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Cognitive aging trajectories differ widely across individuals, and genetic factors such as APOE and BDNF polymorphisms may contribute to this variability. While APOE ε4 has been widely studied, the influence of APOE ε2, particularly in interaction with sex, remains underexplored. This study aims to examine the longitudinal trajectory of APOE ε2 individuals on cognitive performance, and their interactions with sex, age, and BDNF Val66Met polymorphism, in a population-based cohort of older adults with vascular risk. We analyzed data from 386 participants (mean age: 71.8) from the Barcelona-AsIA Neuropsychology Study, followed over a 7-year period. Verbal memory, verbal fluency, and visuospatial domains were assessed. Linear regression models tested associations between cognitive change and genotypes, controlling for age, sex, education, depression, and vascular risk. Interaction terms and permutation testing were applied. Regression to the mean (RTM) effects were assessed. BDNF showed no significant associations with cognitive performance. RTM effects were evident across subgroups, particularly among ε2 carriers, suggesting this phenomenon partly explains the divergent results over time. APOE ε2 does not confer a consistent protective effect on cognition over time. Our results highlight that APOE ε2 may be detrimental to verbal memory in aging males.

Peripheral artery disease (PAD) and non-compressible artery disease (NCAD) constitute predictors of subclinical atherosclerosis easily assessed through the ankle brachial index (ABI). Although both diseases show substantial genetic influences, few genetic association studies have focused on the ABI and PAD, and none have focused on NCAD. To overcome these limitations, we assessed the role of several candidate genes on the ABI, both in its continuous distribution and in the clinical manifestations associated to its extreme values: PAD and NCAD. We examined 13 candidate genomic regions in 1606 participants from the ARTPER study, a prospective population-based cohort, with the ABI assessed through ultrasonography. Association analyses were conducted independently for individuals with PAD (ABI < 0.9) or with NCAD (ABI > 1.4) vs. healthy participants. After including potential covariates and correction for multiple testing, minor alleles in the genetic markers rs10757278 and rs1333049, both in the 9p21.3 region, were significantly associated with a decreased risk of NCAD. Associations with the ABI showed limited support to these results. No significant associations were detected for PAD. The locus 9p21.3 constitutes the first genetic locus associated with NCAD, an assessment of subclinical atherosclerosis feasible for implementation in primary healthcare settings that has been systematically neglected from genetic studies.

Multiple sclerosis (MS) is a highly heterogeneous demyelinating disease of the central nervous system (CNS) that needs for reliable biomarkers to foresee disease severity. Recently, myeloid-derived suppressor cells (MDSCs) have emerged as an immune cell population with an important role in MS. The monocytic-MDSCs (M-MDSCs) share the phenotype with Ly-6C hi -cells in the MS animal model, experimental autoimmune encephalomyelitis (EAE), and have been retrospectively related to the severity of the clinical course in the EAE. However, no data are available about the presence of M-MDSCs in the CNS of MS patients or its relation with the future disease aggressiveness. In this work, we show for the first time cells exhibiting all the bona-fide phenotypical markers of M-MDSCs associated with MS lesions, whose abundance in these areas appears to be directly correlated with longer disease duration in primary progressive MS patients. Moreover, we show that blood immunosuppressive Ly-6C hi -cells are strongly related to the future severity of EAE disease course. We found that a higher abundance of Ly-6C hi -cells at the onset of the EAE clinical course is associated with a milder disease course and less tissue damage. In parallel, we determined that the abundance of M-MDSCs in blood samples from untreated MS patients at their first relapse is inversely correlated with the Expanded Disability Status Scale (EDSS) at baseline and after a 1-year follow-up. In summary, our data point to M-MDSC load as a factor to be considered for future studies focused on the prediction of disease severity in EAE and MS.

Pharmacological treatments play an important role in managing symptoms of schizophrenia but can also be associated with side effects. The aim of this study was to understand the impact of schizophrenia and its pharmacological treatment on patients' health-related quality of life (HRQoL) and to explore patient preferences around treatment benefits and side effects. This study employed a mixed methods approach with two stages of recruitment of adult patients in Spain. Stage 1 included qualitative and quantitative elements (including included two validated patient-reported outcome measures: PETiT and EQ-5D-5L) administered in telephone interviews with people with schizophrenia. Stage 2 consisted of a quantitative online survey completed by people with schizophrenia attending outpatient clinics. Responses to quantitative items across both stages were combined for analysis. Twenty respondents completed the mixed methods interviews (stage 1), and 25 participants completed the online survey (stage 2). Results from stages 1 and 2, showed that participants perceived treatments to have a beneficial impact on controlling their symptoms. However, cognitive side effects were reported to have a detrimental impact on respondents' daily life and were considered a primary reason for treatment cessation in the past. Qualitative findings further showed that most participants hoped future treatments would minimise the impact of cognitive symptoms of schizophrenia. The findings suggest that patients' expectation around treatment efficacy and their acceptability of treatment side effects may indicate their capacity to maintain long-term treatment adherence. Trade-offs that patients may be willing to make between these components may prove useful to consider in clinical practice to improve treatment adherence and hence treatment effectiveness in people with schizophrenia.

A new transdermal delivery system (TDS) for the rate-controlled systemic delivery of buprenorphine is available in 3 patch strengths, with release rates of 35, 52.5, and 70 microg/h over 72 hours, delivering daily amounts of 0.8, 1.2, and 1.6 mg, respectively. Randomized, double-blind, placebo-controlled, Phase III clinical trials in >400 patients with severe pain of malignant or nonmalignant origin have shown the analgesic efficacy of buprenorphine TDS. This study investigated the effectiveness and tolerability of buprenorphine TDS for the relief of chronic pain in routine clinical practice. This was a multicenter, open-label, uncontrolled, prospective, observational, 3-month follow-up study in patients who were beginning buprenorphine TDS treatment for moderate to severe cancer or noncancer pain that had not responded to nonopioid analgesics. Patches were to be changed every 72 hours. Patients were evaluated at 1 and 3 months after the start of treatment. Those who dropped out were considered treatment failures. Pain relief was assessed on a 5-category verbal rating scale, and quality of life was assessed using the European Quality of Life 5D (EQ-5D) questionnaire. Tolerability was determined based on adverse events recorded during the follow-up period. The study recruited 1223 patients, most of whom were outpatients. Of the 1212 patients for whom sex data were available, 820 (67.7%) were women. In the 1188 patients with age data, the mean (SD) age was 64.9 (12.9) years. In the 1175 patients with data on the etiology of pain, 82.4% had noncancer pain. Six hundred eighty-eight (56.3%) patients completed the 3-month follow-up period. The median daily amount of buprenorphine TDS received at the beginning of the study was 0.8 mg (corresponding to 35 microg/h). Over the study period, there was a significant increase in the proportion of patients reporting very good or good pain relief (P < 0.001), from 3.6% (43/1205) at baseline to 63.2% (762/1205) after 1 month and 56.8% (685/1205) after 3 months. Quality of life also improved, from a mean (SD) EQ-5D score of 40.6 (20.5) at baseline to 56.8 (23.5) at 3 months (P < 0.001). Five hundred seventeen (42.3%) of the original 1223 patients experienced adverse events; the investigator judged 397 (32.5%) of these events possibly or probably related to study drug. The likelihood of experiencing a drug-related adverse event was greater in noncancer patients than in cancer patients. The most common adverse events were nausea (11.0%), vomiting (9.2%), and constipation (7.8%); the most common local adverse events were pruritus (1.4%), dermatitis (1.3%), and erythema (1.3%). In the population studied, buprenorphine TDS was effective in alleviating cancer and noncancer pain and was well tolerated overall.

A new transdermal delivery system (TDS) for the rate-controlled systemic delivery of buprenorphine is available in 3 patch strengths, with release rates of 35, 52.5, and 70 μg/h over 72 hours, delivering daily amounts of 0.8, 1.2, and 1.6 mg, respectively. Randomized, double-blind, placebo-controlled, Phase III clinical trials in >400 patients with severe pain of malignant or nonmalignant origin have shown the analgesic efficacy of buprenorphine TDS. This study investigated the effectiveness and tolerability of buprenorphine TDS for the relief of chronic pain in routine clinical practice. This was a multicenter, open-label, uncontrolled, prospective, observational, 3-month follow-up study in patients who were beginning buprenorphine TDS treatment for moderate to severe cancer or noncancer pain that had not responded to nonopioid analgesics. Patches were to be changed every 72 hours. Patients were evaluated at 1 and 3 months after the start of treatment. Those who dropped out were considered treatment failures. Pain relief was assessed on a 5-category verbal rating scale, and quality of life was assessed using the European Quality of Life 5D (EQ-5D) questionnaire. Tolerability was determined based on adverse events recorded during the follow-up period. The study recruited 1223 patients, most of whom were outpatients. Of the 1212 patients for whom sex data were available, 820 (67.7%) were women. In the 1188 patients with age data, the mean (SD) age was 64.9 (12.9) years. In the 1175 patients with data on the etiology of pain, 82.4% had noncancer pain. Six hundred eighty-eight (56.3%) patients completed the 3-month follow-up period. The median daily amount of buprenorphine TDS received at the beginning of the study was 0.8 mg (corresponding to 35 μg/h). Over the study period, there was a significant increase in the proportion of patients reporting very good or good pain relief ( P < 0.001), from 3.6% (43/1205) at baseline to 63.2% (762/1205) after 1 month and 56.8% (685/1205) after 3 months. Quality of life also improved, from a mean (SD) EQ-5D score of 40.6 (20.5) at baseline to 56.8 (23.5) at 3 months ( P < 0.001). Five hundred seventeen (42.3%) of the original 1223 patients experienced adverse events; the investigator judged 397 (32.5%) of these events possibly or probably related to study drug. The likelihood of experiencing a drug-related adverse event was greater in noncancer patients than in cancer patients. The most common adverse events were nausea (11.0%), vomiting (9.2%), and constipation (7.8%); the most common local adverse events were pruritus (1.4%), dermatitis (1.3%), and erythema (1.3%). In the population studied, buprenorphine TDS was effective in alleviating cancer and noncancer pain and was well tolerated overall.

Multiple Sclerosis (MS) is a highly heterogeneous demyelinating disease of the central nervous system (CNS) that needs for reliable biomarkers to foresee disease severity. Previous retrospective investigations in the MS model, experimental autoimmune encephalomyelitis (EAE), highlighted the important relationship between monocytic-myeloid-derived suppressor cells (M-MDSCs) and the experimented severity of the clinical course. In this work, we show for the first time cells resembling M-MDSCs associated to MS lesions, whose abundance was related to milder MS clinical courses. Moreover, Ly-6Chi cells (which are indistinguishable from circulating M-MDSCs in mice) are useful biomarkers to predict a milder severity of the EAE disease course and a lesser tissue damage extent. Finally, the abundance of M-MDSCs in blood from untreated MS patients at their first relapse was inversely correlated with EDSS at baseline and relapse recovery one-year later. In summary, our data point to M-MDSC load as a promising biomarker of patient’s clinical course severity. The abundance of myeloid-derived suppressor cells is related to a milder clinical course in multiple sclerosis patients.