A decade of natalizumab and PML: Has there been a tacit transfer of risk acceptance?

The interplay between each of the stakeholder's responsibilities and desires clearly has resulted in continued widespread use of natalizumab with substantial risks and an ongoing quest for better risk mitigation. In the United States, regulatory actions codified the process of risk acceptance-and risk transfer-by escalating monitoring and information transfer to physicians and patients. Management of medication-related risks is a core function of regulatory agencies such as the Food and Drug Administration (FDA), European Medicines Agency (EMA), and the medical community. The interaction among stakeholders in medicine, pharma, regulatory bodies, physicians, and patients, sometimes has changed without overt review and discussion. Such is the case for natalizumab, an important and widely used disease-modifying therapy for multiple sclerosis. A rather silent but very considerable shift, effectively transferring increased risk for progressive multifocal leukoencephalopathy (PML) to the physicians and patients, has occurred in the past decade. We believe this changed risk should be clearly recognized and considered by all the stakeholders

Application of Nanotechnology in the Manufacturing Sector: A Review

This review of the manufacturing processes in the evolving field of nanotechnology describes the production of nanomaterials by the modification of conventional production techniques. A number of the manufacturing techniques for nanomaterials production and the challenges in the adaptation of the processes to enable nano production are highlighted. Examples of practical applications of nano-structures, materials and components are given. The challenges and risks their applications pose to the wider society are discussed. Suggestions are made on how the social and ethical implications of nanotechnology can best be addressed. A proposition on the way forward for nano production and the integration of their products in the society is also discussed. The challenges and prospects in nano-manufacturing are presented

It's fair for us: Diversity structures cause women to legitimize discrimination

This is a PDF file of an unedited manuscript that has been accepted for publication. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.The article is available in final published form via: doi:10.1016/j.jesp.2014.11.010Three experiments tested the hypothesis that the mere presence (vs. absence) of diversity structures makes it more difficult for women to detect sexism. In Experiment 1, even when a company's hiring decisions disadvantaged women, women perceived the company as more procedurally just for women and were less supportive of sexism litigation when the company offered diversity training, compared to when it did not. In Experiment 2, women perceived a company as more procedurally just for women and as less likely to have engaged in sexism when the company offered diversity training, compared to when it did not. This effect was not moderated by women's endorsement of status legitimizing beliefs. In Experiment 3, women perceived a company as more procedurally just and less discriminatory when the company had been recognized for positive gender diversity practices compared to when it had not. Additionally, these effects were most pronounced among women who endorsed benevolent sexist beliefs and mitigated among those who rejected benevolent sexist beliefs. Together, these experiments demonstrate that diversity structures can make it difficult for women to detect and remedy discrimination, especially women who hold benevolent sexist beliefs.National Science Foundatio

Pathogenesis of progressive multifocal leukoencephalopathy and risks associated with treatments for multiple sclerosis: a decade of lessons learned.

Progressive multifocal leukoencephalopathy (PML) is a rare, devastating demyelinating disease of the CNS caused by the JC virus (JCV) that occurs in patients with compromised immune systems. Detection of PML in systemically immunocompetent patients with multiple sclerosis treated with natalizumab points to a role for this drug in the pathophysiology of PML. Emerging knowledge of the cellular and molecular biology of JCV infection and the pathogenesis of PML-including interplay of this common virus with the human immune system and features of natalizumab that might contribute to PML pathogenesis-provides new opportunities to monitor viral status and predict risk of JCV-associated disease. In the absence of an effective treatment for PML, early detection of the disease in patients with multiple sclerosis who are receiving natalizumab or other immunomodulatory treatments is vital to minimize CNS injury and avoid severe disability. Frequent MRI, stratified along a clinical and virus-specific immune risk profile, can be used to detect presymptomatic PML. Improved approaches to PML risk stratification are needed to guide treatment choices and surveillance of patients with multiple sclerosis

Transporter gene acquisition and innovation in the evolution of Microsporidia intracellular parasites.

The acquisition of genes by horizontal transfer can impart entirely new biological functions and provide an important route to major evolutionary innovation. Here we have used ancient gene reconstruction and functional assays to investigate the impact of a single horizontally transferred nucleotide transporter into the common ancestor of the Microsporidia, a major radiation of intracellular parasites of animals and humans. We show that this transporter provided early microsporidians with the ability to steal host ATP and to become energy parasites. Gene duplication enabled the diversification of nucleotide transporter function to transport new substrates, including GTP and NAD+, and to evolve the proton-energized net import of nucleotides for nucleic acid biosynthesis, growth and replication. These innovations have allowed the loss of pathways for mitochondrial and cytosolic energy generation and nucleotide biosynthesis that are otherwise essential for free-living eukaryotes, resulting in the highly unusual and reduced cells and genomes of contemporary Microsporidia

Proactive and politically skilled professionals: What is the relationship with affective occupational commitment?

The aim of this study is to extend research on employee affective commitment in three ways: (1) instead of organizational commitment the focus is on occupational commitment; (2) the role of proactive personality on affective occupational commitment is examined; and (3) occupational satisfaction is examined as a mediator and political skills as moderator in the relationship between proactive personality and affective occupational commitment. Two connected studies, one in a hospital located in the private sector and one in a university located in the public sector, are carried out in Pakistan, drawing on a total sample of over 400 employees. The results show that proactive personality is positively related to affective occupational commitment, and that occupational satisfaction partly mediates the relationship between proactive personality and affective occupational commitment. No effect is found for a moderator effect of political skills in the relationship between proactive personality and affective occupational commitment. Political skills however moderate the relationship between proactive personality and affective organizational commitment

Refined clothespin relocation test and assessment of motion

Background: Advancements in upper limb prosthesis design have focused on providing increased degrees of freedom for the end effector through multiple articulations of a prosthetic hand, wrist and elbow. Measuring improvement in patient function with these devices requires development of appropriate assessment tools. Objectives: This study presents a refined clothespin relocation test for measuring performance and assessing compensatory motion between able-bodied subjects and subjects with upper limb impairments. Study Design: Comparative analysis Methods: Trunk and head motions of 13 able-bodied subjects who performed the refined clothespin relocation test were compared to the motion of a transradial prosthesis user with a single degree of freedom hand. Results: There were observable differences between the prosthesis user and the able-bodied group. The assessment used provided a clear indication of the differences in motion through analysis of compensatory motion. Conclusion: The refined clothespin relocation test provides additional benefits over the standard clothespin assessment and makes identification of compensatory motions easily identifiable to the researcher. While this paper establishes the method for the new assessment, further validation will need to be performed with more users

Off-trial evaluation of bisphosphonates in patients with metastatic breast cancer

BACKGROUND: Bisphosphonate therapy has been readily accepted as standard of care for individuals with bone metastases from breast cancer. In this study we determined whether the proportion of patients experiencing a skeletal related event (SRE) in a clinical practice population was similar to that observed in phase III randomized controlled studies. METHODS: A retrospective chart review was conducted of 110 patients receiving intravenous bisphosphonates for advanced breast cancer. The proportion of patients experiencing at least one SRE after 12 months of therapy was determined. SRE included vertebral or non-vertebral fracture, cord compression, surgery and/or radiotherapy to bone. RESULTS: The proportion of patients who had an SRE was 30% (28 individuals) and the median time to first event was greater than 350 days. Non-vertebral events and radiotherapy were the most frequent type of SRE, while cord compression and hypercalcaemia were rare (1%). Most patients in the study had bone-only disease (58.2%) and most had multiple bone lesions. In the first 12 months the mean duration of exposure to intravenous bisphosphonates was 261 days and most patients remained on treatment until just before death (median 27 days). CONCLUSION: This study suggests that the rate of clinically relevant SREs is substantially lower than the event rate observed in phase III clinical trials. We attribute this lower rate to observational bias. In the clinical trial setting it is possible that over-detection of skeletal events occurs due to the utilisation of regular skeletal survey or radionucleotide bone scan, whereas these procedures are not routine in clinical practice. Phase IV observational studies need to be conducted to determine the true benefits of bisphosphonate therapy in order to implement rationale use of bisphosphonates

Observation of an Exotic Baryon with S=+1 in Photoproduction from the Proton

The reaction $\gamma p \to \pi^+K^-K^+n$ was studied at Jefferson Lab using a tagged photon beam with an energy range of 3-5.47 GeV. A narrow baryon state with strangeness S=+1 and mass $M=1555\pm 10$ MeV/c$^2$ was observed in the $nK^+$ invariant mass spectrum. The peak's width is consistent with the CLAS resolution (FWHM=26 MeV/c$^2$), and its statistical significance is 7.8 $\pm$ 1.0 ~$\sigma$. A baryon with positive strangeness has exotic structure and cannot be described in the framework of the naive constituent quark model. The mass of the observed state is consistent with the mass predicted by a chiral soliton model for the $\Theta^+$ baryon. In addition, the $pK^+$ invariant mass distribution was analyzed in the reaction $\gamma p\to K^-K^+p$ with high statistics in search of doubly-charged exotic baryon states. No resonance structures were found in this spectrum.Comment: 5 pages, 5 figures, add reference