Airways response of asthmatics after a 30 min exposure, at resting ventilation, to 0.25 ppm NO2 or 0.5 ppm SO2.
We compared the effect of inhaled NO2 and SO2 on airway tone and airway responsiveness in 14 nonsmoking mild asthmatics (mean +/- SD age 34 +/- 14 yrs; mean +/- SD baseline forced expiratory volume in one second (FEV1), 86 +/- 17% pred). On 3 separate days, 30 min tidal breathing (average minute ventilation 10.6 l.min-1) of either filtered air, 0.25 ppm NO2, or 0.5 ppm SO2 was followed by an isocapnic hyperventilation test with 0.75 ppm SO2. To determine the provocative ventilation necessary to increase specific airway resistance (sRaw) by 100% (PV100sRaw) ventilation was increased in steps of 15 l.min-1, each step lasting 3 min. Resting ventilation of filtered air, NO2, or SO2 was followed by a slight but significant overall decrease of sRaw from 8.8 to 7.7 cmH20.s-1, with no differences between the study days. Mean +/- SEM PV100sRaw(SO2) was 46.5 +/- 5.1, 37.7 +/- 3.5 and 45.4 +/- 4.2 l.min-1 after tidal breathing of filtered air, NO2, and SO2, respectively. PV100sRaw(SO2) was significantly lower after NO2 as compared to filtered air or SO2 (p less than 0.01). There was a significant correlation (rs = 0.86) between the individual shift of PV100sRaw(SO2) after NO2 and the shift after SO2 as compared to filtered air. From these individual comparisons we suggest that in asthmatics short-term exposure to NO2 at rest enhances airway responsiveness to hyperventilation of SO2 without altering airway tone, whereas short-term exposure with low concentrations of SO2 does not.


The Residual Innate Lymphoid Cells in NFIL3-Deficient Mice Support Suboptimal Maternal Adaptations to Pregnancy.
Uterine NK cells are innate lymphoid cells (ILC) that populate the uterus and expand during pregnancy, regulating placental development and fetal growth in humans and mice. We have recently characterized the composition of uterine ILCs (uILCs), some of which require the transcription factor NFIL3, but the extent to which NFIL3-dependent cells support successful reproduction in mice is unknown. By mating Nfil3 (-/-) females with wild-type males, here we show the effects of NFIL3 deficiency in maternal cells on both the changes in uILCs during pregnancy and the downstream consequences on reproduction. Despite the presence of CD49a(+)Eomes(-) uILC1s and the considerable expansion of residual CD49a(+)Eomes(+) tissue-resident NK cells and uILC3s in pregnant Nfil3 (-/-) mice, we found incomplete remodeling of uterine arteries and decidua, placental defects, and fetal growth restriction in litters of normal size. These results show that maternal NFIL3 mediates non-redundant functions in mouse reproduction.


Energy and nutrient intake in Mexican children 1 to 4 years old: results from the Mexican National Health and Nutrition Survey 2006.
To document the energy and nutrient intake of Mexican preschool children using data from the Mexican National Health and Nutrition Survey 2006 (ENSANUT 2006). Dietary data from 3 552 children less than 5 years old collected through a semi-quantitative food frequency questionnaire were analyzed. Energy and nutrient daily intakes and adequacies were calculated. Comparisons were made by geographic region, residence locality, and socioeconomic status. The Mexico City region showed the highest energy (103.2%), carbohydrate (109.9%), and fat (110.1%) adequacies. The highest proportion of preschoolers with energy and micronutrients inadequacy (adequacy < 100%) was observed in children of indigenous ethnicity, low socioeconomic status, living in rural localities, and in the south region. This information may help as an indicator of food availability and access in different population strata and as a tool to focus interventions on those who may better benefit from food assistance programs.


Mouse endothelial CD40 expression does not play a role during the development of transplant arteriosclerosis.
Endothelial cells (ECs) are of major interest in allograft rejection. The authors and others have recently shown in different mouse allograft models that, during the development of transplant arteriosclerosis, donor ECs are replaced by recipient ECs. It was the aim of this study to characterize the phenotype of ECs during the development of transplant arteriosclerosis further, with particular interest in their capability to express CD40. Abdominal aortic allografts were transplanted across a full major histocompatibility complex (MHC) barrier using BALB/c (H-2d) mice as donors and C57BL/6 (H-2b) mice as transplant recipients. Aortic allografts were harvested on days 7 and 30 after transplantation and analyzed by double-immunohistochemistry for expression of CD40 and CD31. As the authors have previously shown that ECs in the aortic allograft model are of donor origin on day 7 after transplantation, whereas by day 30 donor ECs have been replaced by ECs of recipient origin, these two time points were chosen for analysis of CD40 expression. Double-immunohistochemistry for CD40 and CD31 revealed no endothelial expression of CD40 at either time point. These initial results obtained with the anti-CD40 monoclonal antibody (mAb) (clone 3/23) were confirmed by two further experiments using two different anti-CD40 mAbs (clone HM40-3 and clone 1/10) that bind to epitopes of the CD40 receptor distinct to that of 3/23. Neither mAb revealed endothelial expression of CD40. Further analysis of the composition of the cellular infiltrate demonstrated that the majority of macrophages were CD40 positive. The data indicate that in this mouse model of aortic transplantation, neither recipient- nor donor-derived ECs express CD40 during the development of transplant arteriosclerosis. Therefore, in contrast to rat or human ECs, CD40 expression by mouse ECs does not seem to play a major role in this form of allograft rejection.


Recent Update of HDAC Inhibitors in Lymphoma.
Modulating epigenetic modification has been recognized for over a decade as an effective therapeutic approach to cancer and many studies of histone deacetylase (HDAC), one of the best known epigenetic modulators, have been published. HDAC modulates cell proliferation and angiogenesis and plays an essential role in cell growth. Research shows that up-regulated HDACs are present in many cancer types and synthetic or natural HDAC inhibitors have been used to silence overregulated HDACs. Inhibiting HDACs may cause arrest of cell proliferation, angiogenesis reduction and cell apoptosis. Recent studies indicate that HDAC inhibitors can provide a therapeutic effect in various cancers, such as B-cell lymphoma, leukemia, multiple myeloma and some virus-associated cancers. Some evidence has demonstrated that HDAC inhibitors can increase the expression of immune-related molecules leading to accumulation of CD8 + T cells and causing unresponsive tumor cells to be recognized by the immune system, reducing tumor immunity. This may be a solution for the blockade of PD-1. Here, we review the emerging development of HDAC inhibitors in various cancer treatments and reduction of tumor immunity.


Predictors of clinical recovery from concussion: a systematic review.
A systematic review of factors that might be associated with, or influence, clinical recovery from sport-related concussion. Clinical recovery was defined functionally as a return to normal activities, including school and sports, following injury. Systematic review. PubMed, PsycINFO, MEDLINE, CINAHL, Cochrane Library, EMBASE, SPORTDiscus, Scopus and Web of Science. Studies published by June of 2016 that addressed clinical recovery from concussion. A total of 7617 articles were identified using the search strategy, and 101 articles were included. There are major methodological differences across the studies. Many different clinical outcomes were measured, such as symptoms, cognition, balance, return to school and return to sports, although symptom outcomes were the most frequently measured. The most consistent predictor of slower recovery from concussion is the severity of a person's acute and subacute symptoms. The development of subacute problems with headaches or depression is likely a risk factor for persistent symptoms lasting greater than a month. Those with a preinjury history of mental health problems appear to be at greater risk for having persistent symptoms. Those with attention deficit hyperactivity disorder (ADHD) or learning disabilities do not appear to be at substantially greater risk. There is some evidence that the teenage years, particularly high school, might be the most vulnerable time period for having persistent symptoms-with greater risk for girls than boys. The literature on clinical recovery from sport-related concussion has grown dramatically, is mostly mixed, but some factors have emerged as being related to outcome.


Proteomic analysis of wild-type and mutant huntingtin-associated proteins in mouse brains identifies unique interactions and involvement in protein synthesis.
Huntington disease is a neurodegenerative disorder caused by a CAG repeat amplification in the gene huntingtin (HTT) that is reflected by a polyglutamine expansion in the Htt protein. Nearly 20 years of research have uncovered roles for Htt in a wide range of cellular processes, and many of these discoveries stemmed from the identification of Htt-interacting proteins. However, no study has employed an impartial and comprehensive strategy to identify proteins that differentially associate with full-length wild-type and mutant Htt in brain tissue, the most relevant sample source to the disease condition. We analyzed Htt affinity-purified complexes from wild-type and HTT mutant juvenile mouse brain from two different biochemical fractions by tandem mass spectrometry. We compared variations in protein spectral counts relative to Htt to identify those proteins that are the most significantly contrasted between wild-type and mutant Htt purifications. Previously unreported Htt interactions with Myo5a, Prkra (PACT), Gnb2l1 (RACK1), Rps6, and Syt2 were confirmed by Western blot analysis. Gene Ontology analysis of these and other Htt-associated proteins revealed a statistically significant enrichment for proteins involved in translation among other categories. Furthermore, Htt co-sedimentation with polysomes in cytoplasmic mouse brain extracts is dependent upon the presence of intact ribosomes. Finally, wild-type or mutant Htt overexpression inhibits cap-dependent translation of a reporter mRNA in an in vitro system. Cumulatively, these data support a new role for Htt in translation and provide impetus for further study into the link between protein synthesis and Huntington disease pathogenesis.


Cloning, expression and characterization of human tissue-specific DNA polymerase lambda2.
DNA polymerase (POL) lambda plays an important role during DNA repair and DNA nonhomologous recombination processes. A novel POL lambda variant was cloned from a human liver cDNA library and named POL lambda2 (GenBank Accession No. AY302442). POL lambda2 has 2206 base pairs in length with an open reading frame of 1452 base pairs encoding a 482-amino-acids protein. Bioinformatics analysis reveals that POL lambda2 spans 7.9 kb on human chromosome 10q24 and is composed of 8 exons and 7 introns. It has the specific domain of DNA polymerase X family-POL Xc at the C-terminus and BRCT domain at the N-terminus. POL lambda2 was localized predominantly in nucleus in transfected L0-2 cells. It was expressed abundantly in liver and testis, weakly in ovary, and undetectably in other tested human tissues. In comparison with the expression ratio between POL lambda and POL lambda2 in normal liver tissues and hepatocellular carcinoma (HCC) adjacent tissues, the ratio was aberrant in 80% of those 15 HCC specimens examined due to the up-regulated expression of POL lambda. This abnormality might be involved in hepatocarcinogenesis. The recombinant POL lambda2 with His-tag was expressed as a soluble active protein in E. coli BL21 (DE3)CONDON Plus and purified by Ni-NTA resin and then desalted by Superdex-75 chromatography in an FPLC system. The analysis using isotope a-(32)P-dCTP incorporation in vitro showed that the purified recombinant POL lambda2 exhibited DNA polymerase activity.


Impaired bone health in inflammatory bowel disease: a case-control study in 80 pediatric patients.
Previous studies have indicated that children with inflammatory bowel disease (IBD) may not achieve optimal bone mass. We evaluated the skeletal characteristics in children and adolescents with IBD. This cross-sectional cohort study comprised 80 IBD patients (median age 14.9 years, range 5-20) with a median disease duration of 3.4 years; 51 had ulcerative colitis, 26 Crohn disease, and 3 unspecified colitis. Eighty age- and gender-matched healthy subjects served as controls. Areal bone mineral density (aBMD), body composition, and vertebral fractures (VFs) were assessed by DXA. Bone age (BA) was determined for IBD patients. Findings were correlated with disease- and treatment-related parameters and biochemistry. IBD patients had lower BA-adjusted lumbar spine and whole-body aBMD (p < 0.001 for both) and whole-body BMC adjusted for height (p = 0.02) than controls. Lean mass and fat mass Z scores did not differ between the groups, but IBD patients had lower whole-body BMC relative to muscle mass (p = 0.006). Despite vitamin D supplementation in 48 %, vitamin D deficiency was common. In IBD cumulative weight-adjusted prednisolone dose >150 mg/kg for the preceding 3 years increased the risk for low whole-body aBMD (OR = 5.5, 95 % CI 1.3-23.3, p = 0.02). VFs were found in 11 % of patients and in 3 % of controls (p = 0.02). IBD in childhood was associated with low aBMD and reduced bone mass accrual relative to muscle mass; the risk for subclinical VFs may be increased. These observations warrant careful follow-up and active preventive measures.


Characterisation of a bystander effect induced in human tissue explant cultures by low let radiation.
The existence of a bystander effect following both alpha and gamma irradiation of many cell lines is not now in dispute. The significance of this effect for cancer risk assessment and radiotherapy treatment planning requires demonstration of its relevance in vivo. The problem in demonstrating the existence of the effect in vivo is that other systemic effects may mask or confound the effect being investigated and it is practically impossible to attribute an effect in a particular cell to a signal produced in another irradiated cell. To approach this problem, an assay has been developed where fragments of human tissue can be irradiated ex vivo and the media harvested and added to unirradiated, clonogenic cells which have a well characterised and stable response to the bystander signal. The variation in the production of a signal from patient to patient can thus be assessed. The results of a study using tissue from over 100 patients attending Beaumont and St Vincent's Hospitals in Dublin for investigation of urological disorders including follow-up after treatment for transitional cell carcinoma (TCC) and resection of suspect prostatic lesions, are now available. Blood samples from the prostate group were also obtained. The results show that there is variation in the effect of the signal produced by irradiated tissue from different patients. This holds for bladder, prostate and blood. Gender, smoking status and the existence of a malignancy influence the expression of the signal by normal tissue. Male gender, smoking and a pre-existing malignancy all reduce the amount or effect of the signal produced into medium when the tissue is exposed. The effects of exposure to medium containing the signal are transmitted to distant progeny of the exposed cell population. The results may be important not only for understanding radiation risk mechanisms for protection but also for radiotherapy treatment planning where they may open new avenues for development of drugs for combined therapy.


Discrete 1 : 1 complexes and higher order assemblies formed from aminobenzene sulphonate anions and a tetraimidazolium "molecular box".
Use of isomeric aminobenzene sulphonate anions in conjunction with a tetraimidazolium "molecular box" leads to self-assembled embedded structures. Simple 1 : 1 complexes are formed at low concentrations in DMSO when the host : guest ratio is 1.0. Higher order species are seen as the concentration is increased or the host-guest ratio is perturbed. The assembly and disassembly of the supramolecular aggregates can be controlled by application of various external stimuli, including changes in concentration, temperature, and protonation state of the guest species.


A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.
Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10-8) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10-8). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).


Effects of Post-Exercise Honey Drink Ingestion on Blood Glucose and Subsequent Running Performance in the Heat.
Glycogen depletion and hypoglycemia have been associated with fatigue and decrement of performance during prolonged exercise. This study investigated the effectiveness of Acacia honey drink as a post-exercise recovery aid on glucose metabolism and subsequent running performance in the heat. Ten subjects participated in this randomized cross-over study. All subjects performed 2 trials. In each trial, all subjects went through a glycogen depletion phase (Run-1), 2-hour rehydration phase and time trial running phase (Run-2). In Run-1, subjects were required to run on a treadmill at 65% VO2max in the heat (31°C, 70% relative humidity) for 60 min. During 2-hour rehydration phase, subjects drank either plain water (PW) or honey drink (HD) with amount equivalent to 150% of body weight loss in 3 boluses (60%, 50% and 40% subsequently) at 0, 30 and 60 min. In Run-2, the longest distance covered in 20 min was recorded for determining running performance. Two-way repeated measured ANOVA and paired t-test were used for analysis. Running distance in Run-2 covered by the subjects in the honey drink HD trial (3420 ± 350 m) was significantly (P < 0.01) longer compared to plain water PW trial (3120 ± 340 m). In general, plasma glucose, serum insulin and osmolality were significantly (P < 0.05) higher in HD compared to PW during the rehydration phase and Run-2. These findings indicate that rehydration with honey drink improves running performance and glucose metabolism compared to plain water in the heat. Thus, honey drink can be recommended for rehydration purpose for athletes who compete in the heat.


Stable and rapid recurrent processing in realistic autoassociative memories.
It is shown that in those autoassociative memories that learn by storing multiple patterns of activity on their recurrent collateral connections, there is a fundamental conflict between dynamical stability and storage capacity. It is then found that the network can nevertheless retrieve many different memory patterns, as predicted by nondynamical analyses, if its firing is regulated by inhibition that is sufficiently multiplicative in nature. Simulations of a model network with integrate-and-fire units confirm that this is a realistic solution to the conflict. The simulations also confirm the earlier analytical result that cued-elicited memory retrieval, which follows an exponential time course, occurs in a time linearly related to the time constant for synaptic conductance inactivation and relatively independent of neuronal time constants and firing levels.


Regulation of hypometabolism: insights into epigenetic controls.
For many animals, survival of severe environmental stress (e.g. to extremes of heat or cold, drought, oxygen limitation, food deprivation) is aided by entry into a hypometabolic state. Strong depression of metabolic rate, often to only 1-20% of normal resting rate, is a core survival strategy of multiple forms of hypometabolism across the animal kingdom, including hibernation, anaerobiosis, aestivation and freeze tolerance. Global biochemical controls are needed to suppress and reprioritize energy use; one such well-studied control is reversible protein phosphorylation. Recently, we turned our attention to the idea that mechanisms previously associated mainly with epigenetic regulation can also contribute to reversible suppression of gene expression in hypometabolic states. Indeed, situations as diverse as mammalian hibernation and turtle anoxia tolerance show coordinated changes in histone post-translational modifications (acetylation, phosphorylation) and activities of histone deacetylases, consistent with their use as mechanisms for suppressing gene expression during hypometabolism. Other potential mechanisms of gene silencing in hypometabolic states include altered expression of miRNAs that can provide post-transcriptional suppression of mRNA translation and the formation of ribonuclear protein bodies in the nucleus and cytoplasm to allow storage of mRNA transcripts until animals rouse themselves again. Furthermore, mechanisms first identified in epigenetic regulation (e.g. protein acetylation) are now proving to apply to many central metabolic enzymes (e.g. lactate dehydrogenase), suggesting a new layer of regulatory control that can contribute to coordinating the depression of metabolic rate.


Nonlinear oscillatory rarefied gas flow inside a rectangular cavity.
The nonlinear oscillation of rarefied gas flow inside a two-dimensional rectangular cavity is investigated on the basis of the Shakhov kinetic equation. The gas dynamics, heat transfer, and damping force are studied numerically via the discrete unified gas-kinetic scheme for a wide range of parameters, including gas rarefaction, cavity aspect ratio, and oscillation frequency. Contrary to the linear oscillation where the velocity, temperature, and heat flux are symmetrical and oscillate with the same frequency as the oscillating lid, flow properties in nonlinear oscillatory cases turn out to be asymmetrical, and second-harmonic oscillation of the temperature field is observed. As a consequence, the amplitude of the shear stress near the top-right corner of the cavity could be several times larger than that at the top-left corner, while the temperature at the top-right corner could be significantly higher than the wall temperature in nearly the whole oscillation period. For the linear oscillation with the frequency over a critical value, and for the nonlinear oscillation, the heat transfer from the hot to cold region dominates inside the cavity, which is contrary to the anti-Fourier heat transfer in a low-speed rarefied lid-driven cavity flow. The damping force exerted on the oscillating lid is studied in detail, and the scaling laws are developed to describe the dependency of the resonance and antiresonance frequencies (corresponding to the damping force at a local maximum and minimum, respectively) on the reciprocal aspect ratio from the near hydrodynamic to highly rarefied regimes. These findings could be useful in the design of the micro-electro-mechanical devices operating in the nonlinear-flow regime.


Prevalence and risk factors for Chagas disease in pregnant women in Casanare, Colombia.
Knowledge of the prevalence and risk factors associated with maternal infection is the first step to develop a surveillance system for congenital transmission of Chagas disease. We conducted a cross-sectional study in Casanare, a disease-endemic area in Colombia. A total of 982 patients were enrolled in the study. A global prevalence of Trypanosoma cruzi infection of 4.0% (95% confidence interval [CI] = 2.8-5.3%) was found. Multivariate analysis showed that the most important risk-associated factors were age > 29 years (adjusted odds ratio [aOR] = 3.4, 95% CI = 0.9-12.4), rural residency (aOR = 2.2, 95% CI = 1.0-4.6), low education level (aOR = 10.2, 95% CI = 1.6-82.7), and previous knowledge of the vector (aOR = 2.2, 95% CI = 1.0-4.9). Relatives and siblings of infected mothers showed a prevalence of 9.3%. These findings may help physicians to investigate congenital cases, screen Chagas disease in siblings and relatives, and provide early treatment to prevent the chronic complications of Chagas disease.


Role of FKBP5 in emotion processing: results on amygdala activity, connectivity and volume.
Accumulating evidence suggests a role of FKBP5, a co-chaperone regulating the glucocorticoid receptor sensitivity, in the etiology of depression and anxiety disorders. Based on recent findings of altered amygdala activity following childhood adversity, the present study aimed at clarifying the impact of genetic variation in FKBP5 on threat-related neural activity and coupling as well as morphometric alterations in stress-sensitive brain systems. Functional magnetic resonance imaging during an emotional face-matching task was performed in 153 healthy young adults (66 males) from a high-risk community sample followed since birth. Voxel-based morphometry was applied to study structural alterations and DNA was genotyped for FKBP5 rs1360780. Childhood adversity was measured using retrospective self-report (Childhood Trauma Questionnaire) and by a standardized parent interview assessing childhood family adversity. Depression was assessed by the Beck Depression Inventory. There was a main effect of FKBP5 on the left amygdala, with T homozygotes showing the highest activity, largest volume and increased coupling with the left hippocampus and the orbitofrontal cortex (OFC). Moreover, amygdala-OFC coupling proved to be associated with depression in this genotype. In addition, our results support previous evidence of a gene-environment interaction on right amygdala activity with respect to retrospective assessment of childhood adversity, but clarify that this does not generalize to the prospective assessment. These findings indicated that activity in T homozygotes increased with the level of adversity, whereas the opposite pattern emerged in C homozygotes, with CT individuals being intermediate. The present results point to a functional involvement of FKBP5 in intermediate phenotypes associated with emotional processing, suggesting a possible mechanism for this gene in conferring susceptibility to stress-related disorders.


Efficacy and Safety of Multiple Dupilumab Dose Regimens After Initial Successful Treatment in Patients With Atopic Dermatitis: A Randomized Clinical Trial.
The dupilumab regimen of 300 mg every 2 weeks is approved for uncontrolled, moderate to severe atopic dermatitis (AD). To assess the efficacy and safety of different dupilumab regimens in maintaining response after 16 weeks of initial treatment. The Study to Confirm the Efficacy and Safety of Different Dupilumab Dose Regimens in Adults With Atopic Dermatitis (LIBERTY AD SOLO-CONTINUE) was a randomized, double-blind, phase 3 clinical trial conducted from March 25, 2015, to October 18, 2016, at 185 sites in North America, Europe, Asia, and Japan. Patients with moderate to severe AD who received dupilumab treatment and achieved an Investigator's Global Assessment score of 0 or 1 or 75% improvement in Eczema Area and Severity Index scores (EASI-75) at week 16 in 2 previous dupilumab monotherapy trials (LIBERTY AD SOLO 1 and 2) were rerandomized in SOLO-CONTINUE. After completing SOLO-CONTINUE, patients were followed up for up to 12 weeks or enrolled in an open-label extension. Data were analyzed from December 5 to 12, 2016. High-responding patients treated with dupilumab in SOLO were rerandomized 2:1:1:1 to continue their original regimen of dupilumab, 300 mg, weekly or every 2 weeks or to receive dupilumab, 300 mg, every 4 or 8 weeks or placebo for 36 weeks. Percentage change in EASI score from baseline during the SOLO-CONTINUE trial, percentage of patients with EASI-75 at week 36, and safety. Among the 422 patients (mean [SD] age, 38.2 [14.5] years; 227 [53.8%] male), continuing dupilumab treatment once weekly or every 2 weeks maintained optimal efficacy, with negligible change in percent EASI improvement from SOLO 1 and 2 baseline during the SOLO-CONTINUE trial (-0.06%; P < .001 vs placebo); percent change with the other regimens dose-dependently worsened (dupilumab every 4 weeks, -3.84%; dupilumab every 8 weeks, -6.84%; placebo, -21.67%). More patients taking dupilumab weekly or every 2 weeks (116 of 162 [71.6%]; P < .001 vs placebo) maintained EASI-75 response than those taking dupilumab every 4 weeks (49 of 84 [58.3%]) or every 8 weeks (45 of 82 [54.9%]) or those taking placebo (24 of 79 [30.4%]). Overall adverse event incidences were 70.7% in the weekly or every 2 weeks group, 73.6% in the every 4 weeks group, 75.0% in the every 8 weeks group, and 81.7% in the placebo group. Treatment groups had similar conjunctivitis rates. Treatment-emergent antidrug antibody incidence was lower with more frequent dupilumab dose regimens (11.3% in the placebo group and 11.7%, 6.0%, 4.3%, and 1.2% in the dupilumab every 8 weeks, every 4 weeks, every 2 weeks, and weekly groups, respectively). In this trial, continued response over time was most consistently maintained with dupilumab administered weekly or every 2 weeks. Longer dosage intervals and placebo resulted in a diminution of response for both continuous and categorical end points. No new safety signals were observed. The approved regimen of 300 mg of dupilumab every 2 weeks is recommended for long-term treatment. ClinicalTrials.gov identifier: NCT02395133.


Long-term survival on capecitabine in two gemcitabine refractory pancreatic cancer patients. Is there a pharmacogenetic explanation?
Capecitabine has shown efficacy in treatment of metastatic pancreatic cancer. Several researchers have identified thymidine phosphorylase, dihydropyrimidine dehydrogenase, or their ratio as indicators of response to capecitabine in various cancers. We report two patients with metastatic pancreatic carcinoma who had long-term survivals on capecitabine after gemcitabine failure. These two cases prompted us to measure thymidine phosphorylase and dihydropyrimidine dehydrogenase levels to facilitate discourses regarding their relationship with efficacy of capecitabine. We also describe a novel method of measuring thymidine phosphorylase level from serum without an invasive tissue biopsy. One patient is alive as of today, with improved performance status, 50 months after capecitabine was started. CA 19-9 and CT scans remained stable during 57 cycles. Her thymidine phosphorylase level was 1.77 compared to a control level of 1.00. Dihydropyrimidine dehydrogenase level was 4.14 compared to a control level of 1.00. Their ratio was 0.43. The other patient was alive on capecitabine for 24 months. His performance status, bilirubin, AST, and ALT improved on capecitabine. CT scans and CA 19-9 remained stable during this period. He had thymidine phosphorylase level of 5.56, dihydropyrimidine dehydrogenase level of 2.74, and their ratio of 2.03. Capecitabine resulted in long term survivals in two patients with metastatic pancreatic cancer after gemcitabine failure. The use of capecitabine as second-line treatment in metastatic pancreatic cancer should be further explored along with the role of thymidine phosphorylase and dihydropyrimidine dehydrogenase levels in its activity. A non-invasive method of thymidine phosphorylase measurement we described should be validated in larger trials.


Epigenetic clues to rheumatoid arthritis.
The innate immune response needs to be tightly regulated to balance elimination of microorganisms with the magnitude of inflammation. The rupture of this balance is crucial for the outcome of diseases such as rheumatoid arthritis (RA) in which an overflowed proinflammatory response is associated with self-damage. Epigenetics alludes to systems controlling gene expression and silencing independent of the germline, but stable enough to be inherited by daughter cells upon mitosis. We will show in this review how pathological processes in RA can be shaped by epigenetics, which may in turn explain differences in phenotypes between subgroups of patients and also between subsets of fibroblasts within the joint. On the whole, the concourse of epigenetic mechanisms can precipitate the aggressive behaviour of cells and the rupture of peripheral tolerance. Targeting these emerging regulatory pathways is a promising approach for RA therapeutics.


Steady Method for the Analysis of Evaporation Dynamics.
Droplet evaporation is an important phenomenon governing many man-made and natural processes. Characterizing the rate of evaporation with high accuracy has attracted the attention of numerous scientists over the past century. Traditionally, researchers have studied evaporation by observing the change in the droplet size in a given time interval. However, the transient nature coupled with the significant mass-transfer-governed gas dynamics occurring at the droplet three-phase contact line makes the classical method crude. Furthermore, the intricate balance played by the internal and external flows, evaporation kinetics, thermocapillarity, binary-mixture dynamics, curvature, and moving contact lines makes the decoupling of these processes impossible with classical transient methods. Here, we present a method to measure the rate of evaporation of spatially and temporally steady droplets. By utilizing a piezoelectric dispenser to feed microscale droplets (R ≈ 9 μm) to a larger evaporating droplet at a prescribed frequency, we can both create variable-sized droplets on any surface and study their evaporation rate by modulating the piezoelectric droplet addition frequency. Using our steady technique, we studied water evaporation of droplets having base radii ranging from 20 to 250 μm on surfaces of different functionalities (45° ≤ θa,app ≤ 162°, where θa,app is the apparent advancing contact angle). We benchmarked our technique with the classical unsteady method, showing an improvement of 140% in evaporation rate measurement accuracy. Our work not only characterizes the evaporation dynamics on functional surfaces but also provides an experimental platform to finally enable the decoupling of the complex physics governing the ubiquitous droplet evaporation process.


Mining the Biomarker Potential of the Urine Peptidome: From Amino Acids Properties to Proteases.
Native biofluid peptides offer important information about diseases, holding promise as biomarkers. Particularly, the non-invasive nature of urine sampling, and its high peptide concentration, make urine peptidomics a useful strategy to study the pathogenesis of renal conditions. Moreover, the high number of detectable peptides as well as their specificity set the ground for the expansion of urine peptidomics to the identification of surrogate biomarkers for extra-renal diseases. Peptidomics further allows the prediction of proteases (degradomics), frequently dysregulated in disease, providing a complimentary source of information on disease pathogenesis and biomarkers. Then, what does urine peptidomics tell us so far? In this paper, we appraise the value of urine peptidomics in biomarker research through a comprehensive analysis of all datasets available to date. We have mined > 50 papers, addressing > 30 different conditions, comprising > 4700 unique peptides. Bioinformatic tools were used to reanalyze peptide profiles aiming at identifying disease fingerprints, to uncover hidden disease-specific peptides physicochemical properties and to predict the most active proteases associated with their generation. The molecular patterns found in this study may be further validated in the future as disease biomarker not only for kidney diseases but also for extra-renal conditions, as a step forward towards the implementation of a paradigm of predictive, preventive and personalized (3P) medicine.


Age Differences in Hospital Mortality for Acute Myocardial Infarction: Implications for Hospital Profiling.
Publicly reported hospital risk-standardized mortality rates (RSMRs) for acute myocardial infarction (AMI) are calculated for Medicare beneficiaries. Outcomes for older patients with AMI may not reflect general outcomes. To examine the relationship between hospital 30-day RSMRs for older patients (aged ≥65 years) and those for younger patients (aged 18 to 64 years) and all patients (aged ≥18 years) with AMI. Retrospective cohort study. 986 hospitals in the ACTION (Acute Coronary Treatment and Intervention Outcomes Network) Registry-Get With the Guidelines. Adults hospitalized for AMI from 1 October 2010 to 30 September 2014. Hospital 30-day RSMRs were calculated for older, younger, and all patients using an electronic health record measure of AMI mortality endorsed by the National Quality Forum. Hospitals were ranked by their 30-day RSMRs for these 3 age groups, and agreement in rankings was plotted. The correlation in hospital AMI achievement scores for each age group was also calculated using the Hospital Value-Based Purchasing (HVBP) Program method computed with the electronic health record measure. 267 763 and 276 031 AMI hospitalizations among older and younger patients, respectively, were identified. Median hospital 30-day RSMRs were 9.4%, 3.0%, and 6.2% for older, younger, and all patients, respectively. Most top- and bottom-performing hospitals for older patients were neither top nor bottom performers for younger patients. In contrast, most top and bottom performers for older patients were also top and bottom performers for all patients. Similarly, HVBP achievement scores for older patients correlated weakly with those for younger patients (R = 0.30) and strongly with those for all patients (R = 0.92). Minority of U.S. hospitals. Hospital mortality rankings for older patients with AMI inconsistently reflect rankings for younger patients. Incorporation of younger patients into assessment of hospital outcomes would permit further examination of the presence and effect of age-related quality differences. American College of Cardiology.


Carbohydrate Intake in Form of Gel Is Associated With Increased Gastrointestinal Distress but Not With Performance Differences Compared With Liquid Carbohydrate Ingestion During Simulated Long-Distance Triathlon.
The ingestion of exogenous carbohydrates (CHO) during prolonged endurance exercise, such as long-distance triathlon, is considered beneficial with regard to performance. However, little is known about whether this performance benefit differs among different forms of CHO administration. To this end, the purpose of our study was to determine the impact of CHO ingestion from a semisolid source (GEL) on measures of performance and gastrointestinal (GI) comfort compared with CHO ingestion from a liquid source (LIQ). Nine well-trained triathletes participated in this randomized crossover study. Each participant completed a 60-min swim, 180-min bike exercise, and a 60-min all-out run in a laboratory environment under 2 conditions, once while receiving 67.2 ± 7.2 g · h-1 (M ± SD) of CHO from GEL and once while receiving 67.8 ± 4.2 g · h-1 of CHO from LIQ. The amount of fluid provided was matched among conditions. Respiratory exchange ratio (RER), blood glucose, and lactate as well as GI discomfort were assessed at regular intervals during the experiment. The distance covered during the final all-out run was not significantly different among participants ingesting GEL (11.81 ± 1.38 km) and LIQ (11.91 ± 1.53 km; p = .89). RER, blood glucose, and lactate did not differ significantly at any time during the experiment. Seven participants reported GI discomfort with GEL, and no athlete reported GI discomfort with LIQ (p = .016). This study suggests that administration of GEL does not alter long-distance triathlon performance when compared with LIQ, but GEL seems to be associated with reduced GI tolerance. Athletes should consider this a potential disadvantage of GEL administration during long-distance triathlon.


Bibliometrics: tracking research impact by selecting the appropriate metrics.
Traditionally, the success of a researcher is assessed by the number of publications he or she publishes in peer-reviewed, indexed, high impact journals. This essential yardstick, often referred to as the impact of a specific researcher, is assessed through the use of various metrics. While researchers may be acquainted with such matrices, many do not know how to use them to enhance their careers. In addition to these metrics, a number of other factors should be taken into consideration to objectively evaluate a scientist's profile as a researcher and academician. Moreover, each metric has its own limitations that need to be considered when selecting an appropriate metric for evaluation. This paper provides a broad overview of the wide array of metrics currently in use in academia and research. Popular metrics are discussed and defined, including traditional metrics and article-level metrics, some of which are applied to researchers for a greater understanding of a particular concept, including varicocele that is the thematic area of this Special Issue of Asian Journal of Andrology. We recommend the combined use of quantitative and qualitative evaluation using judiciously selected metrics for a more objective assessment of scholarly output and research impact.


Modifying cancer-related fatigue by optimizing sleep quality.
Cancer-related fatigue is reported by patients to be the most distressing and persistent symptom experienced during and after treatment. Unrelieved fatigue often accompanies other symptoms and leads to decreased physical functioning and lower health-related quality of life. Various factors, including daytime sleepiness and sleep disturbances, have been reported to influence perceptions of fatigue. This article shares current knowledge about the relationships among cancer-related fatigue, sleep disturbances, and daytime sleepiness, and makes recommendations for routine screening, assessment, and interventions to modify fatigue through optimizing sleep quality in adult cancer patients. Evidence is reviewed for nonpharmacologic and pharmacologic interventions for optimizing sleep quality in patients with acute or chronic insomnia secondary to medical illnesses, including cancer. A summary of interventions is presented that focuses on optimizing sleep quality in attempt to lower fatigue. These interventions may be helpful for adult cancer patients experiencing insomnia but will require further testing to establish their efficacy in this population. Recommendations for research are provided, including the need to increase knowledge on the relationships among fatigue, sleep disturbances, daytime sleepiness, and other symptoms in various disease sites, stages, and treatments of cancer and the need for further testing of the measurements used for the evaluation of sleep quality in clinical practice and research.


Human Monocyte Heterogeneity as Revealed by High-Dimensional Mass Cytometry.
Objective- Three distinct human monocyte subsets have been identified based on the surface marker expression of CD14 and CD16. We hypothesized that monocytes were likely more heterogeneous in composition. Approach and Results- We used the high dimensionality of mass cytometry together with the FlowSOM clustering algorithm to accurately identify and define monocyte subsets in blood of healthy human subjects and those with coronary artery disease (CAD). To study the behavior and functionality of the newly defined monocyte subsets, we performed RNA sequencing, transwell migration, and efferocytosis assays. Here, we identify 8 human monocyte subsets based on their surface marker phenotype. We found that 3 of these subsets fall within the CD16+ nonclassical monocyte population and 4 subsets belong to the CD14+ classical monocytes, illustrating significant monocyte heterogeneity in humans. As nonclassical monocytes are important in modulating atherosclerosis in mice, we studied the functions of our 3 newly identified nonclassical monocytes in subjects with CAD. We found a marked expansion of a Slan+CXCR6+ nonclassical monocyte subset in CAD subjects, which was positively correlated with CAD severity. This nonclassical subset can migrate towards CXCL16 and shows an increased efferocytosis capacity, indicating it may play an atheroprotective role. Conclusions- Our data demonstrate that human nonclassical monocytes are a heterogeneous population, existing of several subsets with functional differences. These subsets have changed frequencies in the setting of severe CAD. Understanding how these newly identified subsets modulate CAD will be important for CAD-based therapies that target myeloid cells.


Capability of 2 gait measures for detecting response to gait training in stroke survivors: Gait Assessment and Intervention Tool and the Tinetti Gait Scale.
To characterize the performance of 2 observational gait measures, the Tinetti Gait Scale (TGS) and the Gait Assessment and Intervention Tool (G.A.I.T.), in identifying improvement in gait in response to gait training. In secondary analysis from a larger study of multimodal gait training for stroke survivors, we measured gait at pre-, mid-, and posttreatment according to G.A.I.T. and TGS, assessing their capability to capture recovery of coordinated gait components. Large medical center. Cohort of stroke survivors (N=44) greater than 6 months after stroke. All subjects received 48 sessions of a multimodal gait-training protocol. Treatment consisted of 1.5 hours per session, 4 sessions per week for 12 weeks, receiving these 3 treatment aspects: (1) coordination exercise, (2) body weight-supported treadmill training, and (3) overground gait training, with 46% of subjects receiving functional electrical stimulation. All subjects were evaluated with the G.A.I.T. and TGS before and after completing the 48-session intervention. An additional evaluation was performed at midtreatment (after session 24). For the total subject sample, there were significant pre-/post-, pre-/mid-, and mid-/posttreatment gains for both the G.A.I.T. and the TGS. According to the G.A.I.T., 40 subjects (91%) showed improved scores, 2 (4%) no change, and 2 (4%) a worsening score. According to the TGS, only 26 subjects (59%) showed improved scores, 16 (36%) no change, and 1 (2%) a worsening score. For 1 treatment group of chronic stroke survivors, the TGS failed to identify a significant treatment response to gait training, whereas the G.A.I.T. measure was successful. The G.A.I.T. is more sensitive than the TGS for individual patients and group treatment response in identifying recovery of volitional control of gait components in response to gait training.


Malaria and nutritional status in children living on the coast of Kenya.
The relation between malnutrition and malaria is controversial. On the one hand, malaria may cause malnutrition, whereas on the other hand, malnutrition itself may modulate susceptibility to the disease. The objective was to investigate the association between Plasmodium falciparum malaria and malnutrition in a cohort of Kenyan children. The study involved the longitudinal follow-up of children aged 0-95 [corrected] mo for clinical malaria episodes and anthropometric measurements through 4 cross-sectional surveys. We used Poisson regression analysis to investigate the association between malaria and nutritional status. The crude incidence rate ratios (IRRs) for malaria during the 6-mo period before assessment in children defined as malnourished on the basis of low height-for-age or low weight-for-age z scores (<-2) were 1.17 (95% CI: 0.91, 1.50; P=0.21) and 0.94 (0.71, 1.25; P=0.67), respectively, which suggests no association between malaria and the subsequent development of protein-energy malnutrition. However, we found that age acted as an effect modifier in the association between malaria episodes and malnutrition on prospective follow-up. The IRR for malaria in children aged 0-2 y, who were subsequently characterized as underweight, was 1.65 (1.10, 2.20; P=0.01), and a significant overall relation between malaria and stunting was found on regression analysis after adjustment for the interaction with age (IRR: 1.91; 1.01, 3.58; P=0.04). Although children living on the coast of Kenya continue to experience clinical episodes of uncomplicated malaria throughout the first decade of life, the effect of malaria on nutritional status appears to be greatest during the first 2 y of life.


Cardiomyocyte d-dopachrome tautomerase protects against heart failure.
The mechanisms contributing to heart failure remain incompletely understood. d-dopachrome tautomerase (DDT) is a member of the macrophage migration inhibitory factor family of cytokines and is highly expressed in cardiomyocytes. This study examined the role of cardiomyocyte DDT in the setting of heart failure. Patients with advanced heart failure undergoing transplantation demonstrated decreased cardiac DDT expression. To understand the effect of loss of cardiac DDT in experimental heart failure, cardiomyocyte-specific DDT-KO (DDT-cKO) and littermate control mice underwent surgical transverse aortic constriction (TAC) to induce cardiac pressure overload. DDT-cKO mice developed more rapid cardiac contractile dysfunction, greater cardiac dilatation, and pulmonary edema after TAC. Cardiomyocytes from DDT-cKO mice after TAC had impaired contractility, calcium transients, and reduced expression of the sarcoplasmic reticulum calcium ATPase. The DDT-cKO hearts also exhibited diminished angiogenesis with reduced capillary density and lower VEGF-A expression after TAC. In pharmacological studies, recombinant DDT (rDDT) activated endothelial cell ERK1/2 and Akt signaling and had proangiogenic effects in vitro. The DDT-cKO hearts also demonstrated more interstitial fibrosis with enhanced collagen and connective tissue growth factor expression after TAC. In cardiac fibroblasts, rDDT had an antifibrotic action by inhibiting TGF-β-induced Smad-2 activation. Thus, endogenous cardiomyocyte DDT has pleiotropic actions that are protective against heart failure.


Association of deep white matter infarction with chronic communicating hydrocephalus: implications regarding the possible origin of normal-pressure hydrocephalus.
The coexistence of cerebrovascular disease leading to deep white matter infarction and normal-pressure hydrocephalus has been noted previously in clinical studies, as both diseases can present with the triad of gait disturbance, dementia, and incontinence. The purpose of this MR study was to determine if the two diseases demonstrated a statistical association. Evidence of patchy periventricular hyperintensity representing presumed deep white matter infarction was sought in 20 patients shunted for normal-pressure hydrocephalus and in 35 additional consecutive patients with clinical symptoms and MR findings consistent with normal-pressure hydrocephalus. Deep white matter infarction was also sought in 62 consecutive age-matched control subjects. There was a statistically significant (p less than .001) higher association (58%) of marked infarction in the 55 patients with normal-pressure hydrocephalus than in the age-matched controls (24%). MR findings of communicating hydrocephalus (ventriculomegaly and increased aqueductal CSF flow void) were sought in 78 consecutive patients with presumed deep white matter infarction, and the degree of severity of the two diseases was also found to be statistically significant (p less than .05). In view of this association, the possibility that the two diseases are related was considered. A potential mechanism is discussed whereby deep white matter infarction leading to decreased periventricular tensile strength could result in communicating hydrocephalus. It is plausible that normal-pressure hydrocephalus may result from a number of different insults to the brain.


Development of a bioanalytical test battery for water quality monitoring: Fingerprinting identified micropollutants and their contribution to effects in surface water.
Surface waters can contain a diverse range of organic pollutants, including pesticides, pharmaceuticals and industrial compounds. While bioassays have been used for water quality monitoring, there is limited knowledge regarding the effects of individual micropollutants and their relationship to the overall mixture effect in water samples. In this study, a battery of in vitro bioassays based on human and fish cell lines and whole organism assays using bacteria, algae, daphnids and fish embryos was assembled for use in water quality monitoring. The selection of bioassays was guided by the principles of adverse outcome pathways in order to cover relevant steps in toxicity pathways known to be triggered by environmental water samples. The effects of 34 water pollutants, which were selected based on hazard quotients, available environmental quality standards and mode of action information, were fingerprinted in the bioassay test battery. There was a relatively good agreement between the experimental results and available literature effect data. The majority of the chemicals were active in the assays indicative of apical effects, while fewer chemicals had a response in the specific reporter gene assays, but these effects were typically triggered at lower concentrations. The single chemical effect data were used to improve published mixture toxicity modeling of water samples from the Danube River. While there was a slight increase in the fraction of the bioanalytical equivalents explained for the Danube River samples, for some endpoints less than 1% of the observed effect could be explained by the studied chemicals. The new mixture models essentially confirmed previous findings from many studies monitoring water quality using both chemical analysis and bioanalytical tools. In short, our results indicate that many more chemicals contribute to the biological effect than those that are typically quantified by chemical monitoring programs or those regulated by environmental quality standards. This study not only demonstrates the utility of fingerprinting single chemicals for an improved understanding of the biological effect of pollutants, but also highlights the need to apply bioassays for water quality monitoring in order to prevent underestimation of the overall biological effect.


Trilinear modeling of event-related potentials.
This paper describes a method for estimating a set of spatial components (brain maps) and temporal components (waveforms) of brain potentials. These components play the role of bases of a coordinate system, in the sense that the brain potentials of any subject can be represented as superpositions of these components. The representation is unique given the spatial and temporal components, and this decomposition is particularly appealing for comparing the brain potentials of different subjects (say alcoholics and controls). It can also be used for single trial modeling, clinical classification of patients, and data filtering. The method is based on the topographic component model (TCM, Möcks 1988) which models brain potentials in a trilinear form. We extend the TCM in two aspects. First, the diagonal amplitude matrix is replaced by a general loading matrix based on some neurophysiological considerations. Secondly, the number of spatial components and the number of temporal components can be different. The spatial components and temporal components are obtained respectively by performing singular value decomposition (SVD). This method is illustrated with visual P3 data.


The two-wavelength method of microspectrophotometry. II. A set of tables to facilitate the calculations.
The calculations required for two-wavelength measurements are time consuming and laborious. In order to circumvent this limitation of the method, a set of tables which combined four operations into one has been designed and is reproduced within. The tables are based on Patau's formulae. The two transmission readings obtained according to the photometric method provide the coordinates which lead directly to a value for the relative absorbance. The product of this absorbance and the area of the photometric field gives the relative amount of chromophore in the field. The range of transmission values covered in the table corresponds to the effective range of the two-wavelength method.


Nutrition and Exercise Rehabilitation in Obesity hypoventilation syndrome (NERO): a pilot randomised controlled trial.
Respiratory management of obesity hypoventilation syndrome (OHS) focusses on the control of sleep-disordered breathing rather than the treatment of obesity. Currently, there are no data from randomised trials of weight loss targeted rehabilitation programmes for patients with OHS. A 3-month multimodal hybrid inpatient-outpatient motivation, exercise and nutrition rehabilitation programme, in addition to non invasive ventilation (NIV), would result in greater per cent weight loss compared with standard care. A single-centre pilot randomised controlled trial allocated patients to either standard care or standard care plus rehabilitation. Primary outcome was per cent weight loss at 12 months with secondary exploratory outcomes of weight loss, exercise capacity and health-related quality of life (HRQOL) at the end of the rehabilitation programme to assess the intervention effect. Thirty-seven patients (11 male, 59.8±12.7 years) with a body mass index of 51.1±7.7 kg/m2 were randomised. At 12 months, there was no between-group difference in per cent weight loss (mean difference -5.9% (95% CI -14.4% to 2.7%; p=0.17)). At 3 months, there was a greater per cent weight loss (mean difference -5% (95% CI -8.3% to -1.4%; p=0.007)), increased exercise capacity (6 min walk test 60 m (95% CI 29.5 to 214.5) vs 20 m (95% CI 11.5 to 81.3); p=0.036) and HRQL (mean difference SF-36 general health score (10 (95% CI 5 to 21.3) vs 0 (95% CI -5 to 10); p=0.02)) in the rehabilitation group. In patients with OHS, a 3-month comprehensive rehabilitation programme, in addition to NIV, resulted in improved weight loss, exercise capacity and QOL at the end of the rehabilitation period, but these effects were not demonstrated at 12 months, in part, due to the limited retention of patients at 12 months. Pre-results; NCT01483716.


Central activation of the A1 adenosine receptor (A1AR) induces a hypothermic, torpor-like state in the rat.
Since central activation of A1 adenosine receptors (A1ARs) plays an important role in the induction of the hypothermic and hypometabolic torpid state in hibernating mammals, we investigated the potential for the A1AR agonist N6-cyclohexyladenosine to induce a hypothermic, torpor-like state in the (nonhibernating) rat. Core and brown adipose tissue temperatures, EEG, heart rate, and arterial pressure were recorded in free-behaving rats, and c-fos expression in the brain was analyzed, following central administration of N6-cyclohexyladenosine. Additionally, we recorded the sympathetic nerve activity to brown adipose tissue; expiratory CO2 and skin, core, and brown adipose tissue temperatures; and shivering EMGs in anesthetized rats following central and localized, nucleus of the solitary tract, administration of N6-cyclohexyladenosine. In rats exposed to a cool (15°C) ambient temperature, central A1AR stimulation produced a torpor-like state similar to that in hibernating species and characterized by a marked fall in body temperature due to an inhibition of brown adipose tissue and shivering thermogenesis that is mediated by neurons in the nucleus of the solitary tract. During the induced hypothermia, EEG amplitude and heart rate were markedly reduced. Skipped heartbeats and transient bradycardias occurring during the hypothermia were vagally mediated since they were eliminated by systemic muscarinic receptor blockade. These findings demonstrate that a deeply hypothermic, torpor-like state can be pharmacologically induced in a nonhibernating mammal and that recovery of normothermic homeostasis ensues upon rewarming. These results support the potential for central activation of A1ARs to be used in the induction of a hypothermic, therapeutically beneficial state in humans.


Proposed federal legislation jeopardizes patient privacy.
In the last year there has been a move to enact federal legislation concerning private health-care information. This move has been fueled by a growing trend toward the computerization and electronic transmission of health-care information. These advances in technology call for appropriate new protections of patients' privacy. Unfortunately, the proposed legislation has not received adequate attention in the medical community. Physicians and patients in general are not aware of the legislation and have not been engaged in shaping its contents. In its current form, the legislation would seriously undermine traditional protections of confidentiality that are ensured by physicians. The flaws of the proposed legislation are examined in this article.


Occupational class inequalities in all-cause and cause-specific mortality among middle-aged men in 14 European populations during the early 2000s.
This study analyses occupational class inequalities in all-cause mortality and four specific causes of death among men, in Europe in the early 2000s, and is the most extensive comparative analysis of occupational class inequalities in mortality in Europe so far. Longitudinal data, obtained from population censuses and mortality registries in 14 European populations, from around the period 2000-2005, were used. Analyses concerned men aged 30-59 years and included all-cause mortality and mortality from all cancers, all cardiovascular diseases (CVD), all external, and all other causes. Occupational class was analysed according to five categories: upper and lower non-manual workers, skilled and unskilled manual workers, and farmers and self-employed combined. Inequalities were quantified with mortality rate ratios, rate differences, and population attributable fractions (PAF). Relative and absolute inequalities in all-cause mortality were more pronounced in Finland, Denmark, France, and Lithuania than in other populations, and the same countries (except France) also had the highest PAF values for all-cause mortality. The main contributing causes to these larger inequalities differed strongly between countries (e.g., cancer in France, all other causes in Denmark). Relative and absolute inequalities in CVD mortality were markedly lower in Southern European populations. We conclude that relative and absolute occupational class differences in all-cause and cause specific mortality have persisted into the early 2000's, although the magnitude differs strongly between populations. Comparisons with previous studies suggest that the relative gap in mortality between occupational classes has further widened in some Northern and Western European populations.


A randomised comparison of monoplane versus biplane fluoroscopy in patients undergoing percutaneous coronary intervention: the RAMBO trial.
Interventional cardiologists are exposed to substantial occupational ionising radiation. This study sought to investigate differences in radiation exposure in biplane versus monoplane coronary angiography and percutaneous coronary interventions (PCI). RAMBO (RAdiation exposure in Monoplane versus Biplane cOronary angiography and interventions) was a prospective, randomised, two-arm, single-centre, open-label trial, enrolling a total of 430 patients undergoing coronary angiography. Patients were randomly assigned to biplane or monoplane imaging. The primary efficacy measure, the operator radiation dose at the level of the left arm as measured by a wearable electronic dosimeter, was significantly higher in the biplane as compared to the monoplane group (4 [1-13] µSv vs 2 [0-6.8] µSv, p<0.001). The dose area product was 11,955 (7,095-18,246) mGy*cm2 and 8,349 (5,851-14,159) mGy*cm2 in the biplane and the monoplane groups, respectively (p<0.001). While fluoroscopy time did not differ between the groups (p=0.89), the amount of contrast medium was lower with biplane as compared with monoplane imaging (p<0.001). Biplane imaging for coronary angiography and PCI is related to an increased radiation exposure for the interventional cardiologist as compared with monoplane imaging. Monoplane imaging should be considered for advanced radioprotection in cardiac catheterisation, with biplane imaging used for selected cases only.


Crude Edible Fig (Ficus carica) Leaf Extract Prevents Diethylstilbestrol (DES)-Induced DNA Strand Breaks in Single-Cell Gel Electrophoresis (SCGE)/Comet Assay: Literature Review and Pilot Study.
Fig (Ficus carica) trees are among the oldest plants on earth. The chemopreventive properties of constituent polyphenols and fiber that implicate figs in having a functional role in averting cancer have not been fully elucidated. We therefore hypothesized that fig leaf extract would inhibit (or attenuate) DES-induced DNA single-strand breakage in MCF10A human breast epithelial cells. To test this hypothesis, MCF10A cells were treated with DES (1, 10, 100 μM), crude fig leaf extract (5, 10, 15 μL), or concomitant doses of DES (100 μM)/fig leaf extract (5, 10, 15 μL). The cells were analyzed for DNA strand breakage using the SCGE/COMET assay with mean olive tail moment as a marker of DNA damage. DES induced DNA strand breaks at all treatment levels compared to DMSO and non-treatment controls. DES at concentrations of 1, 10, and 100 μM produced mean olive tail moments of 1.2082 (177.6%), 1.2702 (186.7%), and 1.1275 (165.7%), respectively, which were statistically significantly (p<0.05) higher than the DMSO control value (0.6803). Exposure to fig leaf extract produced no DNA damage. Rather, a desirable dose-dependent reduction in DES-induced DNA strand breaks was observed. Composite treatment of MCF10A cells with DES and fig leaf extract attenuated DES-induced DNA strand breaks. Taken together, these results suggest a potential mechanism for cancer chemoprevention. Additional studies are necessary to identify relevant active ingredients, confirm the mechanism of action, and further elucidate the therapeutic potential of fig leaf extract for early-stage breast cancer chemoprevention.


The use of systematic reviews in the planning, design and conduct of randomised trials: a retrospective cohort of NIHR HTA funded trials.
A systematic review, with or without a meta-analysis, should be undertaken to determine if the research question of interest has already been answered before a new trial begins. There has been limited research on how systematic reviews are used within the design of new trials, the aims of this study were to investigate how systematic reviews of earlier trials are used in the planning and design of new randomised trials. Documentation from the application process for all randomised trials funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) between 2006 and 2008 were obtained. This included the: commissioning brief (if appropriate), outline application, minutes of the Board meeting in which the outline application was discussed, full application, detailed project description, referee comments, investigator response to referee comments, Board minutes on the full application and the trial protocol. Data were extracted on references to systematic reviews and how any such reviews had been used in the planning and design of the trial. 50 randomised trials were funded by NIHR HTA during this period and documentation was available for 48 of these. The cohort was predominately individually randomised parallel trials aiming to detect superiority between two treatments for a single primary outcome. 37 trials (77.1%) referenced a systematic review within the application and 20 of these (i.e. 41.7% of the total) used information contained in the systematic review in the design or planning of the new trial. The main areas in which systematic reviews were used were in the selection or definition of an outcome to be measured in the trial (7 of 37, 18.9%), the sample size calculation (7, 18.9%), the duration of follow up (8, 21.6%) and the approach to describing adverse events (9, 24.3%). Boards did not comment on the presence/absence or use of systematic reviews in any application. Systematic reviews were referenced in most funded applications but just over half of these used the review to inform the design. There is an expectation from funders that applicants will use a systematic review to justify the need for a new trial but no expectation regarding further use of a systematic review to aid planning and design of the trial. Guidelines for applicants and funders should be developed to promote the use of systematic reviews in the design and planning of randomised trials, to optimise delivery of new studies informed by the most up-to-date evidence base and to minimise waste in research.


The role of ziprasidone in adjunctive use with lithium or valproate in maintenance treatment of bipolar disorder.
This article addresses the clinical role for ziprasidone used adjunctively with a mood stabilizer in maintenance treatment of bipolar disorder. This review also addresses the strengths and limitations of design features in adjunctive studies of second-generation antipsychotic drugs added to mood stabilizers. The principal study relevant to this review enrolled subjects who were ≥18 years of age, experiencing a recent or current manic or mixed bipolar I episode, with at least moderately severe current manic symptoms. To meet criteria for randomization to 6 months maintenance treatment, patients had to have failed a short course of treatment with either lithium or valproate and achieved benefit with added ziprasidone for 8 consecutive weeks. Time to intervention for a new mood episode as well as time to discontinuation for any reason was significantly longer with adjunctive ziprasidone treatment than with monotherapy treatment with mood stabilizer. Three dosages of ziprasidone augmentation were studied. Patients treated with 120 mg/day had better efficacy and overall outcomes than did patients who received 80 or 160 mg/day of ziprasidone. Good evidence exists that adjunctive ziprasidone will likely provide greater overall efficacy coupled with good tolerability for at least a 6-month period than a strategy of continued monotherapy with a mood stabilizer. Changes in open phases of maintenance studies to reduce study enrichment, in study endpoints, and in statistical approaches to analysis of data are warranted.


Calibrating BOLD fMRI activations with neurovascular and anatomical constraints.
Functional magnetic resonance imaging signals, in addition to reflecting neuronal response, also contain physiological variances. These factors may introduce variability into blood oxygen level-dependent (BOLD) activation results, particularly in different population groups. In this study, we hypothesized that the amplitude as well as the spatial extent of BOLD activation could be improved after minimizing the variance caused by the neurovascular and anatomical factors. Subjects were scanned while they performed finger tapping and digit-symbol substitution tasks (DSSTs). Partial volume and neurovascular effects were estimated on a voxelwise basis using subjects' own gray matter volume (GMV), breath holding (BH), and amplitude of low-frequency fluctuation (ALFF). The results showed that all individual's GMV, BH, and ALFF could significantly predict motor and DSST activations in a voxelwise manner. Whole-brain analyses were conducted to regress out the anatomical and neurovascular information. Differential maps (obtained using t-test) indicated that the adjustment tended to suppress activation in regions that were near vessels such as midline cingulate gyrus, bilateral anterior insula, and posterior cerebellum. These results suggest that voxelwise adjustment using GMV and neurovascular parameters can minimize structural and physiological variances among individuals and be used for quantitative comparisons.


Knock-out of β-glucosidase 2 has no influence on dextran sulfate sodium-induced colitis.
The non-lysosomal glucosylceramidase, β-glucosidase (Gba2), hydrolyzes glucosylceramide to glucose and ceramide (Cer). Cer is a potent second-messenger lipid that plays an important role in signaling cascades involved in apoptosis. The aim of this study was to investigate whether Gba2 knock-out (Gba2(-/-)) affects the extent of dextran sulfate sodium (DSS)-induced colitis in mice. Acute colitis was induced in wild-type (WT) and Gba2(-/-) mice by administration of 2% DSS in drinking water. After 7 days, mice underwent colonoscopy and were sacrificed. Both DSS-treated WT (n = 10) and Gba2(-/-) (n = 12) mice showed elevated histological and endoscopic scores compared to respective H(2)O controls (n = 9 each). However, no significant differences between the DSS groups were detected. Flow cytometric analysis of propidium iodide staining, cleavage of caspases-3 and -8, indicative for apoptosis, as well as Cer levels were not altered in DSS-treated WT or Gba2(-/-) mice. Gba2(-/-) resulted in slightly decreased expression of glucocerebrosidase (Gba1) as well as in upregulation of proteins being involved in cellular regeneration, such as STAT3 (signal transducer and activator of transcription), JNK and iNOS, upon DSS treatment. We demonstrate that Gba2(-/-) does not affect the extent of DSS-induced inflammation in mice, however, it might be involved in tissue regeneration in response to toxic agents.


Myalgic encephalomyelitis/chronic fatigue Syndrome (ME/CFS): Investigating care practices pointed out to disparities in diagnosis and treatment across European Union.
ME/CFS is a chronic, complex, multisystem disease that often limits the health and functioning of the affected patients. Diagnosing patients with ME/CFS is a challenge, and many different case definitions exist and are used in clinical practice and research. Even after diagnosis, medical treatment is very challenging. Symptom relief and coping may affect how patients live with their disease and their quality of life. There is no consensus on which diagnostic criteria should be used and which treatment strategies can be recommended for patients. The purpose of the current project was to map the landscape of the Euromene countries in respect of national guidelines and recommendations for case definition, diagnosis and clinical approaches for ME/CFS patients. A 23 items questionnaire was sent out by email to the members of Euromene. The form contained questions on existing guidelines for case definitions, treatment/management of the disease, tests and questionnaires applied, and the prioritization of information for data sampling in research. We obtained information from 17 countries. Five countries reported having national guidelines for diagnosis, and five countries reported having guidelines for clinical approaches. For diagnostic purposes, the Fukuda criteria were most often recommended, and also the Canadian Consensus criteria, the International Consensus Criteria and the Oxford criteria were used. A mix of diagnostic criteria was applied within those countries having no guidelines. Many different questionnaires and tests were used for symptom registration and diagnostic investigation. For symptom relief, pain and anti-depressive medication were most often recommended. Cognitive Behavioral Therapy and Graded Exercise treatment were often recommended as disease management and rehabilitative/palliative strategies. The lack of consistency in recommendations across European countries urges the development of regulations, guidance and standards. The results of this study will contribute to the harmonization of diagnostic criteria and treatment for ME/CFS in Europe.


Causal Discovery from Nonstationary/Heterogeneous Data: Skeleton Estimation and Orientation Determination.
It is commonplace to encounter nonstationary or heterogeneous data, of which the underlying generating process changes over time or across data sets (the data sets may have different experimental conditions or data collection conditions). Such a distribution shift feature presents both challenges and opportunities for causal discovery. In this paper we develop a principled framework for causal discovery from such data, called Constraint-based causal Discovery from Nonstationary/heterogeneous Data (CD-NOD), which addresses two important questions. First, we propose an enhanced constraint-based procedure to detect variables whose local mechanisms change and recover the skeleton of the causal structure over observed variables. Second, we present a way to determine causal orientations by making use of independence changes in the data distribution implied by the underlying causal model, benefiting from information carried by changing distributions. Experimental results on various synthetic and real-world data sets are presented to demonstrate the efficacy of our methods.


Mechano-sensitivity of mitochondrial function in mouse cardiac myocytes.
Mitochondria are an important source of reactive oxygen species (ROS). Although it has been reported that myocardial stretch increases cellular ROS production by activating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), referred to as X-ROS signalling, the involvement of mitochondria in X-ROS is not clear. Mitochondria are organelles that generate adenosine triphosphate (ATP) for cellular energy needs, which are mechanical-load-dependent. Therefore, it would not be surprising if these organelles had mechano-sensitive functions associated with stretch-induced ROS production. In the present study, we investigated the relation between X-ROS and mitochondrial stretch-sensitive responses in isolated mouse cardiac myocytes. The cells were subjected to 10% axial stretch using computer-controlled, piezo-manipulated carbon fibres attached to both cell ends. Cellular ROS production and mitochondrial membrane potential (Δψm) were assessed optically by confocal microscopy. The axial stretch increased ROS production and hyperpolarised Δψm. Treatment with a mitochondrial metabolic uncoupler, carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), at 0.5 μM did not suppress stretch-induced ROS production, whereas treatment with a respiratory Complex III inhibitor, antimycin A (5 μM), blunted the response. Although NOX inhibition by apocynin abrogated the stretch-induced ROS production, it did not suppress stretch-induced hyperpolarisation of Δψm. These results suggest that stretch causes activation of the respiratory chain to hyperpolarise Δψm, followed by NOX activation, which increases ROS production.


Strain induced new phase and indirect-direct band gap transition of monolayer InSe.
The effect of in-plane strain on monolayer InSe has been systematically investigated by using first-principles calculations. It is found that monolayer InSe exhibits superior mechanical flexibility, which can sustain a tensile strain up to 27% in the armchair direction. More importantly, a new phase with inversion symmetry denoted as phase-II is obtained when the tensile strain increases over 25% along the zigzag direction, which is predicted to be metallic and thermodynamically stable at room temperature. And the phase-II InSe could show an out-of-plane negative Poisson's ratio after the uniaxial tensile strain is larger than 5%. Moreover, both uniaxial and biaxial compressive strains can trigger the indirect-to-direct band gap transition in the pristine monolayer InSe and its band gap decreases monotonously with the applied tensile strain, which offers an effective method to tune the electronic properties of monolayer InSe for its promising application in electronics and optoelectronics.


Comparison of gadofluorine-M and Gd-DTPA for noninvasive staging of atherosclerotic plaque stability using MRI.
Inflammation and neovascularization play critical roles in the stability of atherosclerotic plaques. Whole-body quantitative assessment of these plaque features may improve patient risk-stratification for life-threatening thromboembolic events and direct appropriate intervention. In this report, we determined the utility of the MR contrast agent gadofluorine-M (GdF) for staging plaque stability and compared this to the conventional agent Gd-DTPA. Five control and 7 atherosclerotic rabbits were sequentially imaged after administration of Gd-DTPA (0.2 mmol/kg) and GdF (0.1 mmol/kg) using a T(1)-weighted pulse sequence on a 3-T MRI scanner. Diseased aortic wall could be distinguished from normal wall based on wall-to-muscle contrast-to-noise values after GdF administration. RAM-11 (macrophages) and CD-31 (endothelial cells) immunostaining of MR-matched histological sections revealed that GdF accumulation was related to the degree of inflammation at the surface of plaques and the extent of core neovascularization. Importantly, an MR measure of GdF accumulation at both 1 and 24 hours after injection but not Gd-DTPA at peak enhancement was shown to correlate with a quantitative histological morphology index related to these 2 plaque features. GdF-enhanced MRI of atherosclerotic plaques allows noninvasive quantitative information about plaque composition to be acquired at multiple time points after injection (within 1 and up to 24 hours after injection). This dramatically widens the imaging window for assessing plaque stability that is currently attainable with clinically approved MR agents, therefore opening the possibility of whole-body (including coronary) detection of unstable plaques in the future and potentially improved mitigation of cataclysmic cardiovascular events.


Antitumour indolequinones: synthesis and activity against human pancreatic cancer cells.
An important determinant of the growth inhibitory activity of indolequinones against pancreatic cancer cells is substitution on the 2-position with 2-unsubstituted derivatives being markedly more potent. A series of indolequinones bearing a range of substituents on nitrogen and at the indolylcarbinyl position was prepared by copper(II)-mediated reaction of bromoquinones and enamines, followed by functional group interconversions. The compounds were then assayed for their ability to inhibit the growth of pancreatic cancer cells. The pKa of the leaving group at the 3-position was shown to influence growth inhibitory activity that is consistent with the proposed mechanism of action of reduction, loss of leaving group and formation of a reactive iminium species. Substitutions on the indole nitrogen were well tolerated with little influence on growth inhibitory activity while substitutions at the 5- and 6-positions larger than methoxy led to decreased activity. The studies presented define the range of substitutions of 2-unsubstituted indolequinones required for optimal growth inhibitory activity.


[Hygiene tips for kids. Concept and examples of realisation].
Basic hygiene measures aim at promoting and maintaining good health. The necessary routines are most effectively learned and adopted during childhood. These key findings form the basis for the educational programme "Hygiene Tips for Kids" which was initiated at the Department of Hygiene and Public Health at Bonn University under the auspices of WHO Europe in 2003. The programme addresses children, teachers and parents and offers a range of materials and activities tailored to the specific needs of the target groups based on expert advice. The objective is to exert a long-lasting, positive influence on the performance of hygiene routines. Campaigns are usually directed at pre-school, kindergarten and primary school settings, with the public health service personnel playing a crucial role in coordinating and implementing the various activities. Evaluation of a campaign in the federal state of Mecklenburg-Vorpommern has proven a positive effect on hand washing routines in pre-school as well as in the domestic setting. Moreover, Hygiene Tips for Kids has a sustained positive effect on the cooperation and communication between public health authorities and teachers, children and their parents. Teachers implement their own ideas within a framework of standardised information to suit their local needs. A long-term goal would be the obligatory integration of a sensible health education programme in the syllabus of pre-school, kindergarten and primary schools.


Therapeutic vaccination following early antiretroviral therapy elicits highly functional T cell responses against conserved HIV-1 regions.
'Kick and kill' cure strategies aim to induce HIV protein expression in latently infected cells (kick), and thus trigger their elimination by cytolytic T cells (kill). In the Research in Viral Eradication of HIV Reservoirs trial (NCT02336074), people diagnosed with primary HIV infection received immediate antiretroviral therapy (ART) and were randomised 24 weeks later to either a latency-reversing agent, vorinostat, together with ChAdV63.HIVconsv and MVA.HIVconsv vaccines, or ART alone. This intervention conferred no reduction in HIV-1 reservoir size over ART alone, despite boosting virus-specific CD4+ and CD8+ T cells. The effects of the intervention were examined at the cellular level in the two trial arms using unbiased computational analysis of polyfunctional scores. This showed that the frequency and polyfunctionality of virus-specific CD4+ and CD8+ T cell populations were significantly increased over 12 weeks post-vaccination, compared to the ART-only arm. HIV-specific IL-2-secreting CD8+ T cells also expanded significantly in the intervention arm and were correlated with antiviral activity against heterologous HIV in vitro. Therapeutic vaccination during ART commenced in primary infection can induce functional T cell responses that are phenotypically similar to those of HIV controllers. Analytical therapy interruption may help determine their ability to control HIV in vivo.


Suicidal ideation and behavior as adverse events of prescribed medications: An update for pharmacists.
Suicide is the tenth leading cause of death in the US, and the Food and Drug Administration (FDA) has labeled more than 125 prescription drugs for potential adverse effects of suicidal ideation and behavior. Several are in the top 200 for highest dispensed volume, including the entire class of antiepileptics. Also included are drugs used to treat urinary incontinence, an antibiotic, and smoking cessation agents. We describe the importance of pharmacists' identification and management of these complex adverse events and conclude with the potential for Department of Veterans Affairs and other big data longitudinal clinical research projects to provide additional insight into the complex causes of this adverse event. Questions persist about causality (pharmacologic provocation of suicide) in the context of psychiatric treatment response (treatment emergence) and the multifactorial pathogenesis of suicidal behavior, which is distinct from suicidal ideation. In the future, big data with the use of medical records (rather than claims) may provide valuable insights into this question. Pharmacists are encouraged to file adverse event reports for suicide and suicide attempts resulting in death, disability, or hospitalization via MedWatch even if the reports are incomplete. Resources to support pharmacists managing patients at risk include hotlines, chatlines, texting, and free federally funded online training.


An interactive website to aid young women's choice of contraception: feasibility and efficacy RCT.
Effective use of contraception can reduce numbers of unintended pregnancies, but misunderstandings and concerns about contraception abound. Increasingly, women seek health-care information online. To develop an interactive website to aid informed choice of contraceptive method, including long-acting reversible contraception (Phase I), and test its effectiveness in a parallel, single-blind randomised trial (Phase II). Approval came from London - Camden & King's Cross Research Ethics Committee (reference 17/LO/0112). For both phases, women aged 15-30 years were recruited from general practice, sexual health services, maternity services, community pharmacies and an abortion service. In Phase I, we conducted three systematic literature reviews, a review of YouTube (YouTube, LLC, San Bruno, CA, USA) videos about contraception, and focus groups and interviews with young women to explore barriers to and concerns and misperceptions about contraception. We then iteratively co-designed an interactive website, Contraception Choices [URL: www.contraceptionchoices.org (accessed June 2020)], with young women and a software company. In Phase II, we evaluated the website through a randomised trial that began as a feasibility trial. Early demand for Contraception Choices stimulated a design change from a feasibility to an efficacy trial, with follow-up for clinical outcomes at 3 and 6 months. A randomisation list was incorporated into the trial software program to allocate participants to the intervention (website) or control group (standard care). Contraception Choices is a co-designed, evidence-based, interactive website to aid informed choice of contraception. It provides information about different methods, addresses common concerns and offers tailored contraceptive options in response to individual preferences. Qualitative - participant views and experience of the intervention, assessed through qualitative interviews. Quantitative primary outcomes - follow-up rate at 6 months in the initial feasibility trial, using a long-acting reversible contraception method, and satisfaction with contraceptive method at 6 months in the efficacy trial. A total of 927 women were randomised online to the website (n = 464) or control group (n = 463), of whom 739 (80%) provided follow-up data at 6 months [786 women (85%) provided data at 3 and/or 6 months that were included in the analysis of primary outcomes]. There was little difference between groups in the proportion using long-acting reversible contraception at 6 months [30.4% intervention vs. 31.0% control, adjusted odds ratio after imputation 0.87 (95% confidence interval 0.60 to 1.27)] or in satisfaction with contraceptive method [proportion being 'satisfied' or 'very satisfied', 82.6% intervention vs. 82.1% control, adjusted odds ratio 0.93 (95% confidence interval 0.69 to 1.25)]. Qualitative evaluation indicated highly positive views about the website and increased knowledge of contraceptive methods that could dispel misperceptions. Women appreciated having information tailored to their specific needs and felt better prepared before consultations. We did not include intermediate measures, such as knowledge of contraceptive methods, intention to change method or confidence in discussing contraception with a health-care professional, which may have indicated other benefits of using the website. In future, the website should be studied in different settings (e.g. schools and in routine practice) to see whether or not it improves the quality or efficiency of contraceptive consultations. Our systematic review indicated wide-ranging influences on women's use of contraception globally. The website, Contraception Choices, was very popular with young women and contraception service providers. It was not associated with statistically significant differences in use of long-acting reversible contraception or satisfaction with contraceptive method at 6 months. Current Controlled Trials ISRCTN13247829. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 56. See the NIHR Journals Library website for further project information.


Self-aligned optical couplings by self-organized waveguides toward luminescent targets in organic/inorganic hybrid materials.
Self-organization of optical waveguides is observed between two opposed optical fibers placed in a photosensitive organic/inorganic hybrid material, Sunconnect. A luminescent target containing coumarin 481 was deposited onto the edge of one of the two fibers at the core. When a 448-nm write beam was introduced from the other fiber, the write beam and the luminescence from the photoexcited target increased the refractive index of Sunconnect to induce self-focusing. Traces of waveguides were seen to grow from the cores of both fibers and merged into a single self-aligned optical coupling between the fibers. This optical solder functionality enabled increases in both coupling efficiency and tolerance to lateral misalignment of the fibers.


Characteristics and complexity of chronic pain patients referred to a community-based multidisciplinary chronic pain clinic.
Community-based care fills an important service gap for patients living with chronic pain. Better understanding of unmet patient needs in the community may inform improved policy and resource allocation. The aim of this study was to describe patients presenting to a community-based, multidisciplinary chronic pain clinic in Vancouver, British Columbia. This is a retrospective cross-sectional study of 935 unique consecutive patients who completed an intake questionnaire between January 2016 and March 2017. All data were patient reported. Nine hundred thirty-five patient records were analyzed for descriptive characteristics. The mean age of the population was 49.5 (SD = 14.9) years; 70% were female. Approximately 50% of patients lived below the poverty line in Vancouver; 30% were not working due to disability, 51% had pain for more than 5 years, and 63% reported severe functional impairment. Substantial unmet need is demonstrated in this patient population accessing a community-based chronic pain clinic. The population described is mainly of working age with significant functional impairment, reflecting a high level of need due to severity and duration of symptoms, poverty, and other characteristics described.


Vasopressors during adult cardiac arrest: A systematic review and meta-analysis.
To systematically review the literature on the use of vasopressors during adult cardiac arrest to inform an update of international guidelines. PRISMA guidelines were followed. We searched Medline, Embase, Web of Science, CINAHL, and the Cochrane Library for controlled trials and observational studies. The population included adults with cardiac arrest in any setting. Pairs of investigators reviewed studies for relevance, extracted data, and assessed the risk of bias for individual studies. Certainty of evidence was evaluated using GRADE for controlled trials and meta-analyses were performed when at least two studies could be pooled. We included 15 controlled trials and 67 observational studies. The majority of studies included out-of-hospital cardiac arrest only. Meta-analyses were performed for two controlled trials comparing epinephrine to placebo, three comparing vasopressin to epinephrine, and three comparing epinephrine plus vasopressin to epinephrine only. All controlled trials ranged between low to some concern in risk of bias. The certainty of evidence ranged from very low to high. Risk of bias for observational studies was generally critical or serious, largely due to confounding and selection bias. Controlled trial data suggest that epinephrine improves return of spontaneous circulation, survival to hospital discharge, and 3-month survival in out-of-hospital cardiac arrest. The improvement in short-term outcomes appeared more pronounced for non-shockable rhythms. Differences in long-term neurological outcome did not reach statistical significance, although there was a signal toward improved outcomes. Controlled trial data indicated no benefit from vasopressin with or without epinephrine compared to epinephrine only.