Long-term effects of evolocumab in participants with HIV and dyslipidemia: results from the open-label extension period

Objectives: People with HIV (PWH) are at an increased risk of atherosclerotic cardiovascular disease. Suboptimal responses to statin therapy in PWH may result from antiretroviral therapies (ARTs). This open-label extension study aimed to evaluate the long-term safety and efficacy of evolocumab up to 52\u200aweeks in PWH. Design: This final analysis of a multinational, placebo-controlled, double-blind, randomized phase 3 trial evaluated the effect of monthly subcutaneous evolocumab 420\u200amg on low-density lipoprotein cholesterol (LDL-C) during the open-label period (OLP) following 24\u200aweeks of double-blind period in PWH with hypercholesterolemia/mixed dyslipidemia. All participants enrolled had elevated LDL-C or nonhigh-density lipoprotein cholesterol (non-HDL-C) and were on stable maximally tolerated statin and stable ART. Methods: Efficacy was assessed by percentage change from baseline in LDL-C, triglycerides, and atherogenic lipoproteins. Treatment-emergent adverse events (TEAEs) were examined. Results: Of the 467 participants randomized in the double-blind period, 451 (96.6%) received at least one dose of evolocumab during the OLP (mean age of 56.4\u200ayears, 82.5% male, mean duration with HIV of 17.4\u200ayears). By the end of the 52-week OLP, the overall mean (SD) percentage change in LDL-C from baseline was -57.8% (22.8%). Evolocumab also reduced triglycerides, atherogenic lipid parameters (non-HDL-C, apolipoprotein B, total cholesterol, very-low-density lipoprotein cholesterol, and lipoprotein[a]), and increased HDL-C. TEAEs were similar between placebo and evolocumab during the OLP. Conclusion: Long-term administration of evolocumab lowered LDL-C and non-HDL-C, allowing more PWH to achieve recommended lipid goals with no serious adverse events. Trail registration: NCT02833844. Video abstract: http://links.lww.com/QAD/C441

Patient reported outcomes in ALS: characteristics of the self-entry ALS Functional Rating Scale-revised and the Activities-specific Balance Confidence Scale

Objective: This study characterized two patient-reported outcome measures (PROMs): a patient-facing adaptation of the revised amyotrophic lateral sclerosis (ALS) Functional Rating Scale ("self-entry ALSFRS-R") and the Activities-specific Balance Confidence (ABC) Scale. Methods: ALS patients presenting to clinic completed PROMs that included (1) the self-entry ALSFRS-R, (2) the Activities-specific Balance Confidence Scale (ABC Scale), and (3) a question about falls. PROM data were compared to one another and to the traditional ALSFRS-R collected by trained evaluators in clinic ("standard ALSFRS-R"). Results: Over the data collection period, 449 ALS patients completed at least one of the three PROMs. Self-entry vs. standard ALSFRS-R total scores (n = 183) had high agreement (intraclass correlation (ICC)=0.81, 95% CI = 0.67, 0.88). Self-entry ALSFRS-R total scores were significantly higher than standard ALSFRS-R total scores (2.3 points, p < 0.001). In a subset of participants who contributed data at two timepoints, the average ALSFRS-R decline was not significantly different between methods (n = 49). ABC scores correlated highly with self-entry and standard ALSFRS-R Gross Motor subdomain scores (Pearson's r = 0.72, p < 0.001 and Pearson's r = 0.76, p < 0.001, respectively; n = 130). ABC score was negatively correlated with the number of reported falls within the last month (Spearman's r=-0.40; p < 0.001; n = 130). A 10-point decrease in ABC score increased odds of a reported fall by 16%. Conclusions: In a multidisciplinary clinic setting, self-entry and standard ALSFRS-R scores were similar, but not interchangeable. Self-entry scores were higher than standard ALSFRS-R scores but declined at a similar rate to the standard ALSFRS-R. ABC scores correlated with self-reported fall history and thus may provide useful data for clinical care

Moving Toward Multicenter Therapeutic Trials in Amyotrophic Lateral Sclerosis: Feasibility of Data Pooling Using Different Translocator Protein PET Radioligands

Neuroinflammation has been implicated in amyotrophic lateral sclerosis (ALS) and can be visualized using translocator protein (TSPO) radioligands. To become a reliable pharmacodynamic biomarker for ALS multicenter trials, TSPO radioligands have some challenges to overcome. We aimed to investigate whether multicenter data pooling of different TSPO tracers (11C-PBR28 and 18F-DPA714) is feasible, after validation of an established 11C-PBR28 PET pseudo reference analysis technique for 18F-DPA714. Methods: Seven ALS patients from Belgium (58.9 ± 6.7 y old, 5 men and 2 women), 8 healthy volunteers from Belgium (52.1 ± 15.2 y old, 3 men and 5 women), 7 ALS patients from the United States (53.4 ± 9.8 y old, 5 men and 2 women), and 7 healthy volunteers from the United States (54.6 ± 9.6 y old, 4 men and 3 women) from a previously published study underwent dynamic 18F-DPA714 (Leuven, Belgium) or 11C-PBR28 (Boston, Massachusetts) PET/MRI. For 18F-DPA714, maps of total volume of distribution (VT) were compared with SUV ratio (SUVR) images from 40 to 60 min after injection (SUVR40-60) calculated using the pseudo reference regions cerebellum, occipital cortex, and whole brain (WB) without ventricles. For 11C-PBR28, SUVR images from 60 to 90 min after injection using the WB without ventricles were calculated. Results: In line with previous studies, increased 18F-DPA714 uptake (17.0% ± 5.6%) in primary motor cortices was observed in ALS subjects, as measured by both VT and SUVR40-60 approaches. The highest sensitivity was found for SUVR calculated using the WB without ventricles (average cluster, 21.6% ± 0.1%). 18F-DPA714 VT ratio was highly correlated with the SUVR40-60 (r > 0.8, P < 0.001). A similar pattern of increased uptake (average cluster, 20.5% ± 0.5%) in the primary motor cortices was observed in ALS subjects for 11C-PBR28 SUVR calculated using the WB without ventricles. Analysis of the 18F-DPA714 and 11C-PBR28 data together resulted in a more extensive pattern of significantly increased glial activation bilaterally in the primary motor cortices. Conclusion: The same pseudo reference region analysis technique for 11C-PBR28 PET can be extended toward 18F-DPA714 PET. Therefore, in ALS, standardized analysis across these 2 tracers enables pooling of TSPO PET data across multiple centers and increases the power of TSPO as a biomarker for future therapeutic trials.status: publishe

Singapore’s Total Diet Study (2021–2023): Study Design, Methodology, and Relevance to Ensuring Food Safety

A total diet study is often used to evaluate a population’s baseline dietary exposure to chemical hazards from across the diet. In 2021–2023, Singapore carried out a TDS, and this article presents an overview of the study design and methodological selections in Singapore’s TDS, as well as its relevance to ensuring food safety. A food consumption survey was conducted on Singapore citizens and permanent residents, where food consumption patterns of the Singapore population were identified. The selection of chemical hazards and foods for inclusion in Singapore’s TDS, as well as principal considerations on sampling, food preparation, and analytical testing are discussed. Commonly consumed foods by the Singapore population in food categories such as grain and grain-based products, meat and meat products, fish and seafood, vegetables, fruits, milk and dairy products were included in this study, and mean concentrations of chemicals tested in each food category were reported, with food categories possessing higher levels identified. Future work will include dietary exposure assessments for the population and analysis of the contributions by food and cooking method