Interpretation of time-to-event outcomes in randomized trials: an online randomized experiment.

Background: Multiple features in the presentation of randomized controlled trial (RCT) results are known to influence comprehension and interpretation. We aimed to compare interpretation of cancer RCTs with time-to-event outcomes when the reported treatment effect measure is the hazard ratio (HR), difference in restricted mean survival times (RMSTD), or both (HR+RMSTD). We also assessed the prevalence of misinterpretation of the HR. Methods: We carried out a randomized experiment. We selected 15 cancer RCTs with statistically significant treatment effects for the primary outcome. We masked each abstract and created three versions reporting either the HR, RMSTD, or HR+RMSTD. We randomized corresponding authors of RCTs and medical residents and fellows to one of 15 abstracts and one of 3 versions. We asked how beneficial the experimental treatment was (0-10 Likert scale). All participants answered a multiple-choice question about interpretation of the HR. Participants were unaware of the study purpose. Results: We randomly allocated 160 participants to evaluate an abstract reporting the HR, 154 to the RMSTD, and 155 to both HR+RMSTD. The mean Likert score was statistically significantly lower in the RMSTD group when compared with the HR group (mean difference -0.8, 95% confidence interval, -1.3 to -0.4, P < 0.01) and when compared with the HR+RMSTD group (difference -0.6, -1.1 to -0.1, P = 0.05). In all, 47.2% (42.7%-51.8%) of participants misinterpreted the HR, with 40% equating it with a reduction in absolute risk. Conclusion: Misinterpretation of the HR is common. Participants judged experimental treatments to be less beneficial when presented with RMSTD when compared with HR. We recommend that authors present RMST-based measures alongside the HR in reports of RCT results.

60 dB high-extinction auto-configured Mach-Zehnder interferometer.

Imperfections in integrated photonics manufacturing have a detrimental effect on the maximal achievable visibility in interferometric architectures. These limits have profound implications for further technological developments in photonics and in particular for quantum photonic technologies. Active optimization approaches, together with reconfigurable photonics, have been proposed as a solution to overcome this. In this Letter, we demonstrate an ultrahigh (>60 dB) extinction ratio in a silicon photonic device consisting of cascaded Mach-Zehnder interferometers, in which additional interferometers function as variable beamsplitters. The imperfections of fabricated beamsplitters are compensated using an automated progressive optimization algorithm with no requirement for pre-calibration. This work shows the possibility of integrating and accurately controlling linear-optical components for large-scale quantum information processing and other applications.

Psychological stress moderates the relationship between running volume and CD4+ T cell subpopulations.

Endurance-based exercise training can lead to alterations in components of the immune system, but it is unknown how psychological stress (another potent immunomodulator) may impact these changes. The purpose of this study was to determine the moderating role of psychological stress on exercise-induced immune changes. Twenty-nine recreational runners were recruited for this study four weeks before completing a marathon. Each subject reported: weekly training volume (miles/wk) for the week prior to the study visit; completed the Perceived Stress Scale (PSS), the state version of the State-Trait Anxiety Inventory (STAI) and the Penn State Worry Questionnaire (PSWQ); and donated blood for assessment of CD4+ T cell subpopulations and mitogen-induced cytokine production. Participants ran an average of 30 (±13.4) miles (1 mile=1.6 km) per week. Average values (SD) for immune biomarkers were: regulatory T cells (Treg), 3.2% (±1.2%); type 1 regulatory cells (Tr1), 27.1% (±8.3%); T helper 3 (Th3), 1.8% (±0.7%); interferon gamma (IFNγ), 3.1 pg/ml (±1.0); interleukin (IL)-4, 1.4 pg/ml (±1.1); IFNγ/IL-4, 8.6 (±1.2); IL-10, 512 pg/ml (±288). There was a significant relationship between running volume and both Treg cell numbers (slope of the regression line (ß)=0.05, p less than 0.001) and IL-10 production ß=-10.6, p=0.002), and there was a trending relationship between running volume and Tr1 cell numbers (ß=-0.2%, p=0.064). Perceived stress was a trending moderator of the running volume-Treg relationship, whereas worry was a significant moderator of the running volume-IFNγ and running volume-IFNγ/IL-4 relationships. These data indicate that various forms of psychological stress can impact endurance exercise-based changes in certain immune biomarkers. These changes may reflect an increased susceptibility to clinical risks in some individuals.

Increased Circulating Anti-inflammatory Cells in Marathon-trained Runners.

Exercise training can alter immune function. Marathon training has been associated with an increased susceptibility to infectious diseases and an increased activity of inflammatory-based diseases, but the precise mechanisms are unknown. The purpose of this study was to compare levels of circulating CD4+ T cell subsets in the periphery of marathon-trained runners and matched non-marathon controls. 19 recreational marathoners that were 4 weeks from running a marathon and 19 demographically-matched healthy control subjects had the percentage of CD4+ T cell subpopulations (T helper 1, T helper 2, T helper 1/T helper 2 ratio, regulatory T cells, CD4+ IL10+, and CD4+ TGFß+ (Transforming Growth Factor-beta) measured by flow cytometry. Marathon-trained runners had significantly less T helper 1 and regulatory T cells and significantly more T helper 2, CD4+ IL10+, and TGFß+ cells than the control subjects. The alterations in the percentage of T helper 1 and T helper 2 cells led to a significantly lower T helper 1/T helper 2 ratio in the marathon-trained runners. These data suggest that endurance-based training can increase the number of anti-inflammatory cells. This may be a potential mechanism for the increased incidence of both infectious and inflammatory diseases observed in endurance athletes.

Glucocorticoid receptor BclI polymorphism associates with immunomodulatory response to stress hormone in human peripheral blood mononuclear cells.

Glucocorticoid receptor (GR) variants have been found to be associated with stress-related disorders. Our previous in vivo study revealed that the CC allele of GR BclI single-nucleotide polymorphism (SNP) was more common in the high-stress group, which had lower levels of both regulatory T cells (Treg) and Th1 cytokine. The current study was to investigate the associations between GR BclI polymorphism and immunomodulatory response to stress hormone in vitro in human peripheral blood mononuclear cells (PBMC). Blood samples were collected from 18 normal volunteers including 9 subjects with BclI polymorphism GG allele and 9 with wild-type (WT) CC allele. PBMC were cultured with 10(-8) m dexamethasone (DEX), which mimics the plasma cortisol level observed during periods of psychological stress for 24 h and 11 days. Gene expressions of transcription factors, stress hormone and cytokine receptors were analysed by real-time RT-PCR. FoxP3 mRNA was significantly altered in the BclI WT (decreased at 24 h and increased at 11 days) but not in the GG allele. GR mRNA was up-regulated at 24 h and down-regulated at 11 days in CC alleles (P < 0.01 and P < 0.05), rather than in GG alleles. The expression of ß-2 adrenergic receptor (ß2AR) was increased at 24 h in both CC and GG alleles (P < 0.01 and P < 0.001), but decreased significantly at 11 days in only GG alleles. Expression of T-bet and GATA-3 was altered simultaneously in 24-h culture with DEX from both groups. The BclI polymorphism of GR identifies different immunomodulatory responses to corticosteroids, which may explain, at least in part, the variability in individual sensitivity to stressors.

Quantum-correlated photon pair generation in chalcogenide As2S3 waveguides.

We theoretically investigate the generation of quantum-correlated photon pairs through spontaneous four-wave mixing in chalcogenide As(2)S(3) waveguides. For reasonable pump power levels, we show that such photonic-chip-based photon-pair sources can exhibit high brightness (approximately 1 x 10(9) pairs/s) and high correlation (approximately 100) if the waveguide length is chosen properly or the waveguide dispersion is engineered. Such a high correlation is possible in the presence of Raman scattering because the Raman profile exhibits a low gain window at a Stokes shift of 7.4 THz, though it is constrained due to multi-pair generation. As the proposed scheme is based on photonic chip technologies, it has the potential to become an integrated platform for the implementation of on-chip quantum technologies.

Annealing dynamics of waveguide Bragg gratings: evidence of femtosecond laser induced colour centres.

There is still significant speculation regarding the nature of femtosecond laser induced index change in bulk glasses with colour centre formation and densification the main candidates. In the work presented here, we fabricated waveguide Bragg gratings in doped and undoped phosphate glasses and use these as a diagnostic for monitoring subtle changes in the induced refractive index during photo- and thermal annealing experiments. Reductions in grating strengths during such experiments were attributed to the annihilation of colour centres.

Cooperative effects of corticosteroids and catecholamines upon immune deviation of the type-1/type-2 cytokine balance in favor of type-2 expression in human peripheral blood mononuclear cells.

A growing number of studies show strong associations between stress and altered immune function. In vivo studies of chronic and acute stress have demonstrated that cognitive stressors are strongly correlated with high levels of catecholamines (CT) and corticosteroids (CS). Although both CS and CT individually can inhibit the production of T-helper 1 (TH1, type-1 like) cytokines and simultaneously promote the production of T-helper 2 (TH2, type-2 like) cytokines in antigen-specific and mitogen stimulated human leukocyte cultures in vitro, little attention has been focused on the effects of combination CT and CS in immune responses that may be more physiologically relevant. We therefore investigated the combined effects of in vitro CT and CS upon the type-1/type-2 cytokine balance of human peripheral blood mononuclear cells (PBMC) as a model to study the immunomodulatory effects of superimposed acute and chronic stress. Results demonstrated a significant decrease in type-1 cytokine production (IFN-gamma) and a significant increase in type-2 cytokine production (IL-4, IL-10) in our CS+CT incubated cultures when compared to either CT or CS agents alone. Furthermore, variable enhancement of type-1/type-2 immune deviation occurred depending upon when the CT was added. The data suggest that CS can increase the sensitivity of PBMC to the immunomodulatory effects of CT and establishes an in vitro model to study the combined effects of in vivo type-1/type-2 cytokine alterations observed in acute and chronic stress.

Study of the influence of femtosecond laser polarisation on direct writing of waveguides.

Optical devices were fabricated in fused silica using the femtosecond direct write technique. We found that the transmission of light through directly written waveguides, whether straight or curved, can be increased by writing waveguides using circularly rather than linearly polarised radiation.

Silica and PM1648 modify human alveolar macrophage antigen-presenting cell activity in vitro.

Some inhaled particles are known to lead to inflammation and lung pathology, whereas others do not appear to have long-term effects. Potential mechanisms to account for these differences are only beginning to be understood. In this article we examine whether silica and PM1648 (a model urban particulate) caused selective deletion of the suppressor human alveolar macrophage (HAM) phenotype (RFD1+/7+), and whether this affected cytokine production in an antigen-presenting cell (APC) assay with autologous T lymphocytes. HAM were exposed to the bioactive particulates, silica and PM1648, for 24 hours, then isolated free of extracellular particulates and nonviable cells; HAM were then cultured with autologous lymphocytes in an 11-day APC assay. Silica exposure up-regulated a TH1 lymphocyte-derived cytokine, interferon gamma (IFN-gamma), and a TH2 lymphocyte-derived cytokine, interleukin-4 (IL-4). PM1648 exposure primarily upregulated IL-4. Neither particle exposure had a significant effect on interleukin-10 (IL-10) production. Control particulate exposures with titanium dioxide (TiO2) and wollastonite (Woll) caused no altered APC activity. Silica and PM1648 demonstrated selective toxicity to suppressor macrophages (RFD1+/7+). We propose that, because of the suppressor macrophage phenotype disabling, the activator macrophage (RFD1+/7-) operates free of the suppressor macrophage's influence, enhancing APC activity with increased lymphocyte-derived proinflammatory cytokine production.

Dexamethasone promotes type 2 cytokine production primarily through inhibition of type 1 cytokines.

Glucocorticoids, at concentrations mimicking stress-physiologic plasma levels, cause an in vitro shift in the type 1/type 2 cytokine balance of human peripheral blood mononuclear cells (PBMC) toward a predominant type 2 response. The mechanisms of these immune alterations are currently unknown but may involve modulation of key cytokines known to regulate the type 1/type 2 cytokine balance. Therefore, we sought to determine the role of cytokines previously reported to regulate the type 1/type 2 cytokine balance, including interleukin-12 (IL-12), interferon-gamma (IFN-gamma, IL-10, IL-4, and IL-13, in the glucocorticoid-mediated human type 1/type 2 cytokine alterations. Human PBMC were stimulated in vitro with tetanus toxoid in the presence of 10(-8) M dexamethasone (DEX). Cultures were supplemented with recombinant human (rHuIL-12), rHuIFN-gamma, or neutralizing monoclonal antibodies (mAb) against IL-4, IL-10, or IL-13. DEX decreased IFN-gamma production and increased IL-4 and IL-10 production by tetanus-stimulated PBMC. The addition of either recombinant IL-12p70 or IFN-gamma abrogated the DEX-mediated decrease in IFN-gamma and increase in IL-4 production. Neutralization of IL-4 activity partially abrogated the DEX-induced alterations in IFN-gamma and IL-4, but not IL-10, production. Neutralization of IL-10 or IL-13 had no effect on the Dex-mediated type 1/type 2 cytokine alterations. Therefore, the DEX-mediated type 1/type 2 cytokine alterations in tetanus-stimulated PBMC are primarily the result of downregulation of type 1 cytokines, subsequently permitting the production of type 2 cytokines.

Increased fecal IgE among infants in a rural community of Egypt: an analysis of associated risk factors.

Newborns in rural Bilbeis, Egypt were followed to 1-year of age to document the incidence and risk factors associated with the development of fecal IgE. Factors associated with increased fecal IgE included infants aged 3-6 months (relative risk (RR) = 3.28, 95 per cent confidence intervals (CI) = 1.03-13.60, p < 0.05) and mother being vaccinated antenatally (RR = 2.17, CI - 1.01-4.61, p < 0.05). Decreased fecal IgE was observed with consumption of rice (RR = 0.37, CI = 0.12-0.94, p < 0.05), biscuits (RR = 0.43, CI = 0.15-0.99, p < 0.05), potatoes (RR = 0.39, CI = 0.11-0.98, p < 0.05), and fruits and vegetables (RR = 0.20, CI = 0.02-0.80, p < 0.05). After multivariate adjustment, increased risk was observed with consumption of milk pudding (RR = 7.48, CI = 1.54-36.20, p < 0.05) and wet-nursed infants (RR = 2.77, CI = 1.17-6.54, p < 0.05). Infants who were completely breastfed (RR = 0.13, CI = 0.02-0.68, p < 0.05) and infants' family owning a television set (RR = 0.29, CI = 0.12-0.67, p < 0.05) were less likely to develop fecal IgE. Our findings indicate that prelacteal feeding with certain foods, early supplementation of breastfeeding, and sociodemographic factors are associated with increased fecal IgE.

Pathophysiology of bronchial inflammation: chemoreceptors as therapeutic targets.

Asthma is an inflammatory disease characterized by reversible airway obstruction from a combination of bronchoconstriction and inflammatory changes including airway edema, infiltration of inflammatory cells such as eosinophils, mast cells, CD4+ T helper cells and monocyte/macrophages. Pharmacotherapy approaches include relievers of acute symptoms and controllers of inflammation. Inhaled corticosteroids are the sentinel therapy for asthma inflammation but are not always totally effective for a variety of reasons. With the increased understanding about the molecular basis for asthma inflammation, new therapies are emerging to target specific molecular networks, including antibodies against IgE and the TH2 cytokine IL-5; soluble IL-4 receptors and recombinant TH1 cytokines such as IL-12. Further, allergen immunotherapy for asthma is based upon its ability to change a TH2 to a TH1 response by inhibiting IL-4 and/or stimulating IFN gamma production. Although each of these modalities have their potential strengths and weaknesses, the approach offers a fresh attempt to better define the syndrome called asthma, show diversity of etiologies within even the same patient, and develop more effective, long lasting therapies for patients with this condition.

Role of CD28/B7 costimulation in the dexamethasone-induced suppression of IFN-gamma.

In vitro exposure of peripheral blood mononuclear cells (PBMC) to glucocorticoids (GC), at concentrations observed during psychologic stress, induces a shift in the human type 1/type 2 cytokine balance toward a type 2 cytokine response. The mechanisms involved in these cytokine alterations are unknown but likely include modulation of regulatory cytokines or the interaction between the antigen-presenting cell (APC) and T lymphocyte or both. The CD28/B7 costimulation pathway has been reported to modulate the type 1/type 2 cytokine balance and may contribute to the GC-associated cytokine alterations. Therefore, we sought to determine the effect of dexamethasone (Dex) on the expression and function of the human CD28/B7 costimulatory pathway and whether these alterations contribute to the Dex-induced type 1/type 2 cytokine alterations. Dex inhibited the expression of both CD80 and CD86 on THP-1 cells, a human acute monocytic leukemia cell line, as determined by flow cytometry. Dex also inhibited the expression of CD28 and CTLA-4 on phytohemagglutinin (PHA)-stimulated CD3+ T lymphocytes, which was attenuated by the addition of interleukin-12 (IL-12). Lastly, activation of CD28 with anti-CD28 antibody attenuated the Dex-induced decrease in interferon-gamma (IFN-gamma) production by anti-CD3 antibody-stimulated PBMC. These data suggest that Dex induces a modulation of the CD28/B7 costimulatory pathway that contributes to the shift in the type 1/type 2 cytokine balance toward a predominant type 2 cytokine response.

Therapeutic options in allergic disease: antihistamines as systemic antiallergic agents.

As has been reported throughout this supplement, the pathophysiologic factors of allergic diseases involve many elements of systemic disease-effector-cell recruitment from circulation, stimulation of bone marrow progenitors, systemic effector-cell priming, anaphylactic reactions, and others. With this understanding, allergic inflammation can be thought of as a reflection of systemic immunologic responses with compartmentalized manifestations in various organ systems, including the upper respiratory tract, lungs, gastrointestinal tract, and skin. Thus, any therapeutic approach to the treatment of allergic disease should address, in addition to the localized disease manifestations, the systemic immunologic dysregulation. Second-generation antihistamines (cetirizine, fexofenadine, loratadine) have been used since the 1980s to treat localized allergy symptoms in upper airways, skin, and, in some cases, the lungs; however, the efficacy of these agents in controlling systemic immune dysregulation and chronic allergic inflammation (eg, nasal congestion) has not been proved. The potential role of newer antihistamines in the amelioration of both localized and systemic aspects of allergic disease represents an active area of interest. Desloratadine, a new selective histamine H(1)-receptor antagonist with potent antihistaminic and anti-inflammatory activity, is introduced and its potential for treating the systemic aspects of allergic disease is discussed.

Stress, immune regulation, and immunity: applications for asthma.

The neuroendocrine mediators reach the cells of the immune system either through the peripheral circulation or through direct innervation of lymphoid organs. Primary and secondary lymphoid organs are innervated by sympathetic nerve fibers. Lymphocytes and monocytes express receptors for several stress hormones, including CRH, ACTH, cortisol, norepinephrine, and epinephrine. Therefore, it is reasonable to conclude that the neuroendocrine hormones released during a stressful event could alter immune function and subsequently alter the course of immune-based diseases. The impact of psychological stress on immune function has been the subject of extensive research efforts. Using a variety of models from largely healthy humans undergoing various forms of natural and experimental stress models, stress has been associated with suppression of NK activity, mitogen- and antigen-induced lymphocyte proliferation and in vitro production of IL-2 and IFN-gamma. Psychological stress is also associated with a higher rate of in vivo hypoergy to common recall-delayed type hypersensitivity antigens. These studies have suggested that psychological stress suppresses various components of CMI responses. Also, data suggest that chronic stress does not simply suppress the immune system, but induces a shift in the type-1/type-2 cytokine balance toward a predominant type-2 cytokine response. Such a change would favor the inflammatory milieu characteristic of asthma and allergic diseases. Recent studies using well-controlled teenage asthmatic subjects demonstrated immunological changes (decreased NK cell cytotoxicity and cytokine alterations) in response to exam stress. These immune alterations are consistent with a cytokine milieu that could potentially worsen asthma. However, there were no changes in peak flow rates, self-report asthma symptoms, or medication use. The lack of correlation between stress and asthma symptoms may have been related to the timing of the visits in relation to the stressor, the duration of the stressor, disease severity, or a lack of accurate self-report data. Alternatively, stress-mediated exacerbations of asthma may require multiple alterations by stress, including cytokine dysregulation or vagal-mediated airway hyperresponsiveness. The rationale for stress management in asthma is based upon the notion that stress causes a change in immune balance that would favor asthma activity in susceptible individuals. This immune imbalance can be found in TH1/TH2 cytokine changes that occur with stress. Although it has not yet been demonstrated that stress can cause or directly influence the development of asthma, it is interesting to note that both the incidence and prevalence of asthma continue to increase and are higher in urban than in rural areas. Among other differences is the well-appreciated higher chronic stress levels associated with urban living.

Determining allergic versus nonallergic drug reactions.

Drug sensitivity is a major clinical problem that is incompletely understood. Much effort continues in identifying patients at risk for developing drug sensitivities, predicting the various immune mechanisms most likely to be activated by a specific drug, and developing more reliable tests to identify the drug-allergic patient.

Beta-adrenergic modulation of human type-1/type-2 cytokine balance.

BACKGROUND: Neuroendocrine mediators are increasingly recognized as immunomodulatory agents. Lymphocytes and monocytes express receptors for a variety of neuroendocrine mediators, including catecholamines. It has been reported that beta-adrenergic agonists decrease IFN-gamma production, with varying effects on IL-4 and IL-5 production. OBJECTIVE: Our purpose was to determine the effects of catecholamines (including beta-adrenergic agonists) on the type-1/type-2 cytokine balance in tetanus-stimulated human PBMCs. METHOD: Human PBMCs were stimulated with tetanus in the presence of epinephrine (EPI), norepinephrine, or terbutaline. IFN-gamma, IL-4, IL-5, and IL-10 levels in the supernatants were determined by ELISA. RESULTS: PBMCs stimulated in the presence of EPI produced decreased levels of IFN-gamma and increased levels of IL-10, IL-4, and IL-5. A small decrease in IFN-gamma production and an increase in IL-10, IL-4, and IL-5 production were also observed with norepinephrine. Terbutaline induced similar alterations in the type-1/type-2 cytokine balance compared with EPI, indicating that the beta(2)adrenergic receptor is involved in these cytokine alterations. Furthermore, these cytokine alterations were blocked by propranolol. Finally, IL-12p70 prevented the cytokine alterations, suggesting that the mechanism of beta-adrenergic-induced cytokine alterations involves a decrease in IL-12. CONCLUSION: beta-Adrenergic agonists induce a shift in the human type-1/type-2 cytokine balance toward a type-2 response. These data provide a potential mechanism to explain the paradoxical increase in asthma morbidity and mortality associated with the chronic use of scheduled dosing of short-acting beta-adrenergic agonists.