New insights into the burden and costs of multiple sclerosis in Europe

BACKGROUND: The current focus in multiple sclerosis (MS) is on early diagnosis and drug intervention, with a view to modifying disease progression. Consequently, healthcare costs have shifted from inpatient care and rehabilitation to outpatient care. OBJECTIVES: This European burden of illness study provides data that can be combined with other evidence to assess whether management approaches provide value to society. METHODS: A cross-sectional study was conducted in 16 countries. Patients reported on their disease, health-related quality of life (HRQoL) and resource consumption. Descriptive analyses were performed by disease severity. Costs are reported from a societal perspective in 2015€ PPP (adjusted for purchasing power parity). RESULTS: The 16,808 participants had a mean age of 51.5 years, and 52% had relapsing–remitting multiple sclerosis (RRMS). Work capacity declined from 82% to 8%, and utility declined from normal population values to less than zero with advancing disease. Mean costs were 22,800€ PPP in mild, 37,100€ PPP in moderate and 57,500€ PPP in severe disease; healthcare accounted for 68%, 47% and 26%, respectively. Fatigue and cognitive difficulties were reported by 95% and 71% of participants, respectively; both had a significant independent effect on utility. CONCLUSION: Costs and utility were highly correlated with disease severity, but resource consumption was heavily influenced by healthcare systems organisation and availability of services

Trapped in a vicious loop: Toll-like receptors sustain the spontaneous cytokine production by rheumatoid synovium

Synovial tissue of patients with rheumatoid arthritis (RA) spontaneously produces several cytokines, of which a fundamental role in joint inflammation and destruction has been established. However, the factors sustaining this phenomenon remain poorly understood. In a recent report, blockade of Toll-like receptor 2 (TLR2) was found to inhibit the spontaneous release of inflammatory cytokines by intact RA synovial explant cultures. Adding to the recent evidence implicating other TLRs (in particular, TLR4), this observation highlights the potential of TLRs as therapeutic targets to suppress the local production of multiple cytokines and to control the chronic inflammatory loop in RA

Gene therapy in animal models of rheumatoid arthritis: are we ready for the patients?

Rheumatoid arthritis (RA) is a chronic inflammatory disease of the synovial joints, with progressive destruction of cartilage and bone. Anti-tumour necrosis factor-α therapies (e.g. soluble tumour necrosis factor receptors) ameliorate disease in 60–70% of patients with RA. However, the need for repeated systemic administration of relatively high doses in order to achieve constant therapeutic levels in the joints, and the reported side effects are downsides to this systemic approach. Several gene therapeutic approaches have been developed to ameliorate disease in animal models of arthritis either by restoring the cytokine balance or by genetic synovectomy. In this review we summarize strategies to improve transduction of synovial cells, to achieve stable transgene expression using integrating viruses such as adeno-associated viruses, and to achieve transcriptionally regulated expression so that drug release can meet the variable demands imposed by the intermittent course of RA. Evidence from animal models convincingly supports the application of gene therapy in RA, and the feasibility of gene therapy was recently demonstrated in phase I clinical trials

The Geography of Sexual Orientation: Structural Stigma and Sexual Attraction, Behavior, and Identity Among Men Who Have Sex with Men Across 38 European Countries.

: While the prevalence of sexual identities and behaviors of men who have sex with men (MSM) varies across countries, no study has examined country-level structural stigma toward sexual minorities as a correlate of this variation. Drawing on emerging support for the context-dependent nature of MSM's open sexual self-identification cross-nationally, we examined country-level structural stigma as a key correlate of the geographic variation in MSM's sexual attraction, behavior, and identity, and concordance across these factors. Data come from the European MSM Internet Survey, a multi-national dataset containing a multi-component assessment of sexual orientation administered across 38 European countries (N = 174,209). Country-level stigma was assessed using a combination of national laws and policies affecting sexual minorities and a measure of attitudes toward sexual minorities held by the citizens of each country. Results demonstrate that in more stigmatizing countries, MSM were significantly more likely to report bisexual/heterosexual attractions, behaviors, and identities, and significantly less likely to report concordance across these factors, than in less stigmatizing countries. Settlement size moderated associations between country-level structural stigma and odds of bisexual/heterosexual attraction and behavior, such that MSM living in sparsely populated locales within high-structural stigma countries were the most likely to report bisexual or heterosexual behaviors and attractions. While previous research has demonstrated associations between structural stigma and adverse physical and mental health outcomes among sexual minorities, this study was the first to show that structural stigma was also a key correlate not only of sexual orientation identification, but also of MSM's sexual behavior and even attraction. Findings have implications for understanding the ontology of MSM's sexuality and suggest that a comprehensive picture of MSM's sexuality will come from attending to the local contexts surrounding this important segment of the global population.<br/

Dementia With Lewy Bodies A Clinicopathologic Series of False-positive Cases

Diagnosing dementia with Lewy bodies (DLB) is challenging as symptoms are heterogenous and not specific to the disease. Here we present a clinicopathologic series of false-positive DLB cases. Patients were enrolled retrospectively from the Netherlands Brain Bank when they met the clinical criteria of probable DLB, but with a pathologic diagnosis other than DLB or Parkinson’s disease dementia. Twenty-two false-positive cases were selected. Alzheimer disease with or without copathology was the most common (64%) pathologic diagnosis. Other pathologic diagnoses, such as frontotemporal dementia, multiple-system atrophy, Creutzfeldt-Jakob disease, and autoimmune encephalitis, were also encountered. Atypical clinical signs for DLB were present in almost half of the cases and could be a trigger to consider other diagnoses than DLB. Additional diagnostic examinations, feedback of pathologic diagnosis, and the creation of a set of clinical features that are indicative of other conditions, could reduce the amount of false-positive DLB cases

Laser-heated capillary discharge plasma waveguides for electron acceleration to 8 GeV

A plasma channel created by the combination of a capillary discharge and inverse Bremsstrahlung laser heating enabled the generation of electron bunches with energy up to 7.8 GeV in a laser-driven plasma accelerator. The capillary discharge created an initial plasma channel and was used to tune the plasma temperature, which optimized laser heating. Although optimized colder initial plasma temperatures reduced the ionization degree, subsequent ionization from the heater pulse created a fully ionized plasma on-axis. The heater pulse duration was chosen to be longer than the hydrodynamic timescale of ≈ 1 ns, such that later temporal slices were more efficiently guided by the channel created by the front of the pulse. Simulations are presented which show that this thermal self-guiding of the heater pulse enabled channel formation over 20 cm. The post-heated channel had lower on-axis density and increased focusing strength compared to relying on the discharge alone, which allowed for guiding of relativistically intense laser pulses with a peak power of 0.85 PW and wakefield acceleration over 15 diffraction lengths. Electrons were injected into the wake in multiple buckets and times, leading to several electron bunches with different peak energies. To create single electron bunches with low energy spread, experiments using localized ionization injection inside a capillary discharge waveguide were performed. A single injected bunch with energy 1.6 GeV, charge 38 pC, divergence 1 mrad, and relative energy spread below 2% full-width half-maximum was produced in a 3.3 cm-long capillary discharge waveguide. This development shows promise for mitigation of energy spread and future high efficiency staged acceleration experiments