Efficacy and safety of using auditory-motor entrainment to improve walking after stroke: a multi-site randomized controlled trial of InTandemTM.

Walking slowly after stroke reduces health and quality of life. This multi-site, prospective, interventional, 2-arm randomized controlled trial (NCT04121754) evaluated the safety and efficacy of an autonomous neurorehabilitation system (InTandemTM) designed to use auditory-motor entrainment to improve post-stroke walking. 87 individuals were randomized to 5-week walking interventions with InTandem or Active Control (i.e., walking without InTandem). The primary endpoints were change in walking speed, measured by the 10-meter walk test pre-vs-post each 5-week intervention, and safety, measured as the frequency of adverse events (AEs). Clinical responder rates were also compared. The trial met its primary endpoints. InTandem was associated with a 2x larger increase in speed (Δ: 0.14 ± 0.03 m/s versus Δ: 0.06 ± 0.02 m/s, F(1,49) = 6.58, p = 0.013), 3x more responders (40% versus 13%, χ2(1) ≥ 6.47, p = 0.01), and similar safety (both groups experienced the same number of AEs). The auditory-motor intervention autonomously delivered by InTandem is safe and effective in improving walking in the chronic phase of stroke.

Referring Attention-Deficit/Hyperactivity Disorder: Gaining Perspective From Advanced Practice Providers in Primary Care.

The objective of the current study is to identify provider, patient, and family characteristics associated with pediatric advanced practice provider (APP) decisions to refer to a subspecialist for diagnosis and management of attention-deficit/hyperactivity disorder (ADHD). We conducted a cross-sectional electronic survey of pediatric primary care APPs using member lists of professional organizations. T tests and chi-square analysis were conducted to identify group differences. Most respondents rated themselves as comfortable diagnosing and managing ADHD. We found no significant difference between groups based on comfort level or likelihood to refer. APPs working in suburban settings report significantly lower levels of comfort. Self-designation as the practice's primary provider for behavioral/mental health concerns had significantly higher levels of comfort and were less likely to refer. In a limited sample, most APPs reported comfort diagnosing and managing ADHD. Activities to identify and ameliorate gaps in ADHD knowledge and care need to consider this growing part of the workforce.

Feasibility and Proof-of-Concept of Delivering an Autonomous Music-Based Digital Walking Intervention to Persons with Parkinson's Disease in a Naturalistic Setting.

BACKGROUND: Reduced motor automaticity in Parkinson's disease (PD) negatively impacts the quality, intensity, and amount of daily walking. Rhythmic auditory stimulation (RAS), a clinical intervention shown to improve walking outcomes, has been limited by barriers associated with the need for ongoing clinician input. OBJECTIVE: To assess the feasibility, proof-of-concept, and preliminary clinical outcomes associated with delivering an autonomous music-based digital walking intervention based on RAS principles to persons with PD in a naturalistic setting. METHODS: Twenty-three persons with PD used the digital intervention independently for four weeks to complete five weekly 30-minute sessions of unsupervised, overground walking with music-based cues. The intervention progressed autonomously according to real-time gait sensing. Feasibility of independent use was assessed by examining participant adherence, safety, and experience. Intervention proof-of-concept was assessed by examining spatiotemporal metrics of gait quality, daily minutes of moderate intensity walking, and daily steps. Preliminary clinical outcomes were assessed following intervention completion. RESULTS: Participants completed 86.4% of sessions and 131.1% of the prescribed session duration. No adverse events were reported. Gait speed, stride length, and cadence increased within sessions, and gait variability decreased (p < 0.05). Compared to baseline, increased daily moderate intensity walking (mean Δ= +21.44 minutes) and steps (mean Δ= +3,484 steps) occurred on designated intervention days (p < 0.05). Quality of life, disease severity, walking endurance, and functional mobility were improved after four weeks (p < 0.05). CONCLUSIONS: Study findings supported the feasibility and potential clinical utility of delivering an autonomous digital walking intervention to persons with PD in a naturalistic setting.

Spiritual well-being in long-term survivors with chronic graft-versus-host disease after hematopoietic stem cell transplantation.

Spiritual well-being (Sp-WB) is a resource that supports adaptation and resilience, strengthening quality of life (QOL) in patients with cancer or other chronic illnesses. However, the relationship between Sp-WB and QOL in patients with chronic graft-versus-host disease (cGVHD) remains unexamined. Fifty-two participants completed the Functional Assessment of Chronic Illness Therapy-Spiritual WellBeing (FACIT-Sp) questionnaire as part of a multidisciplinary study of cGVHD. Sp-WB was generally high. Those with the lowest Sp-WB had a significantly longer time since diagnosis of cGVHD (P = 0.05) than those with higher Sp-WB. There were no associations between Sp-WB and demographics, cGVHD severity, or intensity of immunosuppression. Participants with the lowest Sp-WB reported inferior physical (P = 0.0009), emotional (P = 0.003), social (P = 0.027), and functional well-being (P < 0.0001) as well as lower overall QOL (P < 0.0001) compared with those with higher Sp-WB. They also had inferior QOL relative to population norms. Differences between the group reporting the lowest Sp-WB and those groups who reported the highest Sp-WB scores consistently demonstrated a significant difference for all QOL subscales and for overall QOL. Controlling for physical, emotional, and social well-being, Sp-WB was a significant independent predictor of contentment with QOL. Our results suggest that Sp-WB is an important factor contributing to the QOL of patients with cGVHD. Research is needed to identify factors that diminish Sp-WB and to test interventions designed to strengthen this coping resource in patients experiencing the late effects of treatment.

Exploring distal regions of the A3 adenosine receptor binding site: sterically constrained N6-(2-phenylethyl)adenosine derivatives as potent ligands.

We synthesized phenyl ring-substituted analogues of N(6)-(1S,2R)-(2-phenyl-1-cyclopropyl)adenosine, which is highly potent in binding to the human A(3)AR with a Ki value of 0.63 nM. The effects of these structural changes on affinity at human and rat adenosine receptors and on intrinsic efficacy at the hA(3)AR were measured. A 3-nitrophenyl analogue was resolved chromatographically into pure diastereomers, which displayed 10-fold stereoselectivity in A(3)AR binding in favor of the 1S,2R isomer. A molecular model defined a hydrophobic region (Phe168) in the putative A(3)AR binding site around the phenyl moiety. A heteroaromatic group (3-thienyl) could substitute for the phenyl moiety with retention of high affinity of A(3)AR binding. Other related N(6)-substituted adenosine derivatives were included for comparison. Although the N(6)-(2-phenyl-1-cyclopropyl) derivatives were full A(3)AR agonists, several other derivatives had greatly reduced efficacy. N(6)-Cyclopropyladenosine was an A(3)AR antagonist, and adding either one or two phenyl rings at the 2-position of the cyclopropyl moiety restored efficacy. N(6)-(2,2-Diphenylethyl)adenosine was an A(3)AR antagonist, and either adding a bond between the two phenyl rings (N(6)-9-fluorenylmethyl) or shortening the ethyl moiety (N(6)-diphenylmethyl) restored efficacy. A QSAR study of the N(6) region provided a model that was complementary to the putative A(3)AR binding site in a rhodopsin-based homology model. Thus, a new series of high-affinity A(3)AR agonists and related nucleoside antagonists was explored through both empirical and theoretical approaches.

Modulation of adenosine receptor affinity and intrinsic efficacy in adenine nucleosides substituted at the 2-position.

We studied the structural determinants of binding affinity and efficacy of adenosine receptor (AR) agonists. Substituents at the 2-position of adenosine were combined with N(6)-substitutions known to enhance human A(3)AR affinity. Selectivity of binding of the analogues and their functional effects on cAMP production were studied using recombinant human A(1), A(2A), A(2B), and A(3)ARs. Mainly sterically small substituents at the 2-position modulated both the affinity and intrinsic efficacy at all subtypes. The 2-cyano group decreased hA(3)AR affinity and efficacy in the cases of N(6)-(3-iodobenzyl) and N(6)-(trans-2-phenyl-1-cyclopropyl), for which a full A(3)AR agonist was converted into a selective antagonist; the 2-cyano-N(6)-methyl analogue was a full A(3)AR agonist. The combination of N(6)-benzyl and various 2-substitutions (chloro, trifluoromethyl, and cyano) resulted in reduced efficacy at the A(1)AR. The environment surrounding the 2-position within the putative A(3)AR binding site was explored using rhodopsin-based homology modeling and ligand docking.