Hydrogels Containing Gradients in Vascular Density Reveal Dose-Dependent Role of Angiocrine Cues on Stem Cell Behavior.

Biomaterials that replicate patterns of microenvironmental signals from the stem cell niche offer the potential to refine platforms to regulate stem cell behavior. While significant emphasis has been placed on understanding the effects of biophysical and biochemical cues on stem cell fate, vascular-derived or angiocrine cues offer an important alternative signaling axis for biomaterial-based stem cell platforms. Elucidating dose-dependent relationships between angiocrine cues and stem cell fate are largely intractable in animal models and 2D cell cultures. In this study, microfluidic mixing devices are leveraged to generate 3D hydrogels containing lateral gradients in vascular density alongside murine hematopoietic stem cells (HSCs). Regional differences in vascular density can be generated via embossed gradients in cell, matrix, or growth factor density. HSCs co-cultured alongside vascular gradients reveal spatial patterns of HSC phenotype in response to angiocrine signals. Notably, decreased Akt signaling in high vessel density regions led to increased expansion of lineage-positive hematopoietic cells. This approach offers a combinatorial tool to rapidly screen a continuum of microenvironments with varying vascular, biophysical, and biochemical cues to reveal the influence of local angiocrine signals on HSC fate.

Targeted self-regulation interventions in low-income children: Clinical trial results and implications for health behavior change.

Self-regulation, known as the ability to harness cognitive, emotional, and motivational resources to achieve goals, is hypothesized to contribute to health behaviors across the lifespan. Enhancing self-regulation early in life may increase positive health outcomes. During pre-adolescence, children assume increased autonomy in health behaviors (e.g., eating; physical activity), many of which involve self-regulation. This article presents results from a clinical trial (NCT03060863) that used a factorial design to test behavioral interventions designed to enhance self-regulation, specifically targeting executive functioning, emotion regulation, future-oriented thinking, and approach biases. Participants were 118 children (9-12 years of age, M = 10.2 years) who had a history of living in poverty. They were randomized to receive up to four interventions that were delivered via home visits. Self-regulation was assayed using behavioral tasks, observations, interviews, and parent- and child-report surveys. Results were that self-regulation targets were reliably assessed and that interventions were delivered with high fidelity. Intervention effect sizes were very small to moderate (d range = .02-.65, median = .14), and most were not statistically significant. Intercorrelation analyses indicated that associations between measures within each target varied based on the self-regulation target evaluated. Results are discussed with regard to the role of self-regulation-focused interventions in child health promotion. Implications of findings are reviewed for informing next steps in behavioral self-regulation interventions among children from low-income backgrounds.

Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression: The SURE-PD3 Randomized Clinical Trial.

Importance: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. Objective: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. Design, Participants, and Setting: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019. Interventions: Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years. Main Outcomes and Measures: The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity. Results: Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years). Conclusions and Relevance: Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD. Trial Registration: ClinicalTrials.gov Identifier: NCT02642393.

Precision Health: The Role of the Social and Behavioral Sciences in Advancing the Vision.

BACKGROUND: In 2015, Collins and Varmus articulated a vision for precision medicine emphasizing molecular characterization of illness to identify actionable biomarkers to support individualized treatment. Researchers have argued for a broader conceptualization, precision health. Precision health is an ambitious conceptualization of health, which includes dynamic linkages between research and practice as well as medicine, population health, and public health. The goal is a unified approach to match a full range of promotion, prevention, diagnostic, and treatment interventions to fundamental and actionable determinants of health; to not just address symptoms, but to directly target genetic, biological, environmental, and social and behavioral determinants of health. PURPOSE: The purpose of this paper is to elucidate the role of social and behavioral sciences within precision health. MAIN BODY: Recent technologies, research frameworks, and methods are enabling new approaches to measure, intervene, and conduct social and behavioral science research. These approaches support three opportunities in precision health that the social and behavioral sciences could colead including: (a) developing interventions that continuously "tune" to each person's evolving needs; (b) enhancing and accelerating links between research and practice; and (c) studying mechanisms of change in real-world contexts. There are three challenges for precision health: (a) methods of knowledge organization and curation; (b) ethical conduct of research; and (c) equitable implementation of precision health. CONCLUSIONS: Precision health requires active coleadership from social and behavioral scientists. Prior work and evidence firmly demonstrate why the social and behavioral sciences should colead with regard to three opportunity and three challenge areas.

Adolescent Interventions to Manage Self-Regulation in Type 1 Diabetes (AIMS-T1D): randomized control trial study protocol.

BACKGROUND: Self-regulation (SR), or the capacity to control one's thoughts, emotions, and behaviors in order to achieve a desired goal, shapes health outcomes through many pathways, including supporting adherence to medical treatment regimens. Type 1 Diabetes (T1D) is one specific condition that requires SR to ensure adherence to daily treatment regimens that can be arduous and effortful (e.g., monitoring blood glucose). Adolescents, in particular, have poor adherence to T1D treatment regimens, yet it is essential that they assume increased responsibility for managing their T1D as they approach young adulthood. Adolescence is also a time of rapid changes in SR capacity and thus a compelling period for intervention. Promoting SR among adolescents with T1D may thus be a novel method to improve treatment regimen adherence. The current study tests a behavioral intervention to enhance SR among adolescents with T1D. SR and T1D medical regimen adherence will be examined as primary and secondary outcomes, respectively. METHODS: We will use a randomized control trial design to test the impact of a behavioral intervention on three SR targets: Executive Functioning (EF), Emotion Regulation (ER), and Future Orientation (FO); and T1D medical regimen adherence. Adolescents with T1D (n = 94) will be recruited from pediatric endocrinology clinics and randomly assigned to treatment or control group. The behavioral intervention consists of working memory training (to enhance EF), biofeedback and relaxation training (to enhance ER), and episodic future thinking training (to enhance FO) across an 8-week period. SR and treatment regimen adherence will be assessed at pre- and post-test using multiple methods (behavioral tasks, diabetes device downloads, self- and parent-report). We will use an intent-to-treat framework using generalized linear mixed models to test our hypotheses that: 1) the treatment group will demonstrate greater improvements in SR than the control group, and 2) the treatment group will demonstrate better treatment regimen adherence outcomes than the control group. DISCUSSION: If successful, SR-focused behavioral interventions could improve health outcomes among adolescents with T1D and have transdiagnostic implications across multiple chronic conditions requiring treatment regimen adherence. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03688919; registered September 28, 2018.

Advancing Health Policy and Program Research in Diabetes: Findings from the Natural Experiments for Translation in Diabetes (NEXT-D) Network.

PURPOSE OF REVIEW: To advance our understanding of the impacts of policies and programs aimed at improving detection, engagement, prevention, and clinical diabetes management in the USA, we synthesized findings from a network of studies that used natural experiments to evaluate diabetes health policies and programs. FINDINGS: Studies from the Natural EXperiments for Translation in Diabetes (NEXT-D) network used rigorous longitudinal quasi-experimental study designs (e.g., interrupted time series) and analytical methods (e.g., difference-in-differences) to augment causal inference. Investigators partnered with health system stakeholders to evaluate whether glucose testing rates changed from before-to-after clinic interventions (e.g., integrating electronic screening decision prompts in New York City) or employer programs (e.g., targeted messaging and waiving copayments for at-risk employees). Other studies examined participation and behavior change in low- (e.g., wellness coaching) or high-intensity lifestyle modification programs (e.g., diabetes prevention program-like interventions) offered by payers or employers. Lastly, studies assessed how employer health insurance benefits impacted healthcare utilization, adherence, and outcomes among people with diabetes. NEXT-D demonstrated that low-intensity interventions to facilitate glucose testing and enhance engagement in lifestyle modification were associated with small improvements in weight but large improvements in screening and testing when supported by electronic health record-based decision-support. Regarding high-intensity diabetes prevention program-like lifestyle programs offered by payers or employers, enrollment was modest and led to weight loss and marginally lower short-term health expenditures. Health plans that incentivize patient behaviors were associated with increases in medication adherence. Meanwhile, shifting patients to high-deductible health plans was associated with no change in medication use and preventive screenings, but patients with diabetes delayed accessing healthcare for acute complications (e.g., cellulitis). Findings were more pronounced among lower-income patients, who experienced increased rates and acuity of emergency department visits for diabetes complications and other high-severity conditions. Findings from NEXT-D studies provide informative data that can guide programs and policies to facilitate detection, prevention, and treatment of diabetes in practice.

Spatial capture-mark-resight estimation of animal population density.

Sightings of previously marked animals can extend a capture-recapture dataset without the added cost of capturing new animals for marking. Combined marking and resighting methods are therefore an attractive option in animal population studies, and there exist various likelihood-based non-spatial models, and some spatial versions fitted by Markov chain Monte Carlo sampling. As implemented to date, the focus has been on modeling sightings only, which requires that the spatial distribution of pre-marked animals is known. We develop a suite of likelihood-based spatial mark-resight models that either include the marking phase ("capture-mark-resight" models) or require a known distribution of marked animals (narrow-sense "mark-resight"). The new models sacrifice some information in the covariance structure of the counts of unmarked animals; estimation is by maximizing a pseudolikelihood with a simulation-based adjustment for overdispersion in the sightings of unmarked animals. Simulations suggest that the resulting estimates of population density have low bias and adequate confidence interval coverage under typical sampling conditions. Further work is needed to specify the conditions under which ignoring covariance results in unacceptable loss of precision, or to modify the pseudolikelihood to include that information. The methods are applied to a study of ship rats Rattus rattus using live traps and video cameras in a New Zealand forest, and to previously published data.

Primary Care Behavioral Health (PCBH) Model Research: Current State of the Science and a Call to Action.

The Primary Care Behavioral Health (PCBH) model of service delivery is being used increasingly as an effective way to integrate behavioral health services into primary care. Despite its growing popularity, scientifically robust research on the model is lacking. In this article, we provide a qualitative review of published PCBH model research on patient and implementation outcomes. We review common barriers and potential solutions for improving the quantity and quality of PCBH model research, the vital data that need to be collected over the next 10 years, and how to collect those data.

Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease: A Randomized Clinical Trial.

IMPORTANCE: Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity. OBJECTIVE: To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease. DESIGN, SETTING, AND PARTICIPANTS: Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites. INTERVENTIONS: Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout. MAIN OUTCOMES AND MEASURES: Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form- physical functioning subscale score (SF-36), and the change in the Berg Balance Test. RESULTS: Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group difference was -2.5 units (95% CI, -3.7 to -1.3) (P < .001). Treatment success, as measured by the PGIC, occurred in 23 patients (51%) in the deutetrabenazine group vs 9 (20%) in the placebo group (P = .002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group (P = .002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) (P = .03). There was no difference between groups (mean difference of 1.0 unit; 95% CI, -0.3 to 2.3; P = .14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia. CONCLUSIONS AND RELEVANCE: Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks. Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01795859.

National Randomized Controlled Trial of Virtual House Calls for People with Parkinson's Disease: Interest and Barriers.

BACKGROUND: Delivering specialty care remotely directly into people's homes can enhance access for and improve the healthcare of individuals with chronic conditions. However, evidence supporting this approach is limited. MATERIALS AND METHODS: Connect.Parkinson is a randomized comparative effectiveness study that compares usual care of individuals with Parkinson's disease in the community with usual care augmented by virtual house calls with a Parkinson's disease specialist from 1 of 18 centers nationally. Individuals in the intervention arm receive four virtual visits from a Parkinson's disease specialist over 1 year via secure, Web-based videoconferencing directly into their homes. All study activities, including recruitment, enrollment, and assessments, are conducted remotely. Here we report on interest, feasibility, and barriers to enrollment in this ongoing study. RESULTS: During recruitment, 11,734 individuals visited the study's Web site, and 927 unique individuals submitted electronic interest forms. Two hundred ten individuals from 18 states enrolled in the study from March 2014 to June 2015, and 195 were randomized. Most participants were white (96%) and college educated (73%). Of the randomized participants, 73% had seen a Parkinson's disease specialist within the previous year. CONCLUSIONS: Among individuals with Parkinson's disease, national interest in receiving remote specialty care directly into the home is high. Remote enrollment in this care model is feasible but is likely affected by differential access to the Internet.

Diffusion imaging of nigral alterations in early Parkinson's disease with dopaminergic deficits.

BACKGROUND: This study reports the baseline characteristics of diffusion tensor imaging data in Parkinson's disease (PD) patients and healthy control subjects from the Parkinson's Progression Markers Initiative. The main goals were to replicate previous findings of abnormal diffusion imaging values from the substantia nigra. in a large multicenter cohort and determine whether nigral diffusion alterations are associated with dopamine deficits. METHODS: Two hundred twenty subjects (PD = 153; control = 67) from 10 imaging sites were included. All subjects had a full neurological exam, a ((123) I)ioflupane dopamine transporter (DAT) single-photon emission computer tomography scan, and diffusion tensor imaging. Fractional anisotropy as well as radial and axial diffusivity was computed within multiple regions across the substantia nigra. RESULTS: A repeated-measures analysis of variance found a marginally nonsignificant interaction between regional fractional anisotropy of the substantia nigra and disease status (P = 0.08), conflicting with an earlier study. However, a linear mixed model that included control regions in addition to the nigral regions revealed a significant interaction between regions and disease status (P = 0.002), implying a characteristic distribution of reduced fractional anisotropy across the substantia nigra in PD. Reduced fractional anisotropy in PD was also associated with diminished DAT binding ratios. Both axial and radial diffusivity were also abnormal in PD. CONCLUSIONS: Although routine nigral measurements of fractional anisotropy are clinically not helpful, the findings in this study suggest that more-sophisticated diffusion imaging protocols should be used when exploring the clinical utility of this imaging modality.

Analysis of CYP2D6 genotype and response to tetrabenazine.

Tetrabenazine is effective in the treatment of the chorea associated with Huntington disease and other hyperkinetic movement disorders. Following oral administration, tetrabenazine is hepatically transformed into 2 active metabolites that are CYP2D6 substrates. There are 4 CYP2D6 genotypes: poor metabolizers, intermediate metabolizers, extensive metabolizers, and ultrarapid metabolizers. CYP2D6 genotyping was performed on sequential subjects treated with tetrabenazine, but results were not known at the time of titration. Duration of titration to a stable dose, total daily dose, response rating scores, and adverse events were retrospectively collected and subsequently analyzed. Of 127 patients, the majority (n = 100) were categorized as extensive metabolizers, 14 as intermediate metabolizers, 11 as poor metabolizers, and 2 as ultrarapid metabolizers. Ultrarapid metabolizer patients needed a longer titration (8 vs 3.3, 4.4, and 3 weeks, respectively; P < .01) to achieve optimal benefit and required a higher average daily dose than the other patients, but this difference did not reach statistical significance. The treatment response was less robust in the intermediate metabolizer group when compared with the extensive metabolizer patients (P = .013), but there were no statistically significant differences between the various groups with regard to adverse effects. Our findings demonstrate that, aside from the need for a longer titration in the ultrarapid metabolizers, there are no distinguishing features of patients with various CYP2D6 genotypes, and therefore the current recommendation to systematically genotype all patients prescribed more than 50 mg/day of tetrabenazine should be reconsidered.

Time-lagged variation in pond density and primary productivity affects duck nest survival in the Prairie Pothole Region.

The Prairie Pothole Region (PPR) is the primary breeding region for most species of North American dabbling ducks (Anas spp.). Conservation of these species is guided in part by knowledge of relationships between nest survival probability and habitat features. Positive relationships between duck nest survival and amount and configuration of herbaceous perennial vegetation have been observed in previous studies, but these 2- to 4-year studies might not have adequately characterized the temporal effect of wet-dry episodes on nest survival. Over an eight-year period, we studied nest survival of five species of ducks in the PPR relative to spatial and temporal variation in pond density, primary productivity, and hydrologic status of wetlands, soil, and vegetation on 52 study sites selected to span a gradient of spatial variation in proportion of herbaceous perennial vegetation and in number of wetland basins. We observed the fate of 12 754 nests. Consistent with past studies, 90% of nests that failed to hatch were destroyed by predators. Nest survival probability was positively related to current-year pond density and primary productivity, negatively related to pond density and primary productivity during the previous two years, and positively related to the number of wetland basins on the study site. Predicted relationships between nest survival and proportion or configuration of herbaceous perennial vegetation in the surrounding landscape were not supported. For mallard (Anas platyrhynchos), median estimated nest survival probability ranged from 0.02 (SE = 0.01) to 0.22 (SE = 0.02). Estimated nest survival was greatest on sites with numerous wetland basins that had transitioned from dry, unproductive conditions to wet, productive conditions in the previous 1-2 years. Our results were consistent with time-lagged responses of food webs to resource pulses in a broad array of ecosystems. Our study highlighted the importance of wetland basins and wet-dry episodes to duck nest survival in the PPR. Current habitat conservation efforts focus on landscapes with numerous wetland basins and a high proportion of herbaceous perennial vegetation. Our results suggest that future conservation efforts should focus on preserving high-density wetland complexes across as large a geographic extent as possible even in cropland-dominated landscapes.

Advancing digital health equity: Directions for behavioral and social science research.

The field of digital health is evolving rapidly and encompasses a wide range of complex and changing technologies used to support individual and population health. The COVID-19 pandemic has augmented digital health expansion and significantly changed how digital health technologies are used. To ensure that these technologies do not create or exacerbate existing health disparities, a multi-pronged and comprehensive research approach is needed. In this commentary, we outline five recommendations for behavioral and social science researchers that are critical to promoting digital health equity. These recommendations include: (i) centering equity in research teams and theoretical approaches, (ii) focusing on issues of digital health literacy and engagement, (iii) using methods that elevate perspectives and needs of underserved populations, (iv) ensuring ethical approaches for collecting and using digital health data, and (v) developing strategies for integrating digital health tools within and across systems and settings. Taken together, these recommendations can help advance the science of digital health equity and justice.

The field of digital health is quickly growing and changing. Digital health technologies have the potential to increase access to health-related information and healthcare and improve wellbeing, but it is important that those technologies don't widen existing health disparities or create new ones. Behavioral and social science researchers have a key role to play in centering equity in their research teams and theoretical approaches, focusing on key barriers to access, uptake, and usage, studying digital health in ways that elevate the voices and needs of historically underserved groups, being thoughtful about how digital health data are collected and used, and making sure that digital health tools are designed to be used in real-world settings.

The NIH Science of Behavior Change Program: Looking Toward the Future.

The National Institutes of Health established the Science of Behavior Change (SOBC) program to promote basic research on the initiation, personalization, and maintenance of health behavior change. The SOBC Resource and Coordinating Center now leads and supports activities to maximize the creativity, productivity, scientific rigor, and dissemination of the experimental medicine approach and experimental design resources. Here, we highlight those resources, including the Checklist for Investigating Mechanisms in Behavior-change Research (CLIMBR) guidelines introduced in this special section. We describe the ways in which SOBC can be applied across a range of domains and contexts, and end by considering ways to extend SOBC's perspective and reach, so as to best promote behavior change linked with health, quality of life, and well-being.

National Institutes of Health approaches to dissemination and implementation science: current and future directions.

To address the vast gap between current knowledge and practice in the area of dissemination and implementation research, we address terminology, provide examples of successful applications of this research, discuss key sources of support, and highlight directions and opportunities for future advances. There is a need for research testing approaches to scaling up and sustaining effective interventions, and we propose that further advances in the field will be achieved by focusing dissemination and implementation research on 5 core values: rigor and relevance, efficiency, collaboration, improved capacity, and cumulative knowledge.

Effects of cannabinoid receptor agonist WIN 55,212-2 on blood-brain barrier disruption in focal cerebral ischemia in rats.

This study was performed to investigate whether WIN 55,212-2 (WIN), a cannabinoid receptor agonist, could attenuate blood-brain barrier (BBB) disruption in focal cerebral ischemia in rats and whether the CB 1 receptor antagonist rimonabant could prevent this attenuation. A total of 0.3 or 1 mg/kg of WIN was injected intravenously before and after permanent middle cerebral artery (MCA) occlusion. Some animals were pretreated with rimonabant 2 mg/kg i.p. before receiving 0.3 mg/kg of WIN. At 1 h after MCA occlusion, BBB permeability was determined by measuring the transfer coefficient (K(i)) of (14)C-α-aminoisobutyric acid and the volume of dextran distribution. With MCA occlusion, K(i) increased in the ischemic cortex (IC) in all of the experimental groups. However, the K(i) of the IC of the WIN 0.3 and 1 mg/kg groups was lower (­46 and ­42%, respectively, p < 0.05) than that of the control group. With rimonabant pretreatment, the K(i) of the IC became higher ((+)88%, p < 0.05) than with WIN 0.3 mg/kg alone and similar to that of the control rats. The difference in the volume of dextran distribution between the IC and the contralateral cortex was significant in the control but not in the WIN-treated rats. With rimonabant pretreatment, however, the difference became significant. Our data demonstrated that WIN could attenuate BBB disruption in focal cerebral ischemia and this attenuation could be prevented with rimonabant. Our data suggest an involvement of CB(1) receptors in the regulation of BBB disruption in the early stage of stroke.

The effects of dexmedetomidine on regional cerebral blood flow and oxygen consumption during severe hemorrhagic hypotension in rats.

BACKGROUND: We performed this study to determine how dexmedetomidine would affect regional cerebral blood flow (rCBF) and microregional O(2) consumption during nonhemorrhagic normovolemia and during severe hemorrhagic hypotension in rats. METHODS: Forty-eight male rats were anesthetized with isoflurane and their lungs were mechanically ventilated. Half of the rats were bled to reach a mean arterial blood pressure of 40 to 45 mm Hg and were maintained at this level for at least 30 minutes before rCBF or microregional arterial oxygen saturation (Sao(2)) and venous oxygen saturation (Svo(2)) were determined. The other half were not bled and served as nonhemorrhagic controls. Half of each group was given dexmedetomidine 1 µg/kg/min IV for 45 minutes and the other half was given the same amount of normal saline infusion. The infusion started 10 minutes before blood withdrawal for the hemorrhagic groups. The rCBF was determined using (14)C-iodoantipyrine, and the microregional Sao(2) and Svo(2) were determined using cryomicrospectrophotometry at 45 minutes of infusion. RESULTS: Dexmedetomidine decreased heart rate by 25%, but the decrease of mean arterial blood pressure was not significant. The total amount of blood withdrawn and hemoglobin were similar between the normal saline-treated and the dexmedetomidine-treated groups. In normovolemia, dexmedetomidine significantly decreased rCBF (-58%) in the lateral cortex with a similar percentage decrease (-57%) of calculated O(2) consumption. Microregional Svo(2) was similar between the normal saline-treated group (62.8% ± 1.3% [mean ± SD]) and the dexmedetomidine-treated group (60.7% ± 1.8%) despite a large difference in rCBF. Hemorrhage significantly decreased rCBF (-44%) in the lateral cortex in the normal saline-treated rats with no significant change in regional cerebrovascular resistance. In contrast, in the lateral cortex of the dexmedetomidine-treated rats, the decrease of rCBF was not significant but there was a significant decrease in regional cerebrovascular resistance. A decrease (-25%) in the O(2) consumption was observed in the lateral cortex of the normal saline-treated rats with hemorrhage, but hemorrhage did not decrease O(2) consumption in the dexmedetomidine-treated rats. Despite significantly lower rCBF (-34%) in the dexmedetomidine-treated rats, the Svo(2) was similar between the normal saline-treated (42.8% ± 2.5%) and the dexmedetomidine-treated rats (43.2% ± 2.7%). CONCLUSIONS: Our data showed that in normovolemia, dexmedetomidine produced a proportionate decrease of rCBF and O(2) consumption. Hemorrhage decreased rCBF more than O(2) consumption. Dexmedetomidine prevented rCBF and O(2) consumption from decreasing after hemorrhage. Our data suggest that dexmedetomidine may help provide optimal O(2) supply and consumption balance during hemorrhage.

Improving geriatric care and reducing hospitalisations in regional and remote areas: The benefits of telehealth.

INTRODUCTION: The aim of this study was to compare the effectiveness of two geriatrician models of care, the telegeriatric service (TGS) and visiting geriatrician (VG), in regional and remote settings in terms of potential cost-savings to the health system and impact on health service use (HSU). Furthermore, to establish whether longer wait-times for clinic appointments led to increased HSU by study participants. METHODS: Trends in patient emergency department presentations, hospitalisations and bed-days (HSU) were compared from 18 months before to 12 months after geriatrician appointment for the two services in the Western Australian Midwest region. The relationships between wait times, patient triage level and HSU were modelled. The costs of providing the services were offset against reductions in HSU after appointments. RESULTS: The sample comprised consecutive patients using the TGS (n = 84) and VG service (n = 124). Patient characteristics were similar, although patients using the VG service had longer wait-times, were triaged as more urgent and demonstrated the highest levels of HSU. Both models were effective with similar rates of reduced HSU following appointments. Increased wait-times and higher patient triage urgency were associated with increased HSU. DISCUSSION: Although TGS and VG showed similar reduced rates of HSU, TGS had the capacity to see a higher volume of patients, a broader geographical reach and improved waitlist management. Consequently, TGS was more effective at reducing avoidable hospitalisations and subsequent health deterioration due to shorter wait-times. Whilst face-to-face consultations are recognised as 'gold standard' a combination of the two models is most efficient.

From ideas to interventions: A review and comparison of frameworks used in early phase behavioral translation research.

Developing and testing more effective health-related behavioral interventions is critical to making progress in improving disease prevention and treatment. One way to achieve this goal is to use a systematic and progressive framework that outlines the steps needed to translate theories, findings, and basic understandings about human behavior into risk factor and disease management or mitigation strategies. Although several frameworks and process models have been designed to inform the development and optimization of health-related behavioral interventions, little guidance is available to compare key aspects of these models, clarify their common and unique features, and aid in selecting the best approach for a specific research question. This article describes the major frameworks that focus on early phase translation-that is, approaches that address the design and optimization of behavioral interventions before testing in Phase III efficacy trials. Differences between and common features of these models are described, opportunities for combining frameworks to maximize their impact are noted, and guidance is provided to enable investigators to choose the most useful model(s) when designing and optimizing health-related behavioral interventions. The goal of this article is to promote the consistent use of frameworks that encourage a systematic, progressive approach to behavioral intervention development and testing as one way to encourage the creation of well-characterized, optimized, and potentially more effective health-related behavioral interventions. (PsycInfo Database Record (c) 2022 APA, all rights reserved).