Effects of Oral Cannabinoids on Systemic Inflammation and Viral Reservoir Markers in People with HIV on Antiretroviral Therapy: Results of the CTN PT028 Pilot Clinical Trial.

Chronic HIV infection is characterized by persistent inflammation despite antiretroviral therapy (ART). Cannabinoids may help reduce systemic inflammation in people with HIV (PWH). To assess the effects of oral cannabinoids during HIV, ten PWH on ART were randomized (n = 5/group) to increasing doses of oral Δ9-tetrahydrocannabinol (THC): cannabidiol (CBD) combination (2.5:2.5-15:15 mg/day) capsules or CBD-only (200-800 mg/day) capsules for 12 weeks. Blood specimens were collected prospectively 7-21 days prior to treatment initiation and at weeks 0 to 14. Plasma cytokine levels were determined via Luminex and ELISA. Immune cell subsets were characterized by flow cytometry. HIV DNA/RNA were measured in circulating CD4 T-cells and sperm by ultra-sensitive qPCR. Results from both arms were combined for statistical analysis. Plasma levels of IFN-γ, IL-1ß, sTNFRII, and REG-3α were significantly reduced at the end of treatment (p ˂ 0.05). A significant decrease in frequencies of PD1+ memory CD4 T-cells, CD73+ regulatory CD4 T-cells, and M-DC8+ intermediate monocytes was also observed (p ˂ 0.05), along with a transient decrease in CD28-CD57+ senescent CD4 and CD8 T-cells. Ki-67+ CD4 T-cells, CCR2+ non-classical monocytes, and myeloid dendritic cells increased over time (p ˂ 0.05). There were no significant changes in other inflammatory markers or HIV DNA/RNA levels. These findings can guide future large clinical trials investigating cannabinoid anti-inflammatory properties.

Safety and Tolerability of Oral Cannabinoids in People Living with HIV on Long-Term ART: A Randomized, Open-Label, Interventional Pilot Clinical Trial (CTNPT 028).

BACKGROUND: With anti-inflammatory properties, cannabinoids may be a potential strategy to reduce immune activation in people living with HIV (PLWH) but more information on their safety and tolerability is needed. METHODS: We conducted an open-label interventional pilot study at the McGill University Health Centre in Montreal, Canada. PLWH were randomized to oral Δ9-tetrahydrocannabinol (THC): cannabidiol (CBD) combination (THC 2.5 mg/CBD 2.5 mg) or CBD-only capsules (CBD 200 mg). Individuals titrated doses as tolerated to a maximum daily dose THC 15 mg/CBD 15 mg or 800 mg CBD, respectively, for 12 weeks. The primary outcome was the percentage of participants without any significant toxicity based on the WHO toxicity scale (Grades 0-2 scores). RESULTS: Out of ten individuals, eight completed the study. Two from the CBD-only arm were withdrawn for safety concerns: phlebotomy aggravating pre-existing anemia and severe hepatitis on 800 mg CBD with newly discovered pancreatic adenocarcinoma, respectively. Seven did not have any significant toxicity. Cannabinoids did not alter hematology/biochemistry profiles. CD4 count, CD4/CD8 ratio, and HIV suppression remained stable. Most adverse effects were mild-moderate. CONCLUSIONS: In PLWH, cannabinoids seem generally safe and well-tolerated, though larger studies are needed. Screening for occult liver pathology should be performed and hepatic enzymes monitored, especially with high CBD doses.

Real-world serological responses to extended-interval and heterologous COVID-19 mRNA vaccination in frail, older people (UNCoVER): an interim report from a prospective observational cohort study.

BACKGROUND: The use of COVID-19 vaccines has been prioritised to protect the most vulnerable-notably, older people. Because of fluctuations in vaccine availability, strategies such as delayed second dose and heterologous prime-boost have been used. However, the effectiveness of these strategies in frail, older people are unknown. We aimed to assess the antigenicity of mRNA-based COVID-19 vaccines in frail, older people in a real-world setting, with a rationed interval dosing of 16 weeks between the prime and boost doses. METHODS: This prospective observational cohort study was done across 12 long-term care facilities of the Montréal Centre-Sud - Integrated University Health and Social Services Centre in Montréal, Québec, Canada. Under a rationing strategy mandated by the provincial government, adults aged 65 years and older residing in long-term care facilities in Québec, Canada, with or without previously documented SARS-CoV-2 infection, were administered homologous or heterologous mRNA vaccines, with an extended 16-week interval between doses. All older residents in participating long-term care facilities who received two vaccine doses were eligible for inclusion in this study. Participants were enrolled from Dec 31, 2020, to Feb 16, 2021, and data were collected up to June 9, 2021. Clinical data and blood samples were serially collected from participants at the following timepoints: at baseline, before the first dose; 4 weeks after the first dose; 6-10 weeks after the first dose; 16 weeks after the first dose, up to 2 days before administration of the second dose; and 4 weeks after the second dose. Sera were tested for SARS-CoV-2-specific IgG antibodies (to the trimeric spike protein, the receptor-binding domain [RBD] of the spike protein, and the nucleocapsid protein) by automated chemiluminescent ELISA. Two cohorts were used in this study: a discovery cohort, for which blood samples were collected before administration of the first vaccine dose and longitudinally thereafter; and a confirmatory cohort, for which blood samples were only collected from 4 weeks after the prime dose. Analyses were done in the discovery cohort, with validation in the confirmatory cohort, when applicable. FINDINGS: The total study sample consisted of 185 participants. 65 participants received two doses of mRNA-1273 (Spikevax; Moderna), 36 received two doses of BNT162b2 (Comirnaty; Pfizer-BioNTech), and 84 received mRNA-1273 followed by BNT162b2. In the discovery cohort, after a significant increase in anti-RBD and anti-spike IgG concentrations 4 weeks after the prime dose (from 4·86 log binding antibody units [BAU]/mL to 8·53 log BAU/mL for anti-RBD IgG and from 5·21 log BAU/mL to 8·05 log BAU/mL for anti-spike IgG), there was a significant decline in anti-RBD and anti-spike IgG concentrations until the boost dose (7·10 log BAU/mL for anti-RBD IgG and 7·60 log BAU/mL for anti-spike IgG), followed by an increase 4 weeks later for both vaccines (9·58 log BAU/mL for anti-RBD IgG and 9·23 log BAU/mL for anti-spike IgG). SARS-CoV-2-naive individuals showed lower antibody responses than previously infected individuals at all timepoints tested up to 16 weeks after the prime dose, but achieved similar antibody responses to previously infected participants by 4 weeks after the second dose. Individuals primed with the BNT162b2 vaccine showed a larger decrease in mean anti-RBD and anti-spike IgG concentrations with a 16-week interval between doses (from 8·12 log BAU/mL to 4·25 log BAU/mL for anti-RBD IgG responses and from 8·18 log BAU/mL to 6·66 log BAU/mL for anti-spike IgG responses) than did those who received the mRNA-1273 vaccine (two doses of mRNA-1273: from 8·06 log BAU/mL to 7·49 log BAU/mL for anti-RBD IgG responses and from 6·82 log BAU/mL to 7·56 log BAU/mL for anti-spike IgG responses; mRNA-1273 followed by BNT162b2: from 8·83 log BAU/mL to 7·95 log BAU/mL for anti-RBD IgG responses and from 8·50 log BAU/mL to 7·97 log BAU/mL for anti-spike IgG responses). No differences in antibody responses 4 weeks after the second dose were noted between the two vaccines, in either homologous or heterologous combinations. INTERPRETATION: Interim results of this ongoing longitudinal study show that among frail, older people, previous SARS-CoV-2 infection and the type of mRNA vaccine influenced antibody responses when used with a 16-week interval between doses. In these cohorts of frail, older individuals with a similar age and comorbidity distribution, we found that serological responses were similar and clinically equivalent between the discovery and confirmatory cohorts. Homologous and heterologous use of mRNA vaccines was not associated with significant differences in antibody responses 4 weeks following the second dose, supporting their interchangeability. FUNDING: Public Health Agency of Canada, Vaccine Surveillance Reference Group; and the COVID-19 Immunity Task Force. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Effects of an 8-week training cessation period on cognition and functional capacity in older adults.

BACKGROUND: Multiple types of exercise interventions have been described as effective methods for improving cognition and mobility in older adults. In addition to combined strength and aerobic training, gross motor activities have shown benefits. However, adherence to exercise is a challenge, which may bring about periods of training cessation. Importantly, short-term training cessation may lead to a loss of fitness adaptations. The effects of training cessation on cognition and functional capacity are not well known, especially within the context of dual-tasking in older adults. OBJECTIVES: We examined the effects of an 8-week training cessation period on cognition (executive functioning (EF) in single (ST) and dual-task (DT)) and functional capacity (10 m Walk and 6 Minute Walk Test) of healthy older adults, after one of three training interventions: combined lower body strength and aerobic, combined upper body strength and aerobic, or gross motor activities. MATERIALS AND METHODS: Forty older adults (70.5 ± 5.5 years, 67.5% F) participated in training sessions, 3×/week for 8 weeks prior to training cessation. Pre (T0), post (T1) and follow-up (post-cessation, T2) measures of EF (performance in inhibition and updating/working memory indices of the Random Number Generation task) in ST and DT (treadmill walking at 0.67 m·s-1, 1.11 m·s-1, and 1.56 m·s-1), and functional capacity were assessed. Changes in ST and DT as well as functional capacity tests were analyzed using two-way ANOVAs (time ∗ group) with repeated measures for the time factor (T0, T1 and T2). RESULTS: Improvements in inhibition indices were observed in ST for all time comparisons (T0-T1, T1-T2 and T0-T2). Inhibition in DT improved from T0-T2 and from T1-T2. Working memory declined from T0-T2 and from T1-T2. Functional capacity performance was maintained from T1-T2 (small improvement from T0-T1 and from T0-T2). DISCUSSION: Performances in inhibition were maintained or improved after cessation of training. We found no interaction between training groups, whatever the condition, indicating similar training cessation effects regardless of the intervention. CONCLUSIONS: Multiple types of exercise interventions may lead to positive benefit to inhibition and functional capacity in older adults, and it may also be possible to retain these benefits after a short cessation period.

A 12-Week Cycling Training Regimen Improves Upper Limb Functions in People With Parkinson's Disease.

Background: It has been proposed that physical exercise can help improve upper limb functions in Parkinson's disease (PD) patients; yet evidence for this hypothesis is limited. Objective: To assess the effects of aerobic exercise training (AET) on general upper limb functions in sedentary people with PD and healthy adults (HA). Methods: Two groups, 19 PD patients (Hoehn & Yahr ≤ 2) and 20 HA, matched on age and sedentary level, followed a 3-month stationary bicycle AET regimen. We used the kinematic theory framework to characterize and quantify the different motor control commands involved in performing simple upper-limb movements as drawing lines. Repeated measures ANCOVA models were used to assess the effect of AET in each group, as well as the difference between groups following the training regimen. Results: At baseline, PD individuals had a larger antagonist response, a longer elapsed time between the visual stimulus and the end of the movement, and a longer time of displacement of the stylus than the HA. Following the 12-week AET, PD participants showed significant decreases of the agonist and antagonist commands, as well as the antagonist response spread. A significant group ∗ session interaction effect was observed for the agonist command and the response spread of the antagonist command, suggesting a significant change for these two parameters only in PD patients following the AET. Among the differences observed at baseline, only the difference for the time of movement remained after AET. Conclusion: A 3-month AET has a significant positive impact on the capacity to draw lines in a more efficiency way, in PD patients, indicating an improvement in the upper limb motor function.

The Association between Generalized Anxiety Disorder, Subthreshold Anxiety Symptoms and Fear of Falling among Older Adults: Preliminary Results from a Pilot Study.

OBJECTIVE: A relationship between generalized anxiety disorder (GAD) and fear of falling (FOF) has long been proposed but never specifically studied. This study aimed at analyzing the relationship between FOF and GAD or anxiety symptoms, while controlling for major depressive episodes (MDE), depressive symptoms, fall risk, and sociodemographic variables. METHODS: Twenty-five older adults participated in this pilot study. Assessments included the following: Anxiety Disorder Interview Schedule, Geriatric Anxiety Inventory, Geriatric Depression Scale, Falls-Efficacy Scale-International. A multidisciplinary team evaluated fall risk. RESULTS: FOF was significantly correlated with GAD, MDE, anxiety and depressive symptoms, and fall risk, but not with sociodemographic variables. Multiple regression analyses indicated that GAD and anxiety symptoms were significantly and independently associated with FOF. CONCLUSION: Although the results of this pilot study should be replicated with larger samples, they suggest that FOF is associated with GAD and anxiety symptoms even when considering physical factors that increase the risk of falling. CLINICAL IMPLICATIONS: Treatment of FOF in patients with GAD may present a particular challenge because of the central role of intolerance of uncertainty, which may prevent patients from regaining confidence despite the reduction of fall risk. Clinicians should screen for GAD and anxiety symptoms in patients with FOF to improve detection and treatment.

Relationships between lower body strength and the energy cost of treadmill walking in a cohort of healthy older adults: a cross-sectional analysis.

PURPOSE: Gait speed is associated with survival in older adults and it was suggested that an elevated energy cost of walking (Cw) is an important determinant of gait speed reduction. Thus far, little is known about the factors that contribute to a lower Cw but it was shown that lower body strength training could reduce the Cw. Therefore, the objective of this study was to investigate the relationship between lower body strength and the Cw in a cohort of healthy older adults. METHODS: A total of 48 participants were included in this study (70.7 ± 5.4 years). After a geriatric and a neuropsychological assessment, participants underwent a fitness testing protocol which included a maximal oxygen uptake test, assessment of the Cw at 4 km h-1 on a treadmill, an isokinetic maximal strength test for the ankle, knee and hip joints and a body composition assessment. Relationships between strength variables and the Cw were assessed with partial correlations and linear regression analyses. RESULTS: Hip extensors and hip flexors peak torque was significantly correlated with the Cw (r = -0.36 and -0.32, respectively; p < 0.05). A tendency towards significance was identified for the ankle plantar flexors (r = -0.25, p = 0.09). Hip extensors peak torque was the only significant neuromuscular parameter included in the linear regression analysis (p < 0.05). CONCLUSION: These results show that hip extensors are an important muscle group with regards to the Cw measured on a treadmill in this cohort of healthy older adults.

A 12-Week Cycling Training Regimen Improves Gait and Executive Functions Concomitantly in People with Parkinson's Disease.

Background: There is increasing evidence that executive functions and attention are associated with gait and balance, and that this link is especially prominent in older individuals or those who are afflicted by neurodegenerative diseases that affect cognition and/or motor functions. People with Parkinson's disease (PD) often present gait disturbances, which can be reduced when PD patients engage in different types of physical exercise (PE), such as walking on a treadmill. Similarly, PE has also been found to improve executive functions in this population. Yet, no exercise intervention investigated simultaneously gait and non-motor symptoms (executive functions, motor learning) in PD patients. Objective: To assess the impact of aerobic exercise training (AET) using a stationary bicycle on a set of gait parameters (walking speed, cadence, step length, step width, single and double support time, as well as variability of step length, step width and double support time) and executive functions (cognitive inhibition and flexibility) in sedentary PD patients and healthy controls. Methods: Two groups, 19 PD patients (Hoehn and Yahr ≤2) and 20 healthy adults, matched on age and sedentary level, followed a 3-month stationary bicycle AET regimen. Results: Aerobic capacity, as well as performance of motor learning and on cognitive inhibition, increased significantly in both groups after the training regimen, but only PD patients improved their walking speed and cadence (all p < 0.05; with no change in the step length). Moreover, in PD patients, training-related improvements in aerobic capacity correlated positively with improvements in walking speed (r = 0.461, p < 0.05). Conclusion: AET using stationary bicycle can independently improve gait and cognitive inhibition in sedentary PD patients. Given that increases in walking speed were obtained through increases in cadence, with no change in step length, our findings suggest that gait improvements are specific to the type of motor activity practiced during exercise (i.e., pedaling). In contrast, the improvements seen in cognitive inhibition were, most likely, not specific to the type of training and they could be due to indirect action mechanisms (i.e., improvement of cardiovascular capacity). These results are also relevant for the development of targeted AET interventions to improve functional autonomy in PD patients.

Multiple roads lead to Rome: combined high-intensity aerobic and strength training vs. gross motor activities leads to equivalent improvement in executive functions in a cohort of healthy older adults.

The effects of physical activity on cognition in older adults have been extensively investigated in the last decade. Different interventions such as aerobic, strength, and gross motor training programs have resulted in improvements in cognitive functions. However, the mechanisms underlying the relationship between physical activity and cognition are still poorly understood. Recently, it was shown that acute bouts of exercise resulted in reduced executive control at higher relative exercise intensities. Considering that aging is characterized by a reduction in potential energy ([Formula: see text] max - energy cost of walking), which leads to higher relative walking intensity for the same absolute speed, it could be argued that any intervention aimed at reducing the relative intensity of the locomotive task would improve executive control while walking. The objective of the present study was to determine the effects of a short-term (8 weeks) high-intensity strength and aerobic training program on executive functions (single and dual task) in a cohort of healthy older adults. Fifty-one participants were included and 47 (age, 70.7 ± 5.6) completed the study which compared the effects of three interventions: lower body strength + aerobic training (LBS-A), upper body strength + aerobic training (UBS-A), and gross motor activities (GMA). Training sessions were held 3 times every week. Both physical fitness (aerobic, neuromuscular, and body composition) and cognitive functions (RNG) during a dual task were assessed before and after the intervention. Even though the LBS-A and UBS-A interventions increased potential energy to a higher level (Effect size: LBS-A-moderate, UBS-A-small, GMA-trivial), all groups showed equivalent improvement in cognitive function, with inhibition being more sensitive to the intervention. These findings suggest that different exercise programs targeting physical fitness and/or gross motor skills may lead to equivalent improvement in cognition in healthy older adults. Such results call for further investigation of the multiple physiological pathways by which physical exercise can impact cognition in older adults.

Executive functions, physical fitness and mobility in well-functioning older adults.

The objective of this study was to examine the relationships between executive functions, physical fitness and mobility in well-functioning older adults. Forty-eight well functioning older adults (70.5±5.3years old; 20 men, 28 women) were included in this study. Two median splits were conducted based on each individual's performance for the 10MWT and TUG. Comparisons between groups of slower and faster individuals were made with regard to executive functions and physical fitness parameters. A correlational approach was used to assess the association between variables. Between groups comparisons revealed that faster individuals in mobility tests demonstrate better performances in measures of cognitive flexibility (0.68

Fat mass threshold associated with a significant deterioration of insulin sensitivity in postmenopausal women.

The aim of this study was to establish a cut-off value of percentage of fat mass (%FM) at which insulin sensitivity (IS) is significantly altered in sedentary postmenopausal women. Our results suggest that maintaining a %FM below 41% would minimize the deterioration of IS and its associated risks.

Effects of resistance training combined with antioxidant supplementation on fat-free mass and insulin sensitivity in healthy elderly subjects.

The aim of this study was to verify the effect of resistance training and antioxidant supplementation on fat-free mass (FFM) and insulin sensitivity (IS). The results demonstrate that 6 months of resistance training combined with antioxidant supplementation significantly increased FFM without concomitant significant improvement in IS in older adults.

Effect of resistance training on hematological blood markers in older men and women: a pilot study.

The aim of this study was to examine the effects of resistance training on hematological blood markers in older individuals. Twenty-nine men and women participated to this study. Subjects were randomized in 2 groups: (1) control (n = 13) and (2) resistance training (n = 16). At baseline and after the intervention, subjects were submitted to a blood sample to determine their hematological profile (red blood cells, hemoglobin, hematocrit, platelets, leukocytes, neutrophils, lymphocytes, monocytes, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, red cell distribution width). At baseline, no difference was observed between groups. Moreover, we found no significant difference after the intervention on any of these markers. A 6-month resistance program in healthy older individuals seems to have no beneficial nor deleterious effects on hematological blood parameters. However, resistance training was well tolerated and should be recommended for other health purposes. Further studies are needed to confirm these results in a large population.