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Lymphangioleiomyomatosis (LAM) is a rare genetic lung disease. Unfortunately, treatment with the mTORC1 inhibitor Rapamycin only slows disease progression, and incomplete responses are common. Thus, there remains an urgent need to identify new targets for the development of curative LAM treatments. Nitazoxanide (NTZ) is an orally bioavailable antiprotozoal small molecule drug approved for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum in children and adults, with a demonstrated mTORC1 inhibitory effect in several human cell lines. NTZ’s excellent safety profile characterized by its more than 20 years of clinical use makes it a promising candidate for repurposing. Our rationale for this study was to further investigate NTZ’s effect using in vitro and in vivo LAM models and to elucidate the underlying molecular mechanism beyond mTORC1 inhibition. For this purpose, we investigated cell proliferation, cell viability, and changes in protein phosphorylation and expression in primary human cell cultures derived from LAM lung samples before translating our results into a syngeneic mouse model utilizing Tsc2-null cells. NTZ reduced cell growth for all tested cell lines at a dose of about 30 µM. Lower doses than that had no effect on cell viability, but doses above 45 µM lowered the viability by about 10 to 15% compared to control. Interestingly, our western blot revealed no inhibition of mTORC1 and only a mild effect on active ß-Catenin. Instead, NTZ had a pronounced effect on reducing pAkt. In the mouse model, prophylactic NTZ treatment via the intraperitoneal and oral routes had some effects on reducing lung lesions and improving body weight retention, but the results remain inconclusive.

Information on causes of death (CODs) for patients with multiple sclerosis (MS) in the United States is sparse and limited by standard categorizations of underlying and immediate CODs on death certificates. Prior research indicated that excess mortality among MS patients was largely due to greater mortality from infectious, cardiovascular, or pulmonary causes. To analyze disease categories in order to gain insight to pathways, which lead directly to death in MS patients. Commercially insured MS patients enrolled in the OptumInsight Research database between 1996 and 2009 were matched to non-MS comparators on age/residence at index year and sex. The cause most-directly leading to death from the death certificate, referred to as the \"principal\" COD, was determined using an algorithm to minimize the selection of either MS or cardiac/pulmonary arrest as the COD. Principal CODs were categorized into MS, cancer, cardiovascular, infectious, suicide, accidental, pulmonary, other, or unknown. Infectious, cardiovascular, and pulmonary CODs were further subcategorized. 30,402 MS patients were matched to 89,818 controls, with mortality rates of 899 and 446 deaths/100,000 person-years, respectively. Excluding MS, differences in mortality rate between MS patients and non-MS comparators were largely attributable to infections, cardiovascular causes, and pulmonary problems. Of the 95 excessive deaths (per 100,000 person-years) related to infectious causes, 41 (43.2%) were due to pulmonary infections and 45 (47.4%) were attributed to sepsis. Of the 46 excessive deaths (per 100,000 person-years) related to pulmonary causes, 27 (58.7%) were due to aspiration. No single diagnostic entity predominated for the 60 excessive deaths (per 100,000 person-years) attributable to cardiac CODs. The principal COD algorithm improved on other methods of determining COD in MS patients from death certificates. A greater awareness of the common CODs in MS patients will allow physicians to anticipate potential problems and, thereby, improve the care that they provide.

Multiple sclerosis (MS) is a potentially debilitating autoimmune disease that affects the brain and spinal cord. Disease-modifying therapies have been shown to slow disease progression but were not believed to prolong the survival of patients with MS. The recent 21-Year Long-Term Follow-Up (21Y-LTF) study found a significant survival advantage for patients receiving early treatment with interferon beta (IFNβ)-1b compared with placebo (no early treatment). The aim of this study was to conduct cost-effectiveness analyses estimating the long-term benefit of early treatment with IFNβ-1b among MS patients from a US societal perspective. A Markov model was developed to simulate the experience of patients with MS from the 21Y-LTF study over a lifetime. Patients were randomized to receive either IFNβ-1b or placebo for up to 5 years and then receive a variety of MS treatments (including no treatment) thereafter. Survival data reported from the 21Y-LTF study were incorporated into the model. The model assumes that patients' MS was managed in similar ways for both groups during the uncontrolled phase of the 21Y-LTF study (ie, survival difference between the 2 groups is the result of early use of IFNβ-1b). Health outcomes were life-years and quality-adjusted life-years (QALYs). Costs included treatments, direct disease management, informal care, and lost productivities and were reported in 2011 US dollars. In the modeled placebo group, the median age at death was predicted to be 63.7 years, and the median survival time from disease onset was 36.7 years. Early treatment with IFNβ-1b reduced the lost health benefits by 2.8 life-years and 1.9 QALYs, respectively, after discounting. Total discounted cost for IFNβ-1b–treated patients was $86,223 higher than that of patients receiving placebo. The incremental cost-effectiveness ratio was $46,357 per QALY gained and $30,967 per life-year gained. Sensitivity analyses indicate the robustness of the model's results. Treatment with IFNβ-1b during the earlier disease phase of patients with MS significantly increased patient life-years and QALYs. IFNβ-1b is likely to be a cost-effective intervention for MS.

The emergence of new influenza strains with unpredictable antigenic properties poses a significant vaccination challenge. The increasing incidence of human H5 infections underscores the urgent need for effective pre-pandemic vaccines. The UniFluVec and UniFluVec-wtNS1 viruses were designed as H1N1pdm vaccine candidates. Both viruses contained a heterologous A/Singapore/1/57-like (H2N2) NEP gene, which served as an attenuation factor. UniFluVec additionally carried a truncated to 124 amino acids NS1 gene, and an insertion of conserved influenza sequences. UniFluVec-wtNS1 retained the wild-type NS1 gene. The impact of NS1 and NEP modifications on attenuation and phenotypic markers was assessed in cells and mice. Safety and prophylactic efficacy were assessed in ferrets following a single intranasal immunisation with the maximum feasible dose (8.7 log10 EID50), followed by challenge with the highly pathogenic avian influenza virus (HPAIV) A/Indonesia/5/2005 (H5N1). Modifications in NS1 and NEP independently and synergistically induced a temperature-sensitive phenotype and enhanced type I/II interferon response, resulting in a highly attenuated vaccine profile. UniFluVec, incorporating both modifications within the NS genomic segment, demonstrated superior viral clearance, reducing lung damage, and ensuring 100 % survival in infected animals. The replication-deficient UniFluVec vector demonstrates safety, immunogenicity, and protective efficacy against the heterologous HPAIV strain in ferrets following a single intranasal administration. •UniFluVec, an H1N1pdm vaccine candidate, includes NS1 and NEP modifications to boost attenuation and immunity.•UniFluVec protects ferrets from H5N1, enhancing clearance, limiting lung damage, and ensuring 100 % survival after one dose.•Replication-deficient UniFluVec shows cross-protection, supporting its potential as a pre-pandemic intranasal vaccine.

Objective To examine the long-term impact of early treatment initiation of interferon beta-1b (IFNB1b, Betaferon/Betaseron) in patients with a first event suggestive of multiple sclerosis (MS). Methods In the original placebo-controlled phase of BENEFIT, patients were randomised to IFNB1b 250 μg or placebo subcutaneously every other day. After 2 years or diagnosis of clinically definite MS (CDMS), all patients were offered open-label IFNB1b treatment for a maximum duration of 5 years. Thereafter, patients were enrolled in an observational extension study for up to 8.7 years. Results Of the initial 468 patients, 284 (60.7%; IFNB1b: 178 (61.0% of the original arm), placebo: 106 (60.2% of original arm)) were enrolled in the extension study. 94.2% of patients were receiving IFNB1b. Patients originally randomised to IFNB1b had a reduced risk of developing CDMS by 32.2% over the 8-year observation period (HR 0.678; 95% CI 0.525 to 0.875; p=0.0030), a longer median time to CDMS by 1345 days (95% CI 389 to 2301), and a lower annualised relapse rate (0.196 (95% CI 0.176 to 0.218) versus 0.255 (95% CI 0.226 to 0.287), p=0.0012), with differences mainly emerging in the first year of the study. Cognitive outcomes remained higher in the early treated patients. EDSS remained low over time with a median of 1.5 in both arms. Conclusions These 8-year results provide further evidence supporting early initiation of treatment with IFNB1b in patients with a first event suggestive of MS.

Background: Cognitive dysfunction occurs at the earliest stages of multiple sclerosis (MS), including the stage of clinically isolated syndrome (CIS). Methods: We evaluated the impact of interferon beta-1b (IFNβ-1b) 250 µg on cognitive performance during the CIS stage in the BENEFITstudy. Cognition was assessed by Paced Auditory Serial Addition Test-3” (PASAT-3”) scores. Results: Improvement in PASAT-3” score from baseline to year two was greater for IFNβ-1b treatment than placebo in patients not reaching clinically definite MS (CDMS) by year two. The treatment effect was maintained at year five and was statistically significant. Conclusions: To conclude, early IFNβ-1b treatment had a sustained positive effect on PASAT-3” score over the 5-year BENEFIT study.

Background: Multiple sclerosis (MS) is characterised by inflammatory lesions of the central nervous system. Interferon beta-1b (IFNB-1b) has been shown to improve clinical and magnetic resonance imaging (MRI) measures for patients with MS. Objective: To evaluate whether IFNB-1b in patients presenting with clinically isolated syndromes (CIS) prevented persisting T1 hypointensities on MRI (persistent black holes (PBHs)). Methods: In the placebo-controlled phase, patients (n = 468) were initially randomised to IFNB-1b (n = 292) or placebo (n = 176) for two years or clinically definite MS (CDMS). In the open-label phase (n = 418), both groups were offered IFNB-1b for up to five years. Lesions were classified as PBHs if T1 hypointensity persisted throughout the last available scan (minimum time one year). Results: A total of 435 patients were evaluable for analysis. The number of PBHs/patient was lower in the early rather than the delayed treatment arm during both phases (.42 vs .71, p = .0102 and .70 vs 1.17, p = .0121). Exploratory analyses identified baseline characteristics that affected rate of conversion. Conclusions: Although the rate of lesions that converted to PBH showed no significant differences between groups, the numbers of PBHs per patient out of new lesions was significantly lower in IFNB-1b patients compared to patients on placebo. Trial registration number: NCT00544037.

Objective Some previous studies suggest modest to strong effects of 25‐hydroxyvitamin D (25(OH)D) on multiple sclerosis (MS) activity. The objective of this study was to explore the mechanistic rationale that may explain potential clinical effects of 25(OH)D. Methods This study measured serum 25(OH)D levels and global gene expression profiles over a course of up to 2 years in patients starting treatment with interferon beta‐1b (IFNB‐1b) after a clinically isolated syndrome. MS disease activity was assessed by the number of gadolinium‐enhancing lesions present on repeated magnetic resonance imaging (MRIs). Results The number of gadolinium‐enhancing lesions was highly significantly associated with 25(OH)D levels. Conducting various systems‐level analyses on the molecular level, multiple lines of evidence indicated that 25(OH)D regulates expression dynamics of a large gene–gene interaction system which primarily regulates immune modulatory processes modulating MS activity. The vitamin D response element was significantly enriched in this system, indicating a direct regulation of this gene interaction network through the vitamin D receptor. With increasing 25(OH)D levels, resulting regulation of this system was associated with a decrease in MS activity. Within the complex network of genes that are regulated by 25(OH)D, well‐described targets of IFNB‐1b and a regulator of sphingosine‐1‐phosphate bioavailability were found. The 25(OH)D effects on MS activity were additively enhanced by IFNB‐1b. Interpretation Here, we provide mechanistic evidence that an unbalanced 25(OH)D gene expression system may affect MS activity. Our findings support a potential benefit of monitoring and managing vitamin D levels (e.g., through supplementation) in early MS patients treated with IFN‐beta‐1b.