A Positive Psychology Intervention in Allogeneic Hematopoietic Stem Cell Transplantation Survivors (PATH): A Pilot Randomized Clinical Trial.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) survivors experience significant psychological distress and low levels of positive psychological well-being, which can undermine patient-reported outcomes (PROs), such as quality of life (QoL). Hence, we conducted a pilot randomized clinical trial to assess the feasibility and preliminary efficacy of a telephone-delivered positive psychology intervention (Positive Affect for the Transplantation of Hematopoietic stem cells intervention [PATH]) for improving well-being in HSCT survivors. METHODS: HSCT survivors who were 100 days post-HSCT for hematologic malignancy at an academic institution were randomly assigned to either PATH or usual care. PATH, delivered by a behavioral health expert, entailed 9 weekly phone sessions on gratitude, personal strengths, and meaning. We defined feasibility a priori as >60% of eligible participants enrolling in the study and >75% of PATH participants completing ≥6 of 9 sessions. At baseline and 9 and 18 weeks, patients self-reported gratitude, positive affect, life satisfaction, optimism, anxiety, depression, posttraumatic stress disorder (PTSD), QoL, physical function, and fatigue. We used repeated measures regression models and estimates of effect size (Cohen's d) to explore the preliminary effects of PATH on outcomes. RESULTS: We enrolled 68.6% (72/105) of eligible patients (mean age, 57 years; 50% female). Of those randomized to PATH, 91% completed all sessions and reported positive psychology exercises as easy to complete and subjectively useful. Compared with usual care, PATH participants reported greater improvements in gratitude (ß = 1.38; d = 0.32), anxiety (ß = -1.43; d = -0.40), and physical function (ß = 2.15; d = 0.23) at 9 weeks and gratitude (ß = 0.97; d = 0.22), positive affect (ß = 2.02; d = 0.27), life satisfaction (ß = 1.82; d = 0.24), optimism (ß = 2.70; d = 0.49), anxiety (ß = -1.62; d = -0.46), depression (ß = -1.04; d = -0.33), PTSD (ß = -2.50; d = -0.29), QoL (ß = 7.70; d = 0.41), physical function (ß = 5.21; d = 0.56), and fatigue (ß = -2.54; d = -0.33) at 18 weeks. CONCLUSIONS: PATH is feasible, with promising signals for improving psychological well-being, QoL, physical function, and fatigue in HSCT survivors. Future multisite trials that investigate PATH's efficacy are needed to establish its effects on PROs in this population.

Genetically defined nucleus incertus neurons differ in connectivity and function.

The nucleus incertus (NI), a conserved hindbrain structure implicated in the stress response, arousal, and memory, is a major site for production of the neuropeptide relaxin-3. On the basis of goosecoid homeobox 2 (gsc2) expression, we identified a neuronal cluster that lies adjacent to relaxin 3a (rln3a) neurons in the zebrafish analogue of the NI. To delineate the characteristics of the gsc2 and rln3a NI neurons, we used CRISPR/Cas9 targeted integration to drive gene expression specifically in each neuronal group, and found that they differ in their efferent and afferent connectivity, spontaneous activity, and functional properties. gsc2 and rln3a NI neurons have widely divergent projection patterns and innervate distinct subregions of the midbrain interpeduncular nucleus (IPN). Whereas gsc2 neurons are activated more robustly by electric shock, rln3a neurons exhibit spontaneous fluctuations in calcium signaling and regulate locomotor activity. Our findings define heterogeneous neurons in the NI and provide new tools to probe its diverse functions.

Exploring the experiences of adults with stroke in virtual community-based stroke programs: a qualitative descriptive study.

BACKGROUND: Stroke is among the top contributors to disability and can impact an individual's cognition, physical functioning, and mental health. Since the COVID-19 pandemic, several community-based organizations have started delivering stroke programs virtually. However, participants' experiences in these programs remain understudied, and evidence-based guidelines to inform and optimize virtual stroke program development and delivery are lacking. Thus, this study aimed to describe the perspectives and experiences of individuals with stroke who participated in virtual community-based organization stroke programs, including perceived access and participation facilitators and barriers and suggestions for improving these programs. METHODS: A qualitative descriptive design was used to gather participant experiences through semi-structured interviews. Audio-recorded interviews were conducted on Zoom and transcribed verbatim. Adult participants who had experienced a stroke and attended at least one Canadian virtual community-based organization stroke program were recruited. Data were analyzed using inductive thematic analysis. RESULTS: Twelve participants (32-69 years, 2-23 years post-stroke, eight women and four men) participated in this study. Five themes were identified: (1) motives to join virtual community-based organization stroke programs, including gaining peer connections, knowledge and information; (2) perceived barriers to accessing and participating in virtual community-based organization stroke programs, including technology inequities, difficulties navigating technology, and inadequate facilitation; (3) perceived facilitators to accessing and participating in virtual community-based organization stroke programs, including remote access, virtual platform features and program leader characteristics/skills; (4) unmet needs during virtual community-based organization stroke programs, including in-person connection and individualized support; and (5) suggestions and preferences for improving virtual community-based organization stroke programs, including program facilitation, content and format. CONCLUSIONS: Study findings highlight opportunities to improve virtual community-based organization stroke programs to optimize participant experiences and outcomes. Addressing the barriers and suggestions identified in this study may improve virtual community-based organization stroke programs' access and quality.

Spatiotemporal immune atlas of a clinical-grade gene-edited pig-to-human kidney xenotransplant.

Pig-to-human xenotransplantation is rapidly approaching the clinical arena; however, it is unclear which immunomodulatory regimens will effectively control human immune responses to pig xenografts. Here, we transplant a gene-edited pig kidney into a brain-dead human recipient on pharmacologic immunosuppression and study the human immune response to the xenograft using spatial transcriptomics and single-cell RNA sequencing. Human immune cells are uncommon in the porcine kidney cortex early after xenotransplantation and consist of primarily myeloid cells. Both the porcine resident macrophages and human infiltrating macrophages express genes consistent with an alternatively activated, anti-inflammatory phenotype. No significant infiltration of human B or T cells into the porcine kidney xenograft is detectable. Altogether, these findings provide proof of concept that conventional pharmacologic immunosuppression may be able to restrict infiltration of human immune cells into the xenograft early after compatible pig-to-human kidney xenotransplantation.

Health Care Contact Days Among Older Cancer Survivors.

PURPOSE: Health care contact days-days spent receiving health care outside the home-represent an intuitive, practical, and person-centered measure of time consumed by health care. METHODS: We linked 2019 Medicare Current Beneficiary Survey and traditional Medicare claims data for community-dwelling older adults with a history of cancer. We identified contact days (ie, spent in a hospital, emergency department, skilled nursing facility, or inpatient hospice or receiving ambulatory care including an office visit, procedure, treatment, imaging, or test) and described patterns of total and ambulatory contact days. Using weighted Poisson regression models, we identified factors associated with contact days. RESULTS: We included 1,168 older adults representing 4.51 million cancer survivors (median age, 76.4 years, 52.8% women). The median (IQR) time from cancer diagnosis was 65 (27-126) months. In 2019, these adults had mean (standard deviation) total contact days of 28.4 (27.6) and ambulatory contact days of 24.2 (23.6). These included days for tests (8.0 [8.8]), imaging (3.6 [4.1]), visits with any clinicians (12.4 [11.5]), and visits with primary care clinicians (4.4 [4.7]), and nononcology specialists (7.1 [9.4]) specifically. Sixty-four percent of days with a nonvisit ambulatory service (eg, a test) were not on the same day as a clinician visit. Factors associated with more total contact days included younger age, lower income, more chronic conditions, poor self-rated health, and tendency to "go to doctor as soon as feel bad." CONCLUSION: Older adult cancer survivors spent nearly 1 month of the year receiving health care outside the home. This care was largely ambulatory, often delivered by nononcologists, and varied by factors beyond clinical characteristics. These results highlight the need to recognize patient burdens and improve survivorship care delivery, including through care coordination.

Angiogenesis in bone tissue engineering via ceramic scaffolds: A review of concepts and recent advancements.

Due to organ donor shortages, long transplant waitlists, and the complications/limitations associated with auto and allotransplantation, biomaterials and tissue-engineered models are gaining attention as feasible alternatives for replacing and reconstructing damaged organs and tissues. Among various tissue engineering applications, bone tissue engineering has become a promising strategy to replace or repair damaged bone. We aimed to provide an overview of bioactive ceramic scaffolds in bone tissue engineering, focusing on angiogenesis and the effect of different biofunctionalization strategies. Different routes to angiogenesis, including chemical induction through signaling molecules immobilized covalently or non-covalently, in situ secretion of angiogenic growth factors, and the degradation of inorganic scaffolds, are described. Physical induction mechanisms are also discussed, followed by a review of methods for fabricating bioactive ceramic scaffolds via microfabrication methods, such as photolithography and 3D printing. Finally, the strengths and weaknesses of the commonly used methodologies and future directions are discussed.

Prehospital invasive arterial blood pressure monitoring in critically ill patients attended by a UK helicopter emergency medical service- a retrospective observational review of practice.

BACKGROUND: Accurate haemodynamic monitoring in the prehospital setting is essential. Non-invasive blood pressure measurement is susceptible to vibration and motion artefact, especially at extremes of hypotension and hypertension: invasive arterial blood pressure (IABP) monitoring is a potential solution. This study describes the largest series to date of cases of IABP monitoring being initiated prehospital. METHODS: This retrospective observational study was conducted at East Anglian Air Ambulance (EAAA), a UK helicopter emergency medical service (HEMS). It included all patients attended by EAAA who underwent arterial catheterisation and initiation of IABP monitoring between 1st February 2015 and 20th April 2023. The following data were retrieved for all patients: sex; age; aetiology (medical cardiac arrest, other medical emergency, trauma); site of arterial cannulation; operator role (doctor/paramedic); time of insertion and, where applicable, times of pre-hospital emergency anaesthesia, and return of spontaneous circulation following cardiac arrest. Descriptive analyses were performed to characterise the sample. RESULTS: 13,556 patients were attended: IABP monitoring was initiated in 1083 (8.0%) cases, with a median age 59 years, of which 70.8% were male. 546 cases were of medical cardiac arrest: in 22.4% of these IABP monitoring was initiated during cardiopulmonary resuscitation. 322 were trauma cases, and the remaining 215 were medical emergencies. The patients were critically unwell: 981 required intubation, of which 789 underwent prehospital emergency anaesthesia; 609 received vasoactive medication. In 424 cases IABP monitoring was instituted en route to hospital. CONCLUSION: This study describes over 1000 cases of prehospital arterial catheterisation and IABP monitoring in a UK HEMS system and has demonstrated feasibility at scale. The high-fidelity of invasive arterial blood pressure monitoring with the additional benefit of arterial blood gas analysis presents an attractive translation of in-hospital critical care to the prehospital setting.

Discussion of an approach to starting a JEDI inventory in a College of Pharmacy.

Problem description\The University of Nebraska College of Pharmacy is interested in conducting and learning from an inventory of Justice, Equity, Diversity, and Inclusion (JEDI) within the college. QUALITY IMPROVEMENT METHODS: An extensive literature review was undertaken to define the terms included in JEDI and to craft a listing of ideal inventory components. RESULTS OF CQI INQUIRY: The terms used in JEDI were defined and a list of 148 ideal inventory components was created. This list is further segmented by the JEDI components themselves and by five assessment factors including: representation, curriculum & education, policies & procedures, support & resources, and college climate. INTERPRETATION AND DISCUSSION: The attempt to create an ideal listing of JEDI inventory components resulted in an unusably large number of potential items. This occurred intentionally to allow the next steps in the longitudinal creation of a workable, quantifiable, and evaluative JEDI inventory process. Describing these preliminary efforts are important in the ultimate acceptance of the results of the JEDI inventory. CONCLUSION: Deliberate and extensive listing of initial aspirations for a JEDI inventory of a College of Pharmacy or any institution allows for sufficient input and breadth to help assure that no significant factor is overlooked as the process is refined.

Relations between discrimination, rejection sensitivity, negative affect, and decrements in problem-solving ability following social rejection: An experimental investigation.

INTRODUCTION: While negative affect and problem-solving deficits have been consistently linked to suicidal thoughts and behaviors, the latter are often conceptualized and studied as time- and/or context-invariant. Though requiring additional empirical support, theory suggests that discrimination may strengthen the relation between rejection sensitivity and increases in negative affect as well as declines in problem-solving abilities following rejection. The aim of the current study was to test this claim using a social rejection paradigm (i.e., Cyberball) with young adults experiencing past-month suicidal ideation. METHODS: The sample consisted of 50 participants. Lifetime discrimination and rejection sensitivity were assessed prior to Cyberball. Negative affect and problem-solving abilities were assessed pre- and post-Cyberball. SPSS and the PROCESS macro were used to test relations among variables of interest. RESULTS: Rejection sensitivity predicted greater problem-solving decrements, but not negative affect, following rejection among individuals who had experienced higher (vs. lower) levels of lifetime discrimination. CONCLUSION: Addressing rejection sensitivity and sources of discrimination within the context of treatment may reduce the impact of social rejection on problem-solving abilities among young adults at risk for suicide.

Healthcare contact days among older adults living with dementia.

BACKGROUND: For older adults with dementia and their care partners, accessing health care outside the home involves substantial time, direct and indirect costs, and other burdens. While prior studies have estimated days spent by these individuals in or out of hospitals and nursing homes, ambulatory care burdens are likely substantial yet poorly understand. Therefore, we characterized "health care contact days"-days spent receiving ambulatory or institutional care-in this population. METHODS: We used 2019 Medicare Current Beneficiary Survey data linked to claims for community-dwelling, ≥65-year-old adults with dementia in Traditional Medicare. We measured contact days including ambulatory days (with an office visit, test, imaging, procedure, or treatment) and institutional days (spent in an emergency department, hospital, skilled nursing facility, or hospice facility). We described variation and patterns in contact days. Using multivariable Poisson regression, we identified sociodemographic and clinical factors associated with contact days. RESULTS: In weighted analyses, 887 older adults with dementia (weighted: 2.9 million) had mean (SD) 31.1 (33.7) total contact days/year, of which 21.7 (20.6) were ambulatory. Ten percent had ≥68 contact days in the year. One-third (34%) of ambulatory contact days involved multiple services. In multivariable models, receipt of more ambulatory contact days was associated with younger age (65-74 reference vs. -32.3% [95% CI: -42.2%, -20.7%] for 85+), higher income (>200% Federal Poverty Level [FPL] reference versus -16.6% [95% CI: -26.7%, -5.0%] for ≤200% FPL), and lack of functional impairment (reference versus -14.6% [95% CI: -23.7%, -4.4%]). Each additional chronic condition was associated with 8.2% (95% CI: 6.7%, 9.8%) more ambulatory contact days. CONCLUSIONS: Older adults with dementia spent 31 days a year accessing care which was mostly ambulatory. These days varied widely by both clinical and sociodemographic factors. These results highlight the need to reduce patient burden through strategies such as reducing unneeded care, coordinating care, and shifting care to home settings through telemedicine and home care.

Flow affects the structural and mechanical properties of the fibrin network in plasma clots.

The fibrin network is one of the main components of thrombi. Altered fibrin network properties are known to influence the development and progression of thrombotic disorders, at least partly through effects on the mechanical stability of fibrin. Most studies investigating the role of fibrin in thrombus properties prepare clots under static conditions, missing the influence of blood flow which is present in vivo. In this study, plasma clots in the presence and absence of flow were prepared inside a Chandler loop. Recitrated plasma from healthy donors were spun at 0 and 30 RPM. The clot structure was characterized using scanning electron microscopy and confocal microscopy and correlated with the stiffness measured by unconfined compression testing. We quantified fibrin fiber density, pore size, and fiber thickness and bulk stiffness at low and high strain values. Clots formed under flow had thinner fibrin fibers, smaller pores, and a denser fibrin network with higher stiffness values compared to clots formed in absence of flow. Our findings indicate that fluid flow is an essential factor to consider when developing physiologically relevant in vitro thrombus models used in researching thrombectomy outcomes or risk of embolization.

Health Care Contact Days Among Older Adults in Traditional Medicare : A Cross-Sectional Study.

BACKGROUND: Days spent obtaining health care outside the home can represent not only access to needed care but also substantial time, effort, and cost, especially for older adults and their care partners. Yet, these "health care contact days" have not been characterized. OBJECTIVE: To assess composition of, variation and patterns in, and factors associated with contact days among older adults. DESIGN: Cross-sectional study. SETTING: Nationally representative 2019 Medicare Current Beneficiary Survey data linked to claims. PARTICIPANTS: Community-dwelling adults aged 65 years and older in traditional Medicare. MEASUREMENTS: Ambulatory contact days (days with a primary care or specialty care office visit, test, imaging, procedure, or treatment) and total contact days (ambulatory days plus institutional days in a hospital, emergency department, skilled-nursing facility, or hospice facility); multivariable mixed-effects Poisson regression to identify patient factors associated with contact days. RESULTS: In weighted results, 6619 older adults (weighted: 29 694 084) had means of 17.3 ambulatory contact days (SD, 22.1) and 20.7 total contact days (SD, 27.5) in the year; 11.1% had 50 or more total contact days. Older adults spent most contact days on ambulatory care, including primary care visits (mean [SD], 3.5 [5.0]), specialty care visits (5.7 [9.6]), tests (5.3 [7.2]), imaging (2.6 [3.9]), procedures (2.5 [6.4]), and treatments (5.7 [13.3]). Half of the test and imaging days were not on the same days as office visits (48.6% and 50.1%, respectively). Factors associated with more ambulatory contact days included younger age, female sex, White race, non-Hispanic ethnicity, higher income, higher educational attainment, urban residence, more chronic conditions, and care-seeking behaviors (for example, "go to the doctor…as soon as (I)…feel bad"). LIMITATION: Study population limited to those in traditional Medicare. CONCLUSION: On average, older adults spent 3 weeks in the year getting care outside the home. These contact days were mostly ambulatory and varied widely not only by number of chronic conditions but also by sociodemographic factors, geography, and care-seeking behaviors. These results show factors beyond clinical need that may drive overuse and underuse of contact days and opportunities to optimize this person-centered measure to reduce patient burdens, for example, via care coordination. PRIMARY FUNDING SOURCE: National Institute on Aging.

Home and Community-Based Service Use Varies by Health Care Team and Comorbidity Level of Veterans with Dementia.

Home and community-based services (HCBSs) such as home care and adult day centers are vital to supporting adults with dementia in community settings. We investigated whether HCBS use (use of both home care and adult day, use of one service, and use of neither service) varied between adults receiving care from three types of health-care teams with case management from social workers and nurses, and by comorbidity level, using 2019 data of 143,281 patients with dementia in the Veterans Health Administration. We compared HCBS use by patients' type of case-managed team (Home-Based Primary Care, geriatrics-based primary care, and dementia-focused specialty care) to patients in none of these teams, stratified by patients' non-dementia comorbidities (<4 or ≥4). Each type of health-care team was associated with both home care and adult day services, at each level of comorbidity. Home-Based Primary Care was most consistently associated with other forms of HCBS use, followed by Dementia Clinics and geriatrics-based primary care, for patients with ≥4 non-dementia comorbidities. Our findings suggest that case management in primary and specialty care settings is a contributor to the use of critical community supports by patients with the most complex needs.

Impact of a Virtual Suicide Safety Planning Training on Clinician Knowledge, Self-Efficacy, and Use of Safety Plans in Community Mental Health Clinics.

OBJECTIVE: Safety planning is a critical evidence-based intervention used to prevent suicide among individuals who report suicidal ideation or behavior. There is a dearth of research on optimal ways to disseminate and implement safety plans in community settings. The present study examined one implementation strategy, a 1-hour virtual pre-implementation training, designed to teach clinicians to effectively use an electronic safety plan template (ESPT), integrated with suicide risk assessment tools, in the context of a measurement feedback system. We examined the effect of this training on clinician knowledge and self-efficacy in use of safety planning as well as ESPT completion rates. METHOD: Thirty-six clinicians across two community-based clinical psychology training clinics completed the virtual pre-implementation training as well as pre- and post-training knowledge and self-efficacy assessments. Twenty-six clinicians completed a 6-month follow-up term. RESULTS: Clinicians reported significant improvements in self-efficacy and knowledge from pre- to post-training. They retained significant improvements in self-efficacy and a trend toward greater knowledge at the 6-month follow-up. Of the clinicians who worked with suicidal youth, 81% attempted to use an ESPT and 63% successfully completed all sections of the ESPT. Reasons for partial completion included technological difficulties and time constraints. CONCLUSION: A brief virtual pre-implementation training can improve clinician knowledge and self-efficacy in use of an ESPT with youth at risk for suicide. This strategy also holds the potential to improve the adoption of this novel evidence-based intervention in community-based settings.

Successful use of intravenous and oral levetiracetam in a goat to control refractory seizures secondary to suspected polioencephalomalacia.

OBJECTIVE: To assess the clinical efficacy and plasma concentrations of levetiracetam in a goat with seizures. ANIMAL: A 5-month-old doeling. CLINICAL PRESENTATION, PROGRESSION, AND PROCEDURES: The goat was referred because of progressive anorexia and lethargy over 3 days. Clinical signs consisted of weakness, obtundation, opisthotonos, anisocoria, and cortical blindness. Initial evaluation was most consistent with polioencephalomalacia. TREATMENT AND OUTCOME: Neurologic improvement occurred within 4 hours of thiamine administration, with appetite returning over 12 hours. On day 3 of hospitalization, the goat suffered acute onset repetitive seizures that were incompletely responsive to standard interventions over 3 hours. Administration of IV levetiracetam (60 mg/kg) produced resolution of seizure activity within 20 minutes. Levetiracetam was continued twice daily IV, then PO after day 6. Plasma concentrations were above or within therapeutic ranges (5 to 45 µg/mL) as previously established for other species, following both IV and PO levetiracetam. Oral administration (60 mg/kg, PO, q 12 h) resulted in plasma levetiracetam concentrations of 48.1 µg/mL 2 hours after a dose and 23.4 µg/mL 2 hours prior to the next dose. CLINICAL RELEVANCE: Levetiracetam is a newer anticonvulsant commonly used in humans and small animals due to its efficacy, cost, and wide safety margin. Its use has not previously been reported in domestic small ruminants. In this case, levetiracetam showed excellent clinical efficacy in the face of refractory seizures, with no apparent side effects. Plasma concentrations during oral administration were at the high end of the therapeutic range, indicating absorption in a nonmonogastric species. Further studies are warranted to determine optimal dosing in small ruminants.

Slower pace in early walking onset is related to communication, motor skills, and adaptive function in autistic toddlers.

The onset of walking is a major developmental milestone in early childhood and is critical to the development of language and social communication. Delays in walking have been described in individuals with ASD. Yet, less is known about the quality of early gait development in toddlers with ASD and the relationship to motor skills, social communication, and language. Quantitative measures of locomotion can improve our ability to evaluate subtle and specific motor differences in toddlers with ASD and their relationship to other developmental domains. We used quantitative gait analysis to evaluate locomotion in toddlers with ASD (n = 51) and compared these data to a reference chronological aged (CA) and mental aged (MA) matched typically developing (TD) cohort (n = 45). We also examined the relationship of quantitative gait metrics to developmental measures among toddlers with ASD. We found that although toddlers with ASD achieved a typical age range of walking onset, they exhibited a pattern of slower pace compared to the TD cohort when matched by CA and MA. We also found that slower measures of pace were associated with lower developmental scores of communication, motor skills, and adaptive function. Our findings improve characterization of locomotion in toddlers with ASD and the relationship of motor skills to other developmental domains.

Impact of voluntary exercise training on the metabolic and behavioral characteristics of the rTg4510 transgenic mouse model of frontotemporal dementia.

Frontotemporal dementia (FTD) is a neurodegenerative disorder that affects the frontal and temporal lobes of the brain, primarily in individuals under 65 years of age, and is the second most common form of dementia worldwide. There is no cure for FTD and current treatments offer limited symptomatic relief. Regular physical activity exhibits cognitive and neuroprotective benefits in healthy individuals and in various neurodegenerative diseases, such as Alzheimer's disease, but few studies have examined its efficacy in FTD. Accordingly, we investigated the impact of voluntary exercise training (VET) on the metabolic and behavioral characteristics of the rTg4510 transgenic mouse model of familial FTD. We show that regardless of genotype, VET increased energy expenditure, decreased sleep duration, and improved long-term memory in rTg4510 mice and WT littermates. Moreover, VET appeared to improve hyperactivity, a common feature of FTD, in rTg4510 mice. Although further work is required, these findings provide important insights into the potential benefits of physical activity in FTD.

Integrative Pharmacology in the Treatment of Substance Use Disorders.

The detrimental physical, mental, and socioeconomic effects of substance use disorders (SUDs) have been apparent to the medical community for decades. However, it has become increasingly urgent in recent years to develop novel pharmacotherapies to treat SUDs. Currently, practitioners typically rely on monotherapy. Monotherapy has been shown to be superior to no treatment at all for most substance classes. However, many randomized controlled trials (RCTs) have revealed that monotherapy leads to poorer outcomes when compared with combination treatment in all specialties of medicine. The results of RCTs suggest that monotherapy frequently fails since multiple dysregulated pathways, enzymes, neurotransmitters, and receptors are involved in the pathophysiology of SUDs. As such, research is urgently needed to determine how various neurobiological mechanisms can be targeted by novel combination treatments to create increasingly specific yet exceedingly comprehensive approaches to SUD treatment. This article aims to review the neurobiology that integrates many pathophysiologic mechanisms and discuss integrative pharmacology developments that may ultimately improve clinical outcomes for patients with SUDs. Many neurobiological mechanisms are known to be involved in SUDs including dopaminergic, nicotinic, N-methyl-D-aspartate (NMDA), and kynurenic acid (KYNA) mechanisms. Emerging evidence indicates that KYNA, a tryptophan metabolite, modulates all these major pathophysiologic mechanisms. Therefore, achieving KYNA homeostasis by harmonizing integrative pathophysiology and pharmacology could prove to be a better therapeutic approach for SUDs. We propose KYNA-NMDA-α7nAChRcentric pathophysiology, the "conductor of the orchestra," as a novel approach to treat many SUDs concurrently. KYNA-NMDA-α7nAChR pathophysiology may be the "command center" of neuropsychiatry. To date, extant RCTs have shown equivocal findings across comparison conditions, possibly because investigators targeted single pathophysiologic mechanisms, hit wrong targets in underlying pathophysiologic mechanisms, and tested inadequate monotherapy treatment. We provide examples of potential combination treatments that simultaneously target multiple pathophysiologic mechanisms in addition to KYNA. Kynurenine pathway metabolism demonstrates the greatest potential as a target for neuropsychiatric diseases. The investigational medications with the most evidence include memantine, galantamine, and N-acetylcysteine. Future RCTs are warranted with novel combination treatments for SUDs. Multicenter RCTs with integrative pharmacology offer a promising, potentially fruitful avenue to develop novel therapeutics for the treatment of SUDs.

Perivascular Adipose Tissue Remodels Only after Elevation of Blood Pressure in the Dahl SS Rat Fed a High-Fat Diet.

INTRODUCTION: Tunica media extracellular matrix (ECM) remodeling is well understood to occur in response to elevated blood pressure, unlike the remodeling of other tunicas. We hypothesize that perivascular adipose tissue (PVAT) is responsive to hypertension and remodels as a protective measure. METHODS: The adventitia and PVAT of the thoracic aorta were used in measuring ECM genes from 5 pairs of Dahl SS male rats on 8 or 24 weeks of feeding from weaning on a control (10% Kcal fat) or high-fat (HF; 60%) diet. A PCR array of ECM genes was performed with cDNA from adventitia and PVAT after 8 and 24 weeks. A gene regulatory network of the differentially expressed genes (DEGs) (HF 2-fold > con) was created using Cytoscape. RESULTS: After 8 weeks, 29 adventitia but 0 PVAT DEGs were found. By contrast, at 24 weeks, PVAT possessed 47 DEGs while adventitia had 3. Top DEGs at 8 weeks in adventitia were thrombospondin 1 and collagen 8a1. At 24 weeks, thrombospondin 1 was also a top DEG in PVAT. The transcription factor Adarb1 was identified as a regulator of DEGs in 8-week adventitia and 24-week PVAT. CONCLUSION: These data support that PVAT responds biologically once blood pressure is elevated.