Introduction: Chronic neuropathic pain is difficult to treat and is often refractory to most modalities of treatment. Ziconotide is a novel, potent, non-opioid, calcium channel blocking agent which ...has been shown in clinical trials to be effective in treating chronic neuropathic pain.
Methods: EMBASE, MEDLINE, CINAHL Plus and Web of Science electronic databases were searched for English language studies. Reference sections of articles were examined for further papers and the manufacturer of ziconotide was contacted for further unpublished data. Three randomised controlled trials in ziconotide monotherapy were included and subjected to a random effects meta-analysis.
Results: All three studies used the similar main outcome measure (visual analogue scale of pain intensity; VASPI) and were therefore comparable. A Jadad score was performed for each paper. Frequent serious adverse events (SAEs) were observed which resulted in two of the studies revising the protocol. The metaanalysis revealed a pooled odds ratio (responders on ziconotide vs. placebo) of 2.77 (95% CI, 1.37 to 5.59).
Discussion: The results suggest that ziconotide is beneficial for pain reduction in chronic neuropathic pain. However, there remain some methodological issues that may call into question the validity of the results. It is evident that more work needs to be conducted to further validate the efficacy of ziconotide and to discover new areas of use.
Mucopolysaccharidosis type I is caused by deficiency of α-L-iduronidase. Currently available treatment options include an allogeneic hematopoietic stem cell transplant and enzyme replacement therapy. ...Exogenous enzyme therapy appears promising but the benefits may be attenuated, at least in some patients, by the development of an immune response to the delivered enzyme. The incidence and impact of alloimmune responses in these patients remain unknown.
We developed an immunoglobulin G enzyme-linked immunosorbent assay as well as in vitro catalytic enzyme inhibition and cellular uptake inhibition assays and quantified enzyme inhibition by allo-antibodies. We determined the impact of these antibodies in eight patients who received enzyme therapy before and during hematopoietic stem cell transplantation. In addition, 20 patients who had previously received an allogeneic stem cell transplant were tested to evaluate this treatment as an immune tolerance induction mechanism.
High titer immune responses were seen in 87.5% (7/8) patients following exposure to α-L-iduronidase. These patients exhibited catalytic enzyme inhibition (5/8), uptake inhibition of catalytically active enzyme (6/8) or both (4/8). High antibody titers generally preceded elevation of previously described biomarkers of disease progression. The median time to development of immune tolerance was 101 days (range, 26-137) after transplantation. All 20 patients, including those with mixed chimerism (22%), tested 1 year after transplantation were tolerized despite normal enzyme levels.
We found a high incidence of neutralizing antibodies in patients with mucopolysaccharidosis type I treated with enzyme replacement therapy. We also found that allogeneic hematopoietic stem cell transplantation was an effective and rapid immune tolerance induction strategy.
Although spoilers are commonly believed to ruin the experience of a story, recent research has produced conflicting results about the role spoilers play in enjoyment. In response, scholars have begun ...to explore factors that impact the relationship between spoilers and the narrative experience. A series of three studies were conducted to investigate the relationship between spoilers and processing fluency by examining how expectations regarding a narrative's ending can interact with spoilers to affect fluency and the resulting enjoyment. Three online between-subjects experiments exposed participants to a spoiled or unspoiled preview and then assigned them to watch the season finale of a long-running sitcom with either the original ending that defied expectations or an alternate ending that aligned with genre conventions. Results reveal that both spoilers and whether an ending is expected have a complex relationship with fluency, with the three studies producing slightly different interactions between these two variables. In all three studies, fluency was associated with increased enjoyment.
Public Policy Relevance StatementThree experiments found mixed results for the relationship between spoilers and processing fluency, and, subsequently, about the impact of spoilers on enjoyment. It is still to be determined whether seeking spoilers about a narrative event is likely to help or hinder enjoyment by impacting fluency.
Background
Prurigo nodularis (PN) is characterized by intensely itchy nodules/lesions and skin pain, which can have a substantial impact on health‐related quality of life (HRQoL). Treatment benefits ...on such symptoms and impacts are best assessed in trials using patient‐reported outcome (PROs) instruments such as Skin Pain Numerical Rating Scale (NRS), Sleep‐NRS and Dermatology Life Quality Index (DLQI). However, no guidance exists for interpreting meaningful changes in scores using these PROs in patients with PN.
Objectives
The main objective was to derive within‐patient (responder definition) and between‐group improvement thresholds for interpreting Skin Pain‐NRS, Sleep‐NRS and DLQI total scores in patients with PN. The measurement properties of the three PROs were also evaluated.
Methods
Intention‐to‐treat (ITT), blinded and pooled data were used from the Phase 3 PRIME (NCT04183335) and PRIME2 (NCT04202679) studies evaluating the efficacy of dupilumab in adult patients with PN. Anchor‐ and distribution‐based methods were applied to derive responder definition and between‐group thresholds for Skin Pain‐NRS, Sleep‐NRS and DLQI. Data were additionally used to examine the instrument measurement properties, including reliability, validity and responsiveness.
Results
A total of 311 patients (mean age 49.5 years, 65.3% female) were included in the pooled ITT population. The within‐patient improvement threshold for Skin Pain‐NRS was estimated as 4.0 points, 2.0 points for Sleep‐NRS and 9.0 points for DLQI total score. A 1.5‐point improvement in Skin Pain‐NRS scores, 1.0‐point in Sleep‐NRS and 4.0‐point in DLQI indicated a between‐group meaningful change. Adequate to good psychometric properties were demonstrated for all three instruments.
Conclusions
The results of this study can aid interpretation of Skin Pain‐NRS, Sleep‐NRS and DLQI scores in patients with PN in both clinical trials and clinical practice to better understand and treat PN‐related skin pain and the impact of PN on sleep quality and HRQoL.
Background:Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory condition impacting multiple organ systems.1,2 SLE affects approximately 1.5 million Americans, disproportionately ...females of reproductive age, and is more prevalent in non-Caucasian populations.3 Fatigue and pain are some of the most prominent symptoms of SLE, contributing to the heavy disease burden and disruption to daily life.4 This study aimed to further understand the burden of SLE. Lilly worked with the Lupus Foundation of America (LFA) and Evidera to develop the SLE-UPDATE (Understanding Preferences, Disease Activity and Treatment Expectations) survey.Objectives:To understand the patient-perceived symptom burden of SLE, in particular pain and fatigue, within the current landscape of therapeutic options. This study also focused on current treatment patterns in SLE patients.Methods:This was a cross-sectional, non-interventional, online survey study conducted in partnership with the LFA. English-speaking United States patients aged ≥18 years with a self-reported diagnosis of SLE completed the survey following online screening and informed consent. Descriptive data are presented by means (standard deviation SD) for continuous measures, and frequency (n, %) for dichotomous measures. Demographic, clinical, and patient-reported outcomes were collected including the FACIT-Fatigue (range 0-52, higher scores indicate less fatigue), Pain Numerical Rating Scale (NRS) (0 none to 10 worst imaginable), Worst Joint Pain NRS (0 none to 10 worst imaginable), and the LupusPRO, a validated, lupus-specific quality of life (QoL) instrument (range 0-100, higher scores indicate better QoL).Results:A total of 500 patients with SLE completed the survey. Patients were predominantly female (75%), white/Caucasian (76%), with a mean age of 42.6 years and mean disease duration of 11.1 years.Most patients with SLE rated their overall condition as either good (38%) or fair (31%), with 8% rating poor and 7% excellent. Current non-biologic prescription medication use included: antimalarials 42%, corticosteroids 33%, immunosuppressants 33%, nonsteroidal anti-inflammatory drugs (NSAID) 32%, other analgesics 15% and 10% were using tofacitinib. Biologic therapies were being used by only 19%, including intravenous (IV) Benlysta (37%), subcutaneous (SC) Benlysta (25%), rituximab (17%), and 22% were using other biologics. Fatigue was the most commonly reported symptom (69%), with 40% of patients ranking fatigue as their most bothersome SLE symptom. Forty eight percent of patients with current fatigue rated the severity as moderate and 33% as severe. The mean (SD) FACIT-Fatigue score was 22.9 (12.0). The next most commonly reported symptoms were joint stiffness (57%), sleep problems (55%), joint pain/swelling (53%), and muscle pain (52%). Sixty percent of patients reported experiencing pain all or most of the time over the past seven days. A total of 30% of patients with current joint pain/swelling rated it as severe, and 24% of patients with current joint stiffness rated it as severe. The mean scores for Worst pain NRS and Worst Joint Pain NRS were both 5.8 out of 10.The LupusPRO domains indicated by respondents as the most impacted by SLE were Emotional Health, Pain/Vitality, and Lupus Medications.Conclusion:Fatigue, followed by pain and joint stiffness, were the most common patient-reported symptoms contributing to the overall SLE disease burden. Further research could highlight the efforts required to address the inadequacies in treatment and management of pain and fatigue in this patient population.Disclosure of Interests:Julie Birt Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Monica Hadi: None declared, Nashmel Sargalo: None declared, Ella Brookes: None declared, Paul Swinburn: None declared, Leslie Hanrahan: None declared, Karin Tse: None declared, Natalia Bello Vega Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Kirstin Griffing Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Maria Silk Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Laure Delbecque Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Diane L Kamen Consultant of: Consulted on SLE survey development for Lilly and consulted on SLE trial protocol development for EMD Serono in 2019
Butyrate is a key bioactive product of dietary fibre fermentation thought to play a key role in cancer prevention. One contributory mechanism in this role is the regulation of apoptosis by butyrate. ...As butyrate shows low levels of toxicity, the mechanisms by which it triggers or regulates apoptosis are of great interest. We and others have shown that the proapoptotic protein BAK is upregulated by butyrate. We show here that this observation is conserved across multiple cell lines, that it occurs in all cells in a population and is at the transcriptional level. We have used a promoter-reporter construct to identify the regulatory regions of the BAK promoter and found that much of the transcriptional activity occurs via a single Sp1/Sp3 binding site. We have shown that both Sp1 and Sp3 bind, but upon butyrate treatment Sp1 binding decreases in favour of Sp3 binding. We speculate that this may be an acetylation-mediated event.
Polycrystalline cubic boron nitride (PcBN) cutting tools are used for the machining of ferrous alloys at high speeds and temperatures where the use of diamond is precluded due to graphitisation. To ...accurately predict the life of these tool materials it is necessary to understand inter alia the deformation and relevant mechanisms that occur at the temperatures and pressures associated with cutting. This paper uses Vickers indentation as a means of assessing the role of cBN content, binder phase and cBN grain size on the mechanical properties of a number of polycrystalline cubic boron nitride materials. It will be shown that as experimental temperatures increase, a change in deformation mechanism occurs in the tool materials, confirming that the indentation method is useful in the identification of such changes.
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