The Cost Effectiveness of Lisdexamfetamine Dimesylate for the Treatment of Binge Eating Disorder in the USA

BACKGROUND: Lisdexamfetamine dimesylate (LDX) demonstrated efficacy in terms of reduced binge eating days per week in adults with binge eating disorder (BED) in two randomized clinical trials (RCTs). OBJECTIVE: The objective of this study was to evaluate the cost effectiveness of LDX versus no pharmacotherapy (NPT) in adults with BED from a USA healthcare payer’s perspective. STUDY DESIGN AND METHODS: A decision-analytic Markov cohort model was developed using 1-week cycles and a 52-week time horizon. Markov health states were defined based upon the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria of BED. Model parameter estimates were obtained from RCTs, a survey, and literature. The primary outcome was incremental cost-effectiveness ratio (ICER). The analysis assumed a 12-week course of treatment, based upon RCTs’ treatment duration. One-way deterministic and probabilistic sensitivity analyses were conducted to assess the robustness of the results. RESULTS: Patients on LDX therapy gained 0.006 quality-adjusted life years (QALY) compared to patients on the NPT arm, while the average total cost was US$175 higher for LDX therapy. The estimated ICER for LDX compared with NPT was US$27,618 per QALY, which was shown to be cost effective given a willingness-to-pay threshold of US$50,000. CONCLUSIONS: Treatment of BED with LDX showed increase in QALYs at an acceptable cost and is considered to be cost effective at the commonly used willingness-to-pay threshold in the USA. Based on the available evidence, the current model focused on short-term benefits only. There is a need to generate additional scientific evidence supporting long-term benefits of LDX therapy for BED. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s40261-016-0381-3) contains supplementary material, which is available to authorized users

Treatment of Helminth Co-Infection in Individuals with HIV-1: A Systematic Review of the Literature

Many people living in areas of the world most affected by the HIV/AIDS pandemic are also exposed to other common infections. Parasitic infections with helminths (intestinal worms) are common in Africa and affect over half of the population in some areas. There are plausible biological reasons why treating helminth infections in people with HIV may slow down the progression of HIV to AIDS. Thus, treating people with HIV for helminths in areas with a high prevalence of both HIV and helminth infections may be a feasible strategy to help people with HIV delay progression of their disease or initiation of antiretroviral therapy. After a comprehensive review of the available literature, we conclude that there is not enough evidence to determine whether treating helminth infections in people with HIV is beneficial

Staphylococcus aureus Induces Eosinophil Cell Death Mediated by α-hemolysin

Staphylococcus aureus, a major human pathogen, exacerbates allergic disorders, including atopic dermatitis, nasal polyps and asthma, which are characterized by tissue eosinophilia. Eosinophils, via their destructive granule contents, can cause significant tissue damage, resulting in inflammation and further recruitment of inflammatory cells. We hypothesised that the relationship between S. aureus and eosinophils may contribute to disease pathology. We found that supernatants from S. aureus (SH1000 strain) cultures cause rapid and profound eosinophil necrosis, resulting in dramatic cell loss within 2 hours. This is in marked contrast to neutrophil granulocytes where no significant cell death was observed (at equivalent dilutions). Supernatants prepared from a strain deficient in the accessory gene regulator (agr) that produces reduced levels of many important virulence factors, including the abundantly produced α-hemolysin (Hla), failed to induce eosinophil death. The role of Hla in mediating eosinophil death was investigated using both an Hla deficient SH1000-modified strain, which did not induce eosinophil death, and purified Hla, which induced concentration-dependent eosinophil death via both apoptosis and necrosis. We conclude that S. aureus Hla induces aberrant eosinophil cell death in vitro and that this may increase tissue injury in allergic disease

Correlates of Obsessive–Compulsive Disorder in a Sample of HIV-Positive, Methamphetamine-using Men Who have Sex with Men

Substance use has been identified as a risk factor for elevated levels of obsessive–compulsive disorder (OCD). This study examined methamphetamine use and sexual risk behaviors as correlates of OCD in a sample of 245 HIV-positive men having sex with men (MSM) in San Diego, CA. In a logistic regression analysis, OCD was associated with greater frequency of methamphetamine use, more depressive symptoms, seeking out risky venues and risky sexual partners when “high” on methamphetamine, and reporting fewer sex acts in the past 2 months. These data suggest the need for increased awareness and understanding of the role that OCD may play in the drug use behaviors and risky sexual practices of methamphetamine users

DQB1*0602 rather than DRB1*1501 confers susceptibility to multiple sclerosis-like disease induced by proteolipid protein (PLP)

<p>Abstract</p> <p>Background</p> <p>Multiple sclerosis (MS) is associated with pathogenic autoimmunity primarily focused on major CNS-myelin target antigens including myelin basic protein (MBP), proteolipidprotein (PLP), myelin oligodendrocyte protein (MOG). MS is a complex trait whereby the HLA genes, particularly class-II genes of HLA-DR15 haplotype, dominate the genetic contribution to disease-risk. Due to strong linkage disequilibrium in HLA-II region, it has been hard to establish precisely whether the functionally relevant effect derives from the DRB1*1501, DQA1*0102-DQB1*0602, or DRB5*0101 loci of HLA-DR15 haplotype, their combinations, or their epistatic interactions. Nevertheless, most genetic studies have indicated DRB1*1501 as a primary risk factor in MS. Here, we used 'HLA-humanized' mice to discern the potential relative contribution of DRB1*1501 and DQB1*0602 alleles to susceptibility to "humanized" MS-like disease induced by PLP, one of the most prominent and encephalitogenic target-antigens implicated in human MS.</p> <p>Methods</p> <p>The HLA-DRB1*1501- and HLA-DQB1*0602-Tg mice (MHC-II^-/-), and control non-HLA-DR15-relevant-Tg mice were immunized with a set of overlapping PLP peptides or with recombinant soluble PLP for induction of "humanized" MS-like disease, as well as for ex-vivo analysis of immunogenic/immunodominant HLA-restricted T-cell epitopes and associated cytokine secretion profile.</p> <p>Results</p> <p>PLP autoimmunity in both HLA-DR15-Tg mice was focused on 139-151 and 175-194 epitopes. Strikingly, however, the HLA-DRB1*1501-transgenics were refractory to disease induction by any of the overlapping PLP peptides, while HLA-DQB1*0602 transgenics were susceptible to disease induction by PLP139-151 and PLP175-194 peptides. Although both transgenics responded to both peptides, the PLP139-151- and PLP175-194-reactive T-cells were directed to Th1/Th17 phenotype in DQB1*0602-Tg mice and towards Th2 in DRB1*1501-Tg mice.</p> <p>Conclusions</p> <p>While genome studies map a strong MS susceptibility effect to the region of DRB1*1501, our findings offer a rationale for potential involvement of pathogenic DQ6-associated autoimmunity in MS. Moreover, that DQB1*0602, but not DRB1*1501, determines disease-susceptibility to PLP in HLA-transgenics, suggests a potential differential, functional role for DQB1*0602 as a predisposing allele in MS. This, together with previously demonstrated disease-susceptibility to MBP and MOG in DRB1*1501-transgenics, also suggests a differential role for DRB1*1501 and DQB1*0602 depending on target antigen and imply a potential complex 'genotype/target antigen/phenotype' relationship in MS heterogeneity.</p

Novel Structurally Designed Vaccine for S. aureus α-Hemolysin: Protection against Bacteremia and Pneumonia

Staphylococcus aureus (S. aureus) is a human pathogen associated with skin and soft tissue infections (SSTI) and life threatening sepsis and pneumonia. Efforts to develop effective vaccines against S. aureus have been largely unsuccessful, in part due to the variety of virulence factors produced by this organism. S. aureus alpha-hemolysin (Hla) is a pore-forming toxin expressed by most S. aureus strains and reported to play a key role in the pathogenesis of SSTI and pneumonia. Here we report a novel recombinant subunit vaccine candidate for Hla, rationally designed based on the heptameric crystal structure. This vaccine candidate, denoted AT-62aa, was tested in pneumonia and bacteremia infection models using S. aureus strain Newman and the pandemic strain USA300 (LAC). Significant protection from lethal bacteremia/sepsis and pneumonia was observed upon vaccination with AT-62aa along with a Glucopyranosyl Lipid Adjuvant-Stable Emulsion (GLA-SE) that is currently in clinical trials. Passive transfer of rabbit immunoglobulin against AT-62aa (AT62-IgG) protected mice against intraperitoneal and intranasal challenge with USA300 and produced significant reduction in bacterial burden in blood, spleen, kidney, and lungs. Our Hla-based vaccine is the first to be reported to reduce bacterial dissemination and to provide protection in a sepsis model of S. aureus infection. AT62-IgG and sera from vaccinated mice effectively neutralized the toxin in vitro and AT62-IgG inhibited the formation of Hla heptamers, suggesting antibody-mediated neutralization as the primary mechanism of action. This remarkable efficacy makes this Hla-based vaccine a prime candidate for inclusion in future multivalent S. aureus vaccine. Furthermore, identification of protective epitopes within AT-62aa could lead to novel immunotherapy for S. aureus infection

STM imaging of symmetry-breaking structural distortion in the Bi-based cuprate superconductors

A complicating factor in unraveling the theory of high-temperature (high-Tc) superconductivity is the presence of a "pseudogap" in the density of states, whose origin has been debated since its discovery [1]. Some believe the pseudogap is a broken symmetry state distinct from superconductivity [2-4], while others believe it arises from short-range correlations without symmetry breaking [5,6]. A number of broken symmetries have been imaged and identified with the pseudogap state [7,8], but it remains crucial to disentangle any electronic symmetry breaking from pre-existing structural symmetry of the crystal. We use scanning tunneling microscopy (STM) to observe an orthorhombic structural distortion across the cuprate superconducting Bi2Sr2Can-1CunO2n+4+x (BSCCO) family tree, which breaks two-dimensional inversion symmetry in the surface BiO layer. Although this inversion symmetry breaking structure can impact electronic measurements, we show from its insensitivity to temperature, magnetic field, and doping, that it cannot be the long-sought pseudogap state. To detect this picometer-scale variation in lattice structure, we have implemented a new algorithm which will serve as a powerful tool in the search for broken symmetry electronic states in cuprates, as well as in other materials.Comment: 4 figure

Chikungunya virus adaptation to Aedes albopictus mosquitoes does not correlate with acquisition of cholesterol dependence or decreased pH threshold for fusion reaction

<p>Abstract</p> <p>Background</p> <p>Chikungunya virus (CHIKV) is a mosquito transmitted alphavirus that recently caused several large scale outbreaks/epidemics of arthritic disease in tropics of Africa, Indian Ocean basin and South-East Asia. This re-emergence event was facilitated by genetic adaptation (E1-A226V substitution) of CHIKV to a newly significant mosquito vector for this virus; <it>Aedes albopictus</it>. However, the molecular mechanism explaining the positive effect of the E1-A226V mutation on CHIKV fitness in this vector remains largely unknown. Previously we demonstrated that the E1-A226V substitution is also associated with attenuated CHIKV growth in cells depleted by cholesterol.</p> <p>Methods</p> <p>In this study, using a panel of CHIKV clones that varies in sensitivity to cholesterol, we investigated the possible relationship between cholesterol dependence and <it>Ae. albopictus </it>infectivity.</p> <p>Results</p> <p>We demonstrated that there is no clear mechanistic correlation between these two phenotypes. We also showed that the E1-A226V mutation increases the pH dependence of the CHIKV fusion reaction; however, subsequent genetic analysis failed to support an association between CHIKV dependency on lower pH, and mosquito infectivity phenotypes.</p> <p>Conclusion</p> <p>the E1-A226V mutation probably acts at different steps of the CHIKV life cycle, affecting multiple functions of the virus.</p