Tufts University

Large long-term assessments of opioid effectiveness and dose stability for those with dopamine agonist augmentation of restless legs syndrome (RLS) are lacking. We present 5-year longitudinal findings from the National RLS Opioid Registry. Five-hundred participants taking opioids for RLS were interviewed at baseline about RLS symptoms, opioid medications and doses, sleep, and mental health. Participants subsequently completed online surveys every 6months. Changes from baseline to 5-year follow-up in morphine milligram equivalents (MMEs), excluding those taking buprenorphine, were evaluated by group-based trajectory modeling. Independent associations with opioid dose changes were determined using multiple logistic regression. At 5 years of follow-up, 410 (364 excluding any taking buprenorphine) participants remained for this analysis. Most participants are female (57.1 per cent) and white (98.3 per cent), with an average age of 64.7 (±10.6) and 88.8 per cent had a history of dopamine agonist augmentation. The median daily MME at 5 years was 37.5 (equivalent to methadone 8.0mg or oxycodone 25.0mg), an increase of 7.5 MME from baseline. Opioid doses increased from baseline to 5 years in 49.5 per cent of participants and decreased in 20.0 per cent of participants. Group-based trajectory analysis identified four distinct groups: decrease (3.4 per cent of participants; average MME change = -15.7 ± 12.4), no/little change (66.1 per cent of participants; average MME change = 1.5 ± 8.0), small increase (23.9 per cent of participants; average MME change = 22.0 ± 11.6), and large increase (3.4 per cent of participants; average MME change = 49.2 ± 18.7). RLS severity was stable from baseline (13.3 ± 9.6) to 5 years (13.1 ± 9.0) according to the International Restless Legs Syndrome Study Group Severity Scale. Opioid doses in augmented RLS remain largely stable over 5 years of follow-up. Low-dose opioids provide an effective long-term option for augmented RLS.

Left ventricular (LV) dysfunction is a potential cardioembolic source of ischemic stroke, but its role in recurrent stroke risk and treatment response remains unclear. We explore whether LV injury associates with the risk of recurrent stroke and modifies the association between anticoagulation and stroke recurrence using real-world data. We performed a multicenter, retrospective study of Cardiac Abnormalities in Stroke Prevention and Recurrence cohort across 27 US sites. Patients with LV ejection fraction ≥20% were included. LV injury, defined as LV ejection fraction 20% to 40% and wall motion abnormality, was the primary exposure and treatment effect modifier. The treatment of interest was anticoagulant versus antiplatelet therapy. The composite outcome included recurrent stroke, major bleeding, or death. Outcomes were evaluated using unadjusted and inverse probability weighting adjusted Cox proportional hazards models, with treatment effect modification tested by LV injury status. Among 2685 patients enrolled, 2328 with complete data were analyzed (median age, 65 years; 49.8% female; median follow-up, 1.6 years). LV injury was present in 310 patients (13.3%). Overall, 535 events occurred: 258 recurrent ischemic strokes, 28 hemorrhagic strokes, 67 major hemorrhages, and 256 deaths. LV injury was associated with a higher unadjusted risk of the primary outcome (hazard ratio [HR], 1.51 [95% CI, 1.21-1.87]), though nonsignificant after inverse probability weighting adjustment (adjusted HR, 1.29 [95% CI, 0.97-1.70]). In the LV injury subgroup, anticoagulation versus antiplatelet therapy was associated with a lower risk of the primary outcome (adjusted HR, 0.24 [95% CI, 0.10-0.59]), relative to the non-LV injury subgroup (adjusted HR, 1.28 [95% CI, 0.83-1.95]; p[LV-interaction], 0.001). Similar interactions were seen for EF 20% to 40% (versus >40%; adjusted HR, 0.19 [95% CI, 0.04-0.86]; p[LV-interaction], 0.001) and wall motion abnormality (versus no wall motion abnormality; adjusted HR, 0.33 [95% CI, 0.15-0.73]). After cryptogenic stroke, anticoagulation in those with LV injury was associated with lower rates of recurrent stroke, major bleeding, and death. These findings warrant confirmation in a dedicated randomized controlled trial. URL: https://www.clinicaltrials.gov; Unique identifier: NCT06398366.

Micronutrient inadequacies are estimated to affect billions of people worldwide, yet these estimates exclude fortification. There are no global estimates of the impact of current fortification programmes on micronutrient inadequacies. We aimed to estimate how improving existing programmes or establishing new ones affects the prevalence of micronutrient inadequacies and to estimate their global costs. In this modelling study, we estimated the prevalence of inadequate intakes of 13 micronutrients across 185 countries by integrating global modelled dietary intake data from the Global Dietary Database, with fortification programme parameters from the Global Fortification Data Exchange. We modelled six scenarios: no fortification, current fortification, improved compliance, aligned standards, aligned standards with improved compliance, and aligned standards with improved compliance and expanded coverage. Implementation costs were calculated as the sum of premix, industry-related, and government costs across five fortified foods: wheat flour, maize flour, oil, rice, and salt. Compared with no fortification, current fortification programmes prevent 7·0 billion inadequate person-nutrient intakes annually at a global cost of $1·06 billion (mean of $0·18 [SD 0·28] per person, 2021 US$, across the five fortified foods), with iodine fortification alone preventing 3·3 billion inadequacies. Despite current fortification, 38·6 billion inadequate intakes persist. Improving compliance would prevent 13·1 billion inadequacies at a global cost of $3·48 billion annually (mean $0·23 [SD 0·33] per person). Aligning standards and improving compliance would prevent 17·2 billion inadequacies at $6·56 billion annually (mean $0·63 [SD 0·53] per person). Aligning standards, improving compliance, and expanding coverage would prevent 24·7 billion inadequacies at $9·19 billion annually (mean $1·15 [SD 0·58] per person), although 20·9 billion inadequacies would remain. Fortification is a cost-effective intervention that greatly reduces micronutrient inadequacies, particularly for iodine and iron. Improving compliance offers immediate gains. Aligning with international guidelines and expanding programmes could triple their effects but cannot eliminate all inadequacies, underscoring the importance of complementary approaches to improve diet quality. Swiss Agency for Development and Cooperation and the Gates Foundation.

When hoping to improve their dogs’ behavior, owners often turn to basic obedience/manners courses. Scentwork classes, where dogs use their noses to find treats and odors, could be a potential alternative to these classes, because scentwork-based classes allow dogs to engage in the natural behavior of sniffing. The goal of this experimental study was to determine whether scentwork classes have a more positive impact on dog welfare, behavior, and the human-dog bond than basic obedience classes. Dogs and owners were randomly assigned to four-week long obedience or scentwork classes. Owners completed the Canine Behavioral Assessment and Research Questionnaire (C-BARQ), the Monash Dog Owner Relationship Scale (MDORS), and dogs participated in a judgment bias test before and after their assigned class. There were no significant differences between the groups in C-BARQ or MDORS scores on any scales nor was there a significant difference on the judgment bias test by group. Owners in the total sample and in the Obedience group reported a significant increase in trainability for their dogs, as measured by C-BARQ, from pre- to post-measures whereas owners in the Scentwork group reported a significant increase in C-BARQ hyperactivity for their dogs. Judgment bias test scores improved significantly for the total sample and the Obedience group. There was a significant association between training class and the owners’ perception of their dogs’ quality of life such that owners with dogs in the scentwork classes reported their dogs’ quality of life had improved. These findings suggest that positive training in general might increase positive judgement bias and thus the welfare of dogs, although obedience classes might have more general improvements for training. Although more research is needed to further explore specific potential benefits of scentwork training, the results of this study suggest that dogs participating in scentwork classes are likely to enjoy similar benefits as dogs in other positive reinforcement group courses, giving owners more options for classes based on their individual dogs’ needs and interests. • This study measures change for dogs that took scentwork or obedience • Total sample improved in judgment bias • Dogs who took training improved in obedience and hyperactivity increased for dogs in scentwork • Positive reinforcement training seems to be beneficial for pet dogs • Different courses have different benefits

Functional near-infrared spectroscopy (fNIRS) is impacted by signal contamination from superficial hemodynamics. It is important to develop methods that account for such contamination and provide accurate measurements of cerebral hemodynamics. We aim to investigate whether simulated data with two- or three-layer tissue models are able to reproduce in vivo data collected with dual-slope (DS) frequency-domain (FD) near-infrared spectroscopy (NIRS) on human subjects during brain activation. We performed Monte Carlo simulations to generate DS FD-NIRS data from two- and three-layer media with a range of layer thicknesses and optical properties. We collected in vivo data with DS FD-NIRS (source-detector distances: 25 and 37mm, wavelengths: 690 and 830nm, and modulation frequency: 140MHz) over the occipital lobe of human subjects during visual stimulation. Simulated and in vivo data were analyzed with diffusion theory for a homogeneous medium, and results were compared for each DS FD-NIRS data type. We found that the main qualitative features of in vivo data could be reproduced by simulated data from a three-layer medium, with a second layer (representing the cerebrospinal fluid in the subarachnoid space) that is less absorbing and less scattering than the other two layers, and with a top layer thickness that represents the combined scalp and skull thickness. A three-layer model is a viable improvement over a homogeneous model to analyze DS FD-NIRS data (or any other fNIRS data) to generate more accurate measurements of cerebral hemodynamic changes without a need for large datasets for tomographic reconstructions.