Calculating confidence intervals for impact numbers

BACKGROUND: Standard effect measures such as risk difference and attributable risk are frequently used in epidemiological studies and public health research to describe the effect of exposures. Recently, so-called impact numbers have been proposed, which express the population impact of exposures in form of specific person or case numbers. To describe estimation uncertainty, it is necessary to calculate confidence intervals for these new effect measures. In this paper, we present methods to calculate confidence intervals for the new impact numbers in the situation of cohort studies. METHODS: Beside the exposure impact number (EIN), which is equivalent to the well-known number needed to treat (NNT), two other impact numbers are considered: the case impact number (CIN) and the exposed cases impact number (ECIN), which describe the number of cases (CIN) and the number of exposed cases (ECIN) with an outcome among whom one case is attributable to the exposure. The CIN and ECIN represent reciprocals of the population attributable risk (PAR) and the attributable fraction among the exposed (AF(e)), respectively. Thus, confidence intervals for these impact numbers can be calculated by inverting and exchanging the confidence limits of the PAR and AF(e). EXAMPLES: We considered a British and a Japanese cohort study that investigated the association between smoking and death from coronary heart disease (CHD) and between smoking and stroke, respectively. We used the reported death and disease rates and calculated impact numbers with corresponding 95% confidence intervals. In the British study, the CIN was 6.46, i.e. on average, of any 6 to 7 persons who died of CHD, one case was attributable to smoking with corresponding 95% confidence interval of [3.84, 20.36]. For the exposed cases, the results of ECIN = 2.64 with 95% confidence interval [1.76, 5.29] were obtained. In the Japanese study, the CIN was 6.67, i.e. on average, of the 6 to 7 persons who had a stroke, one case was attributable to smoking with corresponding 95% confidence interval of [3.80, 27.27]. For the exposed cases, the results of ECIN = 4.89 with 95% confidence interval of [2.86, 16.67] were obtained. CONCLUSION: The consideration of impact numbers in epidemiological analyses provides additional information and helps the interpretation of study results, e.g. in public health research. In practical applications, it is necessary to describe estimation uncertainty. We have shown that the calculation of confidence intervals for the new impact numbers is possible by means of known methods for attributable risk measures. Therefore, estimated impact numbers should always be complemented by appropriate confidence intervals

Pirfenidone in idiopathic pulmonary fibrosis:expert panel discussion on the management of drug-related adverse events

Pirfenidone is currently the only approved therapy for idiopathic pulmonary fibrosis, following studies demonstrating that treatment reduces the decline in lung function and improves progression-free survival. Although generally well tolerated, a minority of patients discontinue therapy due to gastrointestinal and skin-related adverse events (AEs). This review summarizes recommendations based on existing guidelines, research evidence, and consensus opinions of expert authors, with the aim of providing practicing physicians with the specific clinical information needed to educate the patient and better manage pirfenidone-related AEs with continued pirfenidone treatment. The main recommendations to help prevent and/or mitigate gastrointestinal and skin-related AEs include taking pirfenidone during (or after) a meal, avoiding sun exposure, wearing protective clothing, and applying a broad-spectrum sunscreen with high ultraviolet (UV) A and UVB protection. These measures can help optimize AE management, which is key to maintaining patients on an optimal treatment dose.Correction in: Advances in Therapy, Volume 31, Issue 5, pp 575-576 , doi: 10.1007/s12325-014-0118-8</p

Evaluation of the clinical value of bone metabolic parameters for the screening of osseous metastases compared to bone scintigraphy

BACKGROUND: Bone metastases are common in many types of cancer. As screening methods different imaging modalities are available. A new approach for the screening of osseous metastases represents the measurement of bone metabolic markers. Therefore aim of this study was to evaluate the usefulness of the determination of bone metabolic markers aminoterminal propeptide of type I procollagen (PINP, osteoblastic activity) and the carboxyterminal pyridinoline cross-linked telopeptide of type I collagen (ICTP, osteoclastic activity) for the detection of bone metastases associated with other malignancies. METHODS: 88 patients aged 21 – 82 years with malignant tumors were prospectively studied. The serum concentrations of PINP and ICTP were measured and compared to the results of bone scintigraphy, radiological bone series, CT, MRI and clinical follow-up. RESULTS: Osseous metastases were found in 21 patients. 19 of them were correctly identified by bone scintigraphy (sensitivity: 90%). For bone metabolic markers results were as follows: ICTP sensitivity: 71%, specificity: 42%; PINP sensitivity: 24%, specificity: 96%. CONCLUSIONS: As markers of bone metabolism PINP and ICTP showed low sensitivity and/or specificity for the detection of osseous metastases. The presented markers did not seem to be sufficient enough to identify patients with bone metastases or to replace established screening methods

Evidence for anti-angiogenic and pro-survival functions of the cerebral cavernous malformation protein 3

Mutations in CCM1, CCM2, or CCM3 lead to cerebral cavernous malformations, one of the most common hereditary vascular diseases of the brain. Endothelial cells within these lesions are the main disease compartments. Here, we show that adenoviral CCM3 expression inhibits endothelial cell migration, proliferation, and tube formation while downregulation of endogenous CCM3 results in increased formation of tube-like structures. Adenoviral CCM3 expression does not induce apoptosis under normal endothelial cell culture conditions but protects endothelial cells from staurosporine-induced cell death. Tyrosine kinase activity profiling suggests that CCM3 supports PDPK-1/Akt-mediated endothelial cell quiescence and survival

External Urethral Sphincter Pressure Measurement: An Accurate Method for the Diagnosis of Detrusor External Sphincter Dyssynergia?

Combined pelvic floor electromyography (EMG) and videocystourethrography (VCUG) during urodynamic investigation are the most acceptable and widely agreed methods for diagnosing detrusor external sphincter dyssynergia (DESD). Theoretically, external urethral sphincter pressure (EUSP) measurement would provide enough information for the diagnosis of DESD and could simplify the urodynamic investigation replacing combined pelvic floor EMG and VCUG. Thus, we evaluated the diagnostic accuracy of EUSP measurement for DESD. PATIENTS #ENTITYSTARTX00026;A consecutive series of 72 patients (36 women, 36 men) with neurogenic lower urinary tract dysfunction able to void spontaneously was prospectively evaluated at a single university spinal cord injury center. Diagnosis of DESD using EUSP measurement (index test) versus combined pelvic floor EMG and VCUG (reference standard) was assessed according to the recommendations of the Standards for Reporting of Diagnostic Accuracy Initiative.Using EUSP measurement (index test) and combined pelvic floor EMG and VCUR (reference standard), DESD was diagnosed in 10 (14%) and in 41 (57%) patients, respectively. More than half of the patients presented discordant diagnosis between the index test and the reference standard. Among 41 patients with DESD diagnosed by combined pelvic floor EMG and VCUR, EUSP measurement identified only 6 patients. EUSP measurement had a sensitivity of 15% (95% CI 5%-25%), specificity of 87% (95% CI 76%-98%), positive predictive value of 60% (95% CI 30%-90%), and negative predictive value of 56% (95% CI 44%-68%) for the diagnosis of DESD.For diagnosis of DESD, EUSP measurement is inaccurate and cannot replace combined pelvic floor EMG and VCUR

Efficient Colonization and Therapy of Human Hepatocellular Carcinoma (HCC) Using the Oncolytic Vaccinia Virus Strain GLV-1h68

Virotherapy using oncolytic vaccinia virus strains is one of the most promising new strategies for cancer therapy. In this study, we analyzed for the first time the therapeutic efficacy of the oncolytic vaccinia virus GLV-1h68 in two human hepatocellular carcinoma cell lines HuH7 and PLC/PRF/5 (PLC) in cell culture and in tumor xenograft models. By viral proliferation assays and cell survival tests, we demonstrated that GLV-1h68 efficiently colonized, replicated in, and did lyse these cancer cells in culture. Experiments with HuH7 and PLC xenografts have revealed that a single intravenous injection (i.v.) of mice with GLV-1h68 resulted in a significant reduction of primary tumor sizes compared to uninjected controls. In addition, replication of GLV-1h68 in tumor cells led to strong inflammatory and oncolytic effects resulting in intense infiltration of MHC class II-positive cells like neutrophils, macrophages, B cells and dendritic cells and in up-regulation of 13 pro-inflammatory cytokines. Furthermore, GLV-1h68 infection of PLC tumors inhibited the formation of hemorrhagic structures which occur naturally in PLC tumors. Interestingly, we found a strongly reduced vascular density in infected PLC tumors only, but not in the non-hemorrhagic HuH7 tumor model. These data demonstrate that the GLV-1h68 vaccinia virus may have an enormous potential for treatment of human hepatocellular carcinoma in man

A Graph Algorithmic Approach to Separate Direct from Indirect Neural Interactions

Network graphs have become a popular tool to represent complex systems composed of many interacting subunits; especially in neuroscience, network graphs are increasingly used to represent and analyze functional interactions between neural sources. Interactions are often reconstructed using pairwise bivariate analyses, overlooking their multivariate nature: it is neglected that investigating the effect of one source on a target necessitates to take all other sources as potential nuisance variables into account; also combinations of sources may act jointly on a given target. Bivariate analyses produce networks that may contain spurious interactions, which reduce the interpretability of the network and its graph metrics. A truly multivariate reconstruction, however, is computationally intractable due to combinatorial explosion in the number of potential interactions. Thus, we have to resort to approximative methods to handle the intractability of multivariate interaction reconstruction, and thereby enable the use of networks in neuroscience. Here, we suggest such an approximative approach in the form of an algorithm that extends fast bivariate interaction reconstruction by identifying potentially spurious interactions post-hoc: the algorithm flags potentially spurious edges, which may then be pruned from the network. This produces a statistically conservative network approximation that is guaranteed to contain non-spurious interactions only. We describe the algorithm and present a reference implementation to test its performance. We discuss the algorithm in relation to other approximative multivariate methods and highlight suitable application scenarios. Our approach is a tractable and data-efficient way of reconstructing approximative networks of multivariate interactions. It is preferable if available data are limited or if fully multivariate approaches are computationally infeasible.Comment: 24 pages, 8 figures, published in PLOS On

Laser oscillation in a strongly coupled single quantum dot-nanocavity system

Strong coupling of photons and materials in semiconductor nanocavity systems has been investigated because of its potentials in quantum information processing and related applications, and has been testbeds for cavity quantum electrodynamics (QED). Interesting phenomena such as coherent exchange of a single quantum between a single quantum dot and an optical cavity, called vacuum Rabi oscillation, and highly efficient cavity QED lasers have been reported thus far. The coexistence of vacuum Rabi oscillation and laser oscillation appears to be contradictory in nature, because the fragile reversible process may not survive in laser oscillation. However, recently, it has been theoretically predicted that the strong-coupling effect could be sustained in laser oscillation in properly designed semiconductor systems. Nevertheless, the experimental realization of this phenomenon has remained difficult since the first demonstration of the strong-coupling, because an extremely high cavity quality factor and strong light-matter coupling are both required for this purpose. Here, we demonstrate the onset of laser oscillation in the strong-coupling regime in a single quantum dot (SQD)-cavity system. A high-quality semiconductor optical nanocavity and strong SQD-field coupling enabled to the onset of lasing while maintaining the fragile coherent exchange of quanta between the SQD and the cavity. In addition to the interesting physical features, this device is seen as a prototype of an ultimate solid state light source with an SQD gain, which operates at ultra-low power, with expected applications in future nanophotonic integrated systems and monolithic quantum information devices.Comment: 12 pages, 4 figure

The Neural Basis of Object-Context Relationships on Aesthetic Judgment

The relationship between contextual information and object perception has received considerable attention in neuroimaging studies. In the work reported here, we used functional magnetic resonance imaging (fMRI) to investigate the relationship between aesthetic judgment and images of objects in their normal contextual setting versus images of objects in abnormal contextual settings and the underlying brain activity. When object-context relationships are violated changes in visual perception and aesthetic judgment emerges that exposes the contribution of vision to interpretations shaped by previous experience. We found that effects of context on aesthetic judgment modulates different memory sub-systems, while aesthetic judgment regardless of context recruit medial and lateral aspects of the orbitofrontal cortex, consistent with previous findings. Visual cortical areas traditionally associated with the processing of visual features are recruited in normal contexts, irrespective of aesthetic ratings, while prefrontal areas are significantly more engaged when objects are viewed in unaccustomed settings

HLA Class I Binding of HBZ Determines Outcome in HTLV-1 Infection

CD8(+) T cells can exert both protective and harmful effects on the virus-infected host. However, there is no systematic method to identify the attributes of a protective CD8(+) T cell response. Here, we combine theory and experiment to identify and quantify the contribution of all HLA class I alleles to host protection against infection with a given pathogen. In 432 HTLV-1-infected individuals we show that individuals with HLA class I alleles that strongly bind the HTLV-1 protein HBZ had a lower proviral load and were more likely to be asymptomatic. We also show that in general, across all HTLV-1 proteins, CD8(+) T cell effectiveness is strongly determined by protein specificity and produce a ranked list of the proteins targeted by the most effective CD8(+) T cell response through to the least effective CD8(+) T cell response. We conclude that CD8(+) T cells play an important role in the control of HTLV-1 and that CD8(+) cells specific to HBZ, not the immunodominant protein Tax, are the most effective. We suggest that HBZ plays a central role in HTLV-1 persistence. This approach is applicable to all pathogens, even where data are sparse, to identify simultaneously the HLA Class I alleles and the epitopes responsible for a protective CD8(+) T cell response