Patients' Preferences for Sphingosine-1-Phosphate Receptor Modulators in Multiple Sclerosis Based on Clinical Management Considerations: A Choice Experiment.

BACKGROUND: Several sphingosine-1-phosphate receptor (S1PR) modulators are available in the US for treating relapsing forms of multiple sclerosis (RMS). Given that these S1PR modulators have similar efficacy and safety, patients may consider the clinical management characteristics of the S1PR modulators when deciding among treatments. However, none of the S1PR modulators is clearly superior in every aspect of clinical management, and for some treatments, clinical management varies based on a patient's comorbid health conditions (e.g., heart conditions [HC]). OBJECTIVES: This study aimed to determine which S1PR modulator patients with relapsing-remitting multiple sclerosis (RRMS) would prefer based on clinical management considerations, and to estimate how different clinical management considerations might drive these preferences. Preferences were explored separately for patients with and without comorbid HC. METHODS: A multicriteria decision analysis was conducted on S1PR modulators approved to treat RMS: fingolimod, ozanimod, siponimod, and ponesimod. Clinical management preferences of patients with RRMS were elicited in a discrete choice experiment (DCE) in which participants repeatedly chose between hypothetical S1PR modulator profiles based on their clinical management attributes. Attributes included first-dose observations, genotyping, liver function tests, eye examinations, drug-drug interactions, interactions with antidepressants, interactions with foods high in tyramine, and immune system recovery time. Preferences were estimated separately for patients with HC and without HC (noHC). Marginal utilities were calculated from the DCE data for each attribute and level using a mixed logit model. In the multicriteria decision analysis, partial value scores were created by applying the marginal utilities for each attribute and level to the real-world profiles of S1PR modulators. Partial value scores were summed to determine an overall clinical management value score for each S1PR modulator. RESULTS: Four hundred patients with RRMS completed the DCE. Ponesimod had the highest overall value score for patients both without (n = 341) and with (n = 59) HC (noHC: 5.1; HC: 4.0), followed by siponimod (noHC: 4.9; HC: 3.3), fingolimod (noHC: 3.4; HC: 2.8), and ozanimod (noHC: 0.9; HC: 0.8). Overall, immune system recovery time contributed the highest partial value scores (noHC: up to 1.9 points; HC: up to 1.2 points), followed by the number of drug-drug interactions (noHC: up to 1.2 points; HC: up to 1.7 points). CONCLUSIONS: When considering the clinical management of S1PR modulators, the average patient with RRMS is expected to choose a treatment with shorter immune system recovery time and fewer interactions with other drugs. Patients both with and without heart conditions are likely to prefer the clinical management profile of ponesimod over those of siponimod, fingolimod, and ozanimod. This information can help inform recommendations for treating RRMS and facilitate shared decision making between patients and their doctors.

Anhedonia in Neurodegenerative Diseases.

Neurodegenerative diseases are increasingly recognised to be an important cause of brain disorders, particularly in late age. Associated with a wide range of pathologies, they lead to progressive loss of neurons in different regions of the nervous system. Although anhedonia is common in a variety of neurodegenerative diseases, to date it has not been extensively studied in most of these conditions. Here we review the current literature on studies assessing the association between anhedonia and neurodegenerative diseases including Parkinson's Disease, Dementia with Lewy Bodies, Parkinson's Plus Syndromes, Alzheimer's Disease, Vascular Dementia, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis and Huntington's Disease. Much of the research has been conducted in Parkinson's disease where it is evident that there are strong links between apathy (loss of motivation) and anhedonia, although the two syndromes can be dissociated. Intriguingly, drugs that improve apathy can also lead to amelioration of anhedonia in some cases. Overlaps between the two syndromes may also exist across other neurodegenerative conditions, including Frontotemporal Dementia in which imaging has revealed atrophy of both common brain regions associated with anhedonia and apathy, as well as a set of unique brain regions associated with anhedonia. A transdiagnostic perspective might be helpful to investigate whether a common network of brain regions is dysfunctional with anhedonia across neurodegenerative conditions.

Hyperreactivity to uncertainty is a key feature of subjective cognitive impairment.

With an increasingly ageing global population, more people are presenting with concerns about their cognitive function, but not all have an underlying neurodegenerative diagnosis. Subjective cognitive impairment (SCI) is a common condition describing self-reported deficits in cognition without objective evidence of cognitive impairment. Many individuals with SCI suffer from depression and anxiety, which have been hypothesised to account for their cognitive complaints. Despite this association between SCI and affective features, the cognitive and brain mechanisms underlying SCI are poorly understood. Here, we show that people with SCI are hyperreactive to uncertainty and that this might be a key mechanism accounting for their affective burden. Twenty-seven individuals with SCI performed an information sampling task, where they could actively gather information prior to decisions. Across different conditions, SCI participants sampled faster and obtained more information than matched controls to resolve uncertainty. Remarkably, despite their 'urgent' sampling behaviour, SCI participants were able to maintain their efficiency. Hyperreactivity to uncertainty indexed by this sampling behaviour correlated with the severity of affective burden including depression and anxiety. Analysis of MRI resting functional connectivity revealed that SCI participants had stronger insular-hippocampal connectivity compared to controls, which also correlated with faster sampling. These results suggest that altered uncertainty processing is a key mechanism underlying the psycho-cognitive manifestations in SCI and implicate a specific brain network target for future treatment.

Analysis of smoking in patients referred for liver transplantation and its adverse impact of short-term outcomes.

Smoking has been reported to adversely affect the outcome of patients undergoing liver transplantation (LT). We present a clinical and demographic analysis of smoking in patients from a rural Appalachian region referred to our center for LT. We reviewed 237 consecutive patients referred for LT between January 2002 and December 2003. We also reviewed charts of 65 patients that underwent LT at our center during this period and analyzed the length of stay (LOS), one-year survival post LT, and hospital charge information. The mean MELD score was similar between smokers and nonsmokers at the time of referral (12.3 vs. 12.1, respectively, p = 0.8). Smokers had a tendency towards a higher CPT score (8.2 vs. 7.9, p = 0.06). The incidence of difficult-to-manage ascites and encephalopathy was significantly higher in smokers (p < 0.O1 for both ascites and encephalopathy). Of the 65 patients that underwent LT, 69.2% were smokers. While one-year post LT survival was similar (approximately 90%) for both smokers and nonsmokers, the mean length of stay and hospital charge for smokers was significantly higher (13.4 vs. 7.9 days; P = .02 and $129,185 vs. $99,694; P = .02). In conclusion, smokers have a higher incidence of ascites and encephalopathy and thus may be disadvantaged by the MELD allocation scheme for liver transplantation. While post-transplant one-year survival is similar between smokers and nonsmokers, smokers have higher LOS and resource utilization.