Metropolitan Arts Centre

Abstract Introduction Treatment with phosphodiesterase type 5 inhibitors (PDE5i) has been successful in men with ED of vascular origin. Still, approximately 30 to 40% of men with erectile dysfunction (ED) do not respond to the PDE5i drug therapy, and this group of patients still experience low QoL. In addition, patients suffering from neurologic damage, diabetes mellitus, or severe vascular disease may be resistant to PDE5i, or they may be contraindicated. The novel monoamine reuptake inhibitor, IP2015, induced erection by increasing central dopamine and peripheral nitric oxide in rodents and showed positive effects in a phase IIa erotic movie Rigiscan study. Objective The primary objective of the study was to investigate the effects of repeat single oral doses of IP2015 (pudafensine) on male subjects with ED on the ability to develop and maintain an erection. Methods The study was a multicenter, phase II, randomized, double-blind, parallel-group, placebo-controlled in healthy male subjects with erectile dysfunction. Men aged 18-65 years were screened, and after informed consent, those included with severe and moderate erectile dysfunction with a score < 16 in the 15-Question International Index of Erectile Function (IIEF 15) questionnaire. The subjects were randomized to 4-week treatment with a weekly dose of placebo, 5 mg, or 10 mg IP2015. The primary endpoint of the study was the change from baseline in responses to question 3 (Q3) and question 4 (Q4) in the IIEF 15 questionnaire at week 1 (day 1), week 2, week 3, week 4, and Follow-up in subjects administered IP2015 compared to placebo. The other questions in the IIEF-15 questionnaire, safety and plasma concentrations, were secondary endpoints. Analysis was performed by mixed model repeated measures (MMRM). Results The included subjects were in the placebo group (n = 45), 5 mg (n = 42), and 10 mg (n = 43) IP2015. The primary endpoint of the IIEF-15 Q3 score showed a statistically significant increase in the adjusted mean compared to baseline (P = 0.034) and placebo (P = 0.046) at week 3 and compared to baseline (P < 0.05) at the follow-up visits for the 5 mg IP2015 treatment group. For the 10 mg IP2015 and placebo treatment groups at all visits, overall, there was a decrease in adjusted mean scores compared to baseline. For the primary endpoint of the IIEF-15 Q4 score, there was a statistically significant increase in the adjusted mean compared to baseline (P = 0.0096) at the follow-up visit for the 5 mg IPED2015 treatment group. However, this increase was not statistically significant compared to placebo. Concerning the secondary IIEF-15 endpoints, there were positive tendencies for the treatment with the 5 mg IP2015. Treatment-emergent adverse effects (TEAEs) for 5 mg IP2015 were comparable to the placebo group. The TEAEs were headache, dizziness, and nausea; they were dose-dependent, mild, and moderate. There is a linear relation between plasma concentrations and the dose of IP2015. Conclusions The present study shows significant effects of IP2015 in patients with severe and moderate erectile dysfunction. The efficacy of the low dose and TEAEs at the placebo level suggests IP2015 can be used in patients with ED where PDE5 inhibition is insufficient. Disclosure Yes, this is sponsored by industry/sponsor: Initiator Pharma A/S. Clarification: Industry initiated, executed and funded study. Any of the authors act as a consultant, employee or shareholder of an industry for: Initiator Pharma A/S.

'Cerebral palsy' ('CP') is a widely used descriptive label for a spectrum of motor impairments caused by non-progressive brain injury or malformation occurring during early development. Advances in research have significantly refined our understanding of CP, including insights into its genetic, inflammatory, and neurophysiological underpinnings. Research across global contexts, including low- and middle-income countries, has expanded knowledge of clinical features. Shifting societal perceptions, driven by individuals with lived experience, have further influenced how CP is understood, challenging ableist attitudes and promoting inclusive frameworks. Additionally, increased recognition of the needs and experiences of adults with CP has highlighted the importance of further developing appropriate services. The primary aim of this paper is to propose an updated description of CP, developed through a collaborative, multidisciplinary process, as a preliminary formulation that integrates stakeholder perspectives at this stage of the process. By framing it as a foundation for further discussion and refinement, the manuscript emphasizes the output itself rather than the process of its development. A comprehensive stakeholder analysis and mapping approach ensured broad representation, including individuals with CP, families, clinicians, researchers, advocacy groups, and others. Data were collected through surveys, interviews, focus groups, and workshops, facilitating a global dialogue that combined the expertise of those with lived experience with that of clinicians. The description is intended to serve as a preliminary framework to guide clinical practice, research, and policy, emphasizing a shared understanding of CP. The proposed updated description thus lays the foundation for continued refinement, emphasizing the importance of collaboration in advancing the care and inclusion of individuals with CP.

Abstract Presentation Date: 6/8/2024 Presentation Start Time: 9:00:00 AM Background Vaso-occlusive crisis (VOC) is the primary reason for hospitalization among patients with sickle cell disease (SCD). Free heme from ongoing hemolysis contributes to VOC by activating endothelium and blood cells adhesiveness. The resulting blockage of blood circulation produces the characteristic pain of VOC. Hemopexin (Hx) is an endogenous plasma glycoprotein that binds extracellular heme. In people living with SCD, Hx is consumed during hemolysis, leading to its depletion. Administration of Hx relieves experimental vaso-occlusion induced by free heme, hemoglobin or hypoxia-reoxygenation in Townes SCD mice (Gentinetta et al. 2022). We are investigating the potential for plasma-derived human hemopexin (CSL889) to neutralize heme toxicity and normalize blood circulation. We report results of a phase 1, first-in-human study evaluating the safety, tolerability and pharmacokinetics (PK) of CSL889 in adults with SCD [NCT04285827]. Methods This 2-part, multicenter, open-label cohort study was conducted in the US, UK, and the Netherlands. The primary objective was to determine the safety and tolerability of single intravenous (IV) doses of CSL889 in adults with SCD of any genotype. Secondary and exploratory objectives included pharmacokinetics, immunogenicity, and biomarkers of target engagement and mechanism of action. In Part A, 6 ascending single dose levels (3, 10, 30, 60, 120, and 200 mg/kg) were tested in subjects not in VOC (n = 4 per cohort). In Part B, 4 subjects hospitalized for management of VOC with IV opioids received a single IV dose of 60 mg/kg CSL889 within 36 hours of admission. All subjects were followed for approximately 32 days post-infusion of CSL889. The serum assay of Hx measures total Hx and cannot distinguish CSL889 from endogenous Hx, nor heme-bound from free Hx. Noncompartmental analysis of PK was completed using total and pre-dose baseline-adjusted Hx values. Results All 28 subjects self-reported as Black or African American, 15/28 (54%) were female, and age ranged from 20 to 57 years. Most (86%) had HbSS genotype. Half of the subjects in Part A and all in Part B reported concomitant hydroxyurea use. In Part B, 3 subjects were receiving voxelotor and/or crizanlizumab. All Part B subjects had histories of ≥ 3 VOC within the prior 12 months, while most Part A subjects (18/24) had ≤ 2. Seventy treatment emergent adverse events (TEAEs) were reported in 22 subjects (51 mild, 18 moderate and 1 severe). Number or severity of TEAEs did not increase with dose or VOC status. The most common TEAEs were sickle cell anemia with crisis (29% of subjects, all ³1 week after CSL889) and headache (17%). Four TEAEs were considered related to CSL889, all nonserious, of mild severity and resolved: 2 TEAEs of transient dizziness in 2 subjects; and TEAEs of transient increase in fibrin D-dimer and decrease in blood fibrinogen level in 1 subject. Two serious adverse events (SAEs) of moderate severity were reported in 1 subject in Part A, neither related to CSL889 (simultaneous COVID-19 and VOC, both resolved). One SAE of acute chest syndrome occurred in Part B, in the setting of an intercurrent diarrheal illness > 8 days after CSL889; considered not related to CSL889 and all resolved. No ECG changes or other notable lab findings were observed. No subjects developed treatment-emergent anti-CSL889 antibody. Baseline levels of endogenous Hx were low but highly variable (range 7.2 to 499 µg/mL; normal value 2000 µg/mL). Total serum heme was also variable over time, within and across cohorts. CSL889 Tmax was ≤ 2.33 hours and T1/2 ranged from 0.375 to 3.52 days across the dose levels. Mean total Hx Cmax at 200 mg/kg was approximately 2-fold higher than the average healthy human level (Santiago et al 2018). Mean Cmax was comparable within variability based on standard deviation in the subjects with and without VOC that received the same dose (60 mg/kg). Biomarker analysis confirmed target engagement, but no trends in pharmacodynamic biomarker concentrations were observed. Conclusions CSL889 had an excellent safety and tolerability profile when administered as a single dose up to 200 mg/kg in subjects with stable SCD and at 60 mg/kg in subjects with VOC. The observed half-life may support dosing once daily or every other day. These results provide a strong foundation for future trials to evaluate potential efficacy.

Selenium and vitamin E have been identified as promising agents for the chemoprevention of recurrence and progression of non-muscle-invasive bladder cancer. To determine whether selenium and/or vitamin E may prevent disease recurrence in patients with newly diagnosed NMIBC. This multicenter, prospective, double-blinded, placebo-controlled, 2 × 2 factorial randomized clinical trial included patients with newly diagnosed NMIBC recruited from 10 secondary or tertiary care hospitals in the UK. A total of 755 patients were screened for inclusion; 484 did not meet the inclusion criteria, and 1 declined to participate. A total of 270 patients were randomly assigned to 4 groups (selenium plus placebo, vitamin E plus placebo, selenium plus vitamin E, and placebo plus placebo) in a double-blind fashion between July 17, 2007, and October 10, 2011. Eligibility included initial diagnosis of NMIBC (stages Ta, T1, or Tis); randomization within 12 months of first transurethral resection was required. Oral selenium (200 μg/d of high-selenium yeast) and matched vitamin E placebo, vitamin E (200 IU/d of d-alfa-tocopherol) and matched selenium placebo, selenium and vitamin E, or placebo and placebo. Recurrence-free interval (RFI) on an intention-to-treat basis (analyses completed on November 28, 2022). The study randomized 270 patients (mean [SD] age, 68.9 [10.4] years; median [IQR] age, 69 [63-77] years; 202 male [75%]), with 65 receiving selenium and vitamin E placebo, 71 receiving vitamin E and selenium placebo, 69 receiving selenium and vitamin E, and 65 receiving both placebos. Median overall follow-up was 5.5 years (IQR, 5.1-6.1 years); 228 patients (84%) were followed up for more than 5 years. Median treatment duration was 1.5 years (IQR, 0.9-2.5 years). The study was halted because of slow accrual. For selenium (n = 134) vs no selenium (n = 136), there was no difference in RFI (hazard ratio, 0.92; 95% CI, 0.65-1.31; P = .65). For vitamin E (n = 140) vs no vitamin E (n = 130), there was a statistically significant detriment to RFI (hazard ratio, 1.46; 95% CI, 1.02-2.09; P = .04). No significant differences were observed for progression-free interval or overall survival time with either supplement. Results were unchanged after Cox proportional hazards regression modeling to adjust for known prognostic factors. In total, 1957 adverse events were reported; 85 were serious adverse events, and all were considered unrelated to trial treatment. In this randomized clinical trial of selenium and vitamin E, selenium supplementation did not reduce the risk of recurrence in patients with NMIBC, but vitamin E supplementation was associated with an increased risk of recurrence. Neither selenium nor vitamin E influenced progression or overall survival. Vitamin E supplementation may be harmful to patients with NMIBC, and elucidation of the underlying biology is required. isrctn.org Identifier: ISRCTN13889738.

Summary In recent decades the interdisciplinary study of elite gift exchange in various geographical and temporal contexts has transformed historians’ understanding of colonial diplomacy. By combining analysis of textual, visual and material sources with theoretical approaches to material culture and gift exchange from anthropology, scholars have increasingly come to examine colonial diplomacy not only through the high-politics and text-based operations of bureaucrats in imperial metropoles, but also as a material and cultural project operating through the local and personal. This essay uses the published account of John Hanning Speke (1863) and his descriptions of ‘gift exchanges’ in present-day Uganda to understand the materiality of early British diplomacy there. As Speke was the first Briton to reach Uganda, it examines how gift exchanges impacted the logistics and outcomes of his visit. Re-examining his text this way reveals the importance of material knowledge, performance and exchange in early cross-cultural encounters in the region.

From 1808 the British Museum in London began regularly to open its newly established Townley Gallery so that art students could draw from the ancient sculptures housed there. This article documents and comments on this development in art education, based on an analysis of the 165 individuals recorded in the surviving register of attendance at the Museum, covering the period 1809–17. The register is presented as a photographic record, with a transcription and biographical directory. The accompanying essay situates the opening of the Museum’s sculpture rooms to students within a far-reaching set of historical shifts. It argues that this new museum access contributed to the early nineteenth-century emergence of a liberal state. But if the rhetoric surrounding this development emphasized freedom and general public benefit in the spirit of liberalization, the evidence suggests that this new level of access actually served to further entrench the “middle-classification” of art education at this historical juncture.