE were included (102 [79.1%] female; median age, 49 years [interquartile range, 38.3-57.1 years]). Coexisting autoimmune conditions were found in 23 (17.8%). Autoimmune thyroid disease had the highest frequency at 4.7% (n = 6). Multivariable logistic regression analyses showed that patients with CLE who were white (odds ratio [OR], 2.88; 95% CI, 1.00-8.29; P = .0498), never smokers (OR, 3.28; 95% CI, 1.14-9.39; P = .03), had family history of autoimmune disease (OR, 3.54; 95% CI, 1.21-10.39; P = .02), and history of positive antinuclear antibody test result (OR, 4.87; 95% CI, 1.69-14.03; P = .003) had a significant association with having coexisting autoimmune conditions. This study suggests that patients with CLE without concurrent SLE can have increased rates of coexisting autoimmune conditions. Collecting a thorough review of systems can prompt clinicians to pursue further testing and evaluation by other specialists. Future studies investigating development of coexisting autoimmune conditions over time in the CLE population are necessary to confirm these findings.


[The endogenous differentiation factor of the HL-60 cells shows a nuclease activity].
A structural homology between the endogenous differentiation factor of the HL-60 cell line of promyelocyte leukemia (HLDF) and several DNA/RNA-binding and DNA/RNA-hydrolyzing proteins was revealed, and expression of the hldf gene in prokaryotic systems was studied. On the basis of these experiments, the amino acid sequence of an 8-membered fragment of HLDF with potential nuclease activity was identified. The synthetic octapeptide RRWHRLKE was shown to be capable of the cleavage of RNA, linear DNA from phage lambda, and all forms of plasmid DNA. We established that treatment of the HL-60 cell culture with this peptide (10(-6) M) results in an increase in the number of apoptotic cells and suggested that HLDF is involved in processes of apoptosis.


Efficacy of Sofosbuvir Plus Ribavirin in Veterans With Hepatitis C Virus Genotype 2 Infection, Compensated Cirrhosis, and Multiple Comorbidities.
We conducted a phase 4, open-label study with limited exclusion criteria to evaluate the safety and efficacy of sofosbuvir and ribavirin in veterans with hepatitis C virus genotype 2 infection, and compensated cirrhosis. This population is often excluded from clinical studies. We performed a prospective study of treatment-naive (n = 47) and treatment-experienced (n = 19) patients with chronic hepatitis C virus genotype 2 infection and compensated cirrhosis at 15 Department of Veterans Affairs sites. All subjects were given sofosbuvir (400 mg, once daily) plus ribavirin (1000-1200 mg/day) in divided doses for 12 weeks. Patients with major psychiatric diseases or alcohol or substance use disorders were not excluded. The primary endpoint was sustained virologic response 12 weeks after therapy. Fifty-two patients achieved a sustained virologic response 12 weeks after therapy (79%; 95% confidence interval, 67%-88%); 16 of these patients were treatment experienced (84%; 95% confidence interval, 60%-97%) and 36 were treatment naive (77%; 95% confidence interval, 62%-88%). All patients had at least 1 comorbidity. Thirty-five percent had depression, 24% had posttraumatic stress disorder, and 30% had anxiety disorder. In addition, 29% had current substance use. Of the 7 patients (11%) who discontinued the study treatment prematurely, 3 did so because of adverse events. The most common adverse events were fatigue, anemia, nausea, and headache. Serious adverse events occurred in 8 patients. Only 2 of the serious adverse events (anemia and nausea) were considered to be related to study treatment. In a phase 4 study, 12 weeks treatment with sofosbuvir and ribavirin led to a sustained virologic response 12 weeks after therapy in almost 80% of veterans with hepatitis C virus genotype 2 infection, compensated cirrhosis, and multiple comorbidities, regardless of their treatment history. ClinicalTrials.gov, Number: NCT02128542.


Ameliorating Active Ulcerative Colitis via an Orally Available Toll-Like Receptor-9 Modifier: A Prospective Open-Label, Multicenter Phase II Trial.
Treatment of active ulcerative colitis is associated with incomplete efficacy, adverse events, and loss of response. Toll-like receptor-9 mediates innate and adaptive immune response toward intestinal microorganisms. The oral synthetic oligonucleotide toll-like receptor-9 modulator has demonstrated anti-inflammatory properties in colitis murine models and a satisfactory safety profile in humans. To evaluate the efficacy and safety of BL-7040 (a Toll-like receptor-9 modulator) in patients with moderately active ulcerative colitis. Moderately active ulcerative colitis patients were included in this multicenter, open-label phase IIa trial. Concomitant mesalamine and steroids at a stable dose were allowed. Clinical outcome was evaluated using the Mayo score, histology, and mucosal cytokine levels. Side effects were registered. Sixteen out of 22 patients completed a 5-week treatment course and 2-week follow-up. Six patients discontinued the study, three of them due to adverse events. Clinical remission was observed in two patients (12.5 %), and clinical response as well as mucosal healing were achieved in half (50 %) of the patients, while all others remained stable. Furthermore, mucosal neutrophil (p = 0.002) and mucosal interleukin-6 levels (p = 0.046) were significantly reduced in responders compared to non-responders. Toll-like receptor-9 was well tolerated with only one unrelated to study drug serious adverse event (hemoglobin decrease) and 29 mild-to-moderate adverse events. Oral administration of the Toll-like receptor-9 agonist BL-7040 appeared efficacious, safe and well tolerated in patients with moderately active ulcerative colitis.


Simultaneous bandgaps in LiNbO3 phoxonic crystal slab.
We study simultaneous photonic and phononic crystal slabs created in Z-cut lithium niobate membranes. Bandgaps for guided waves are identified using the three-dimensional finite element method (FEM). Three lattices are considered: the square, the hexagonal, and the honeycomb lattices. We investigate the evolution of band gaps as a function of geometrical parameters such as hole radius and membrane thickness. We show the existence of dual photonic and phononic bandgaps in the triangular lattice for suitable geometrical parameters and specific modal symmetries for both the elastic and the electromagnetic fields.


Differential effects of apolipoprotein E isoforms on phosphorylation at specific sites on tau by glycogen synthase kinase-3 beta identified by nano-electrospray mass spectrometry.
Previously published data have shown an allele-specific variation in the in vitro binding of apolipoprotein E (apoE) to tau, which prompted the hypothesis that apoE binding may protect tau from phosphorylation, apoE3 being more efficient than apoE4. We have, therefore, investigated the effects of apoE on tau phosphorylation in vitro by the proline-directed kinase, glycogen synthase kinase (GSK)-3 beta. The phosphopeptide maps of tau alone, of tau with apoE3 and of tau with apoE4 were very similar. When apoE2 was present a further four spots were evident. Additionally, of the 15 peptides phosphorylated in the presence or absence of apoE, subtle differences, some isoform-specific, in the relative amounts of phosphorylation were observed.


Reference intervals for some biochemical parameters in the aged Kenyan population.
Serum levels for sodium, potassium, calcium, inorganic phosphate, urea nitrogen and creatinine were determined in 1101 male and 181 female patients aged 50 years and above. The determinations were carried out on the SMA II (Technicon Instruments Corp. Tarrytown, NY 10591) with a view to establish the reference intervals for this age group. Quality control of the analytical methods was carried alongside with the determinations. The data collected was used to determine the reference intervals using a simple statistical method. The results indicate that sodium and calcium intervals are low with values of 131-142 mMol/L and 1.94-2.32 mMol/L respectively, in the aged Kenyan population as compared to subjects living in the temperate environment while the interval for inorganic phosphate is comparatively high with a value of 1.2-1.97 mMol/L. Reference values for urea nitrogen, potassium and creatinine were found to be similar to those quoted for caucasians.


Neuromuscular diseases: Diagnosis and management.
Neuromuscular diseases (NMDs) affect the peripheral nervous system, which includes the motor neurons and sensory neurons; the muscle itself; or the neuromuscular junction. Thus, the term NMDs encompasses a vast array of different syndromes. Some of these syndromes are of direct relevance to paediatric orthopaedic surgeons, either because the presenting manifestation is a functional sign (e.g., toe-walking) or deformity (e.g., pes cavus or scoliosis) suggesting a need for orthopaedic attention or because orthopaedic abnormalities requiring treatment develop during the course of a known NMD. The main NMDs relevant to the orthopaedic surgeon are infantile spinal muscular atrophy (a motor neuron disease), peripheral neuropathies (chiefly, Charcot-Marie-Tooth disease), congenital muscular dystrophies, progressive muscular dystrophies, and Steinert myotonic dystrophy (or myotonic dystrophy type 1). Muscle weakness is a symptom shared by all these conditions. The paediatric orthopaedic surgeon must be familiar, not only with the musculoskeletal system, but also with many other domains (particularly respiratory and cardiac function and nutrition) that may interfere with the treatment and require preoperative management. Good knowledge of the natural history of each NMD is essential to ensure optimal timing of the therapeutic interventions, which must be performed under the best possible conditions in these usually frail patients. Timing is particularly crucial for the treatment of spinal deformities due to paraspinal muscle hypotonia during growth: depending on the disease and natural history, the treatment may involve non-operative methods or growing rods, followed by spinal fusion. A multidisciplinary approach is always required. Finally, the survival gains achieved in recent years increasingly require attention to preparing for adult life, to orthopaedic problems requiring treatment before the patient leaves the paediatric environment, and to the transition towards the adult healthcare system.