Continuous Quality Improvement in the Substance Abuse and Mental Health Services Administration's Technology Transfer Center Network: A Process Evaluation.

In healthcare and related fields, there is often a gap between research and practice. Scholars have developed frameworks to support dissemination and implementation of best practices, such as the Interactive Systems Framework for Dissemination and Implementation, which shows how scientific innovations are conveyed to practitioners through tools, training, and technical assistance (TA). Underpinning those aspects of the model are evaluation and continuous quality improvement (CQI). However, a recent meta-analysis suggests that the approaches to and outcomes from CQI in healthcare vary considerably, and that more evaluative work is needed. Therefore, this paper describes an assessment of CQI processes within the Substance Abuse and Mental Health Services Administration's (SAMHSA) Technology Transfer Center (TTC) Network, a large TA/TTC system in the United States comprised of 39 distinct centers. We conducted key informant interviews (n = 71 representing 28 centers in the Network) and three surveys (100% center response rates) focused on CQI, time/effort allocation, and Government Performance and Results Act (GPRA) measures. We used data from each of these study components to provide a robust picture of CQI within a TA/TTC system, identifying Network-specific concepts, concerns about conflation of the GPRA data with CQI, and principles that might be studied more generally.

How do the Substance Abuse and Mental Health Services Administration's Technology Transfer Centers Decide What Evidence-Based Practices to Disseminate and Determine How to Do So? A Cross-Sectional Study of a National Network.

It is important to use evidence-based programs and practices (EBPs) to address major public health issues. However, those who use EBPs in real-world settings often require support in bridging the research-to-practice gap. In the US, one of the largest systems that provides such support is the Substance Abuse and Mental Health Services Administration's (SAMHSA's) Technology Transfer Center (TTC) Network. As part of a large external evaluation of the Network, this study examined how TTCs determine which EBPs to promote and how to promote them. Using semi-structured interviews and pre-testing, we developed a "Determinants of Technology Transfer" survey that was completed by 100% of TTCs in the Network. Because the study period overlapped with the onset of the COVID-19 pandemic, we also conducted a retrospective pre/post-pandemic comparison of determinants. TTCs reported relying on a broad group of factors when selecting EBPs to disseminate and the methods to do so. Stakeholder and target audience input and needs were consistently the most important determinant (both before and during COVID-19), while some other determinants fluctuated around the pandemic (e.g., public health mandates, instructions in the funding opportunity announcements). We discuss implications of the findings for technology transfer and frame the analyses in terms of the Interactive Systems Framework for Dissemination and Implementation.

Fertility preservation in patients undergoing gonadotoxic treatments: a Canadian Fertility and Andrology Society clinical practice guideline.

The management of young patients with cancer presents several unique challenges. In general, these patients are ill prepared for the diagnosis and the impact on their fertility. With the improved survival for all tumour types and stages, the need for adequate fertility counselling and a multidisciplinary approach in the reproductive care of these patients is paramount. Recent advances in cryopreservation techniques allow for the banking of spermatozoa, oocytes, embryos and ovarian tissue without compromising survival. This Canadian Fertility and Andrology Society (CFAS) guideline outlines the current understanding of social and medical issues associated with oncofertility, and the medical and surgical technologies available to optimize future fertility.

Organizational Network Analysis of SAMHSA's Technology Transfer Center (TTC) Network.

Technology transfer centers (TTCs) facilitate the movement of evidence-based practices in behavioral healthcare from theory to practice. One of the largest such networks is the Substance Abuse and Mental Health Services Administration's (SAMHSA) TTC Network. This brief report shares findings from an organizational network analysis (ONA) of the network conducted as part of an external evaluation. For non-supervisory TTCs (n = 36) across three focus areas (addiction, prevention, and mental health), the authors computed network density, harmonic closeness, and non-null dyadic reciprocity for five types of interactions (e.g., "collaborated in workgroups"), then, for each interaction type, used Welch's T-test to compare mean harmonic closeness of standalone TTC grantees versus multiple-TTC grantees. ONA identified potentially isolated regional TTCs as well as mismatches between some centers' desired scope and their network centrality and enabled investigation of broader questions around behavioral health support systems. The approach appears useful for evaluating TTCs and similar support networks.

Neuropsychology of cognitive aging in rhesus monkeys.

Aged rhesus monkeys, like aged humans, show declines in cognitive function. We present cognitive test data from a large sample of male and female rhesus monkeys, 34 young (3.5-13.6 years) and 71 aged (19.9-32.5 years of age at the start of cognitive testing). Monkeys were tested on spatiotemporal working memory (delayed response), visual recognition memory (delayed nonmatching-to-sample), and stimulus-reward association learning (object discrimination), tasks with an extensive evidence base in nonhuman primate neuropsychology. On average, aged monkeys performed worse than young on all three tasks. Acquisition of delayed response and delayed nonmatching-to-sample was more variable in aged monkeys than in young. Performance scores on delayed nonmatching-to-sample and object discrimination were associated with each other, but neither was associated with performance on delayed response. Sex and chronological age were not reliable predictors of individual differences in cognitive outcome among the aged monkeys. These data establish population norms for cognitive tests in young and aged rhesus monkeys in the largest sample reported to date. They also illustrate independence of cognitive aging in task domains dependent on the prefrontal cortex and medial temporal lobe. (181 words).

Neuropsychology of cognitive aging in rhesus monkeys.

Aged rhesus monkeys, like aged humans, show declines in cognitive function. We present cognitive test data from a large sample of male and female rhesus monkeys, 34 young (aged 3.5-13.6 years) and 71 aged (aged 19.9-32.5 years at the start of cognitive testing). Monkeys were tested on spatiotemporal working memory (delayed response), visual recognition memory (delayed nonmatching to sample), and stimulus-reward association learning (object discrimination), tasks with an extensive evidence base in nonhuman primate neuropsychology. On average, aged monkeys performed worse than young on all 3 tasks. Acquisition of delayed response and delayed nonmatching to sample was more variable in aged monkeys than in young. Performance scores on delayed nonmatching to sample and object discrimination were associated with each other, but neither was associated with performance on delayed response. Sex and chronological age were not reliable predictors of individual differences in cognitive outcome among the aged monkeys. These data establish population norms for multiple cognitive tests in young and aged rhesus monkeys in the largest sample reported to date. They also illustrate independence of cognitive aging in task domains dependent on the prefrontal cortex and medial temporal lobe.

Early-life behavioral features are associated with chronic emesis in rhesus macaques (Macaca mulatta).

Chronic emesis (CE) is a poorly understood condition in human and nonhuman primates that negatively impacts the quality of life. Early identification of risk factors for the development of CE is likely to improve the ability to manage CE cases successfully and is, therefore, desirable. Using a case-control study, we reviewed the necropsy records of the California National Primate Research Center and identified 24 animals with recorded CE, defined as five or more incidents of emesis in 1 month. A group of 89 healthy rhesus macaques (Macaca mulatta), comparable in age and percent time housed indoors, was similarly identified. Next, we investigated the association between the occurrence of CE during later stages of life after infancy and the behavioral temperament scores attained in infancy, age, sex, birth location, rearing condition, history of self-injurious behavior (SIB), and the number of lifetime sedation events. Our analysis revealed that CE was associated with degrees of temperament constructs obtained in infancy (data was available for n = 113), such as Confidence (odds ratio (OR) = 0.45, 95% CI: 0.18, 1.08, p = 0.07), Gentleness (OR = 0.47, 95% CI: 0.23, 0.96, p = 0.03), Nervousness (OR = 2.04, 95% CI: 0.98, 4.23, p = 0.05), and Vigilance (OR = 0.36, 95% CI: 015, 0.87, p = 0.02), suggesting that CE is linked to behavioral phenomenon measured in early life, long before it becomes a medical concern. Our data suggest that CE was positively correlated with a history of SIB (OR 4.26, 95% CI: 0.98, 18.47, p = 0.04). Accurate prediction of CE can then assist behavioral and colony management professionals in making informed decisions regarding the care of animals at risk of developing CE. Moreover, the novel information we reported here could have valuable implications in human medicine, where gastrointestinal distress is a common complaint affecting a person's quality of life.

A Spontaneous Nonhuman Primate Model of Myopic Foveoschisis.

Purpose: Foveoschisis involves the pathologic splitting of retinal layers at the fovea, which may occur congenitally in X-linked retinoschisis (XLRS) or as an acquired complication of myopia. XLRS is attributed to functional loss of the retinal adhesion protein retinoschisin 1 (RS1), but the pathophysiology of myopic foveoschisis is unclear due to the lack of animal models. Here, we characterized a novel nonhuman primate model of myopic foveoschisis through clinical examination and multimodal imaging followed by morphologic, cellular, and transcriptional profiling of retinal tissues and genetic analysis. Methods: We identified a rhesus macaque with behavioral and anatomic features of myopic foveoschisis, and monitored disease progression over 14 months by fundus photography, fluorescein angiography, and optical coherence tomography (OCT). After necropsy, we evaluated anatomic and cellular changes by immunohistochemistry and transcriptomic changes using single-nuclei RNA-sequencing (snRNA-seq). Finally, we performed Sanger and whole exome sequencing with focus on the RS1 gene. Results: Affected eyes demonstrated posterior hyaloid traction and progressive splitting of the outer plexiform layer on OCT. Immunohistochemistry showed increased GFAP expression in Müller glia and loss of ramified Iba-1+ microglia, suggesting macro- and microglial activation with minimal photoreceptor alterations. SnRNA-seq revealed gene expression changes predominantly in cones and retinal ganglion cells involving chromatin modification, suggestive of cellular stress at the fovea. No defects in the RS1 gene or its expression were detected. Conclusions: This nonhuman primate model of foveoschisis reveals insights into how acquired myopic traction leads to phenotypically similar morphologic and cellular changes as congenital XLRS without alterations in RS1.

Mosaic embryo transfer-first report of a live born with nonmosaic partial aneuploidy and uniparental disomy 15.

Objective: To inform clinicians of the first known case of a live born diagnosed with syndromic partial trisomy 15 and maternal uniparental disomy 15 resulting from a mosaic embryo transfer (MET). We believe that this case will highlight the need for standardized practice guidelines to address the potential risk of MET and the importance of prenatal follow-up after a pregnancy is achieved from a MET. Design: Case report. Setting: In vitro fertilization with preimplantation genetic testing for aneuploidy (PGT-A) and MET was completed at a fertility clinic in Canada. Postnatal testing and diagnosis were performed at the Medical Genetics Department of a hospital in Canada. Patients: A newborn male with a diagnosis of partial trisomy 15 and uniparental disomy (UPD) 15. Interventions: Mosaic embryo transfer after PGT-A was performed. Diagnostic testing performed after birth included a karyotype, fluorescence in situ hybridization analysis, chromosomal microarray, and microsatellite UPD testing. Main Outcome Measures: Confirmed nonmosaic partial aneuploidy of trisomy 15 and UPD15 in a symptomatic newborn conceived from MET. Results: Singleton pregnancy was achieved after a double embryo transfer involving 1 embryo diagnosed by PGT-A with high-level mosaic trisomy 15 and high-level mosaic deletion on chromosome 20 (mos(del(20)(q11.23-qter)). Routine prenatal screening and detailed fetal ultrasound did not identify any concerns. Postnatal genetic investigations, triggered by feeding difficulties in the newborn period, diagnosed the proband with maternal UPD15 and a supernumerary marker chromosome composed of 2 noncontiguous regions of chromosome 15. This karyotype is likely resulting from incomplete trisomy rescue occurring on the paternal chromosome 15. Conclusions: This case highlights the need for better guidelines and management of pregnancies achieved after MET.

Developing and validating SARS-CoV-2 assays for nonhuman primate surveillance.

INTRODUCTION: In early 2020, the California National Primate Research Center implemented surveillance to address the threat of SARS-CoV-2 infection in its nonhuman primate colony. MATERIALS/METHODS: To detect antiviral antibodies, multi-antigen assays were developed and validated on enzyme immunoassay and multiplex microbead immunofluorescent assay (MMIA) platforms. To detect viral RNA, RT-PCR was also performed. RESULTS/CONCLUSION: Using a 4plex, antibody was identified in 16/16 experimentally infected animals; and specificity for spike, nucleocapsid, receptor binding domain, and whole virus antigens was 95.2%, 93.8%, 94.3%, and 97.1%, respectively on surveillance samples. Six laboratories compared this MMIA favorably with nine additional laboratory-developed or commercially available assays. Using a screen and confirm algorithm, 141 of the last 2441 surveillance samples were screen-reactive requiring confirmatory testing. Although 35 samples were reactive to either nucleocapsid or spike; none were reactive to both. Over 20 000 animals have been tested and no spontaneous infections have so far been confirmed across the NIH sponsored National Primate Research Centers.

Multi-site proficiency testing for validation and standardization of assays to detect specific pathogen-free viruses, coronaviruses, and other agents in nonhuman primates.

In efforts to increase rigor and reproducibility, the USA National Primate Research Centers (NPRCs) have focused on qualification of reagents, cross-laboratory validations, and proficiency testing for methods to detect infectious agents and accompanying immune responses in nonhuman primates. The pathogen detection working group, comprised of laboratory scientists, colony managers, and leaders from the NPRCs, has championed the effort to produce testing that is reliable and consistent across laboratories. Through multi-year efforts with shared proficiency samples, testing percent agreement has increased from as low as 67.1% for SRV testing in 2010 to 92.1% in 2019. The 2019 average agreement for the four basic SPF agents improved to >96% (86.5% BV, 98.9 SIV, 92.1 SRV, and 97.0 STLV). As new pathogens such as SARS coronavirus type 2 emerge, these steps can now be quickly replicated to develop and implement new assays that ensure rigor, reproducibly, and quality for NHP pathogen detection.

Clinical presentation, treatment, and genetic and histopathological analysis of juvenile cataracts and secondary glaucoma in a rhesus macaque (Macaca mulatta).

This report describes the clinical and histological findings, genetic study, and treatment in a 1.3-year-old rhesus macaque with bilateral cataracts and unilateral secondary glaucoma. Intravitreal injection of gentamicin decreased the intraocular pressure from 56 to <2 mm Hg. A putative genetic cause of the cataracts was not identified.

Recent Treatment Strategies in Alzheimer's Disease and Chronic Traumatic Encephalopathy.

Neurotrauma has been well linked to the progression of neurodegenerative disease. Much work has been done characterizing chronic traumatic encephalopathy, but less has been done regarding the contribution to Alzheimer's Disease. This review focuses on AD and its association with neurotrauma. Emerging clinical trials are discussed as well as novel mechanisms. We then address how some of these mechanisms are shared with CTE and emerging pre-clinical studies. This paper is a user-friendly resource that summarizes the emerging findings and proposes further investigation into key areas of interest. It is intended to serve as a catalyst for both research teams and clinicians in the quest to improve effective treatment and diagnostic options.

Tuberculosis detection in nonhuman primates is enhanced by use of testing algorithms that include an interferon-γ release assay.

OBJECTIVE: To develop a testing algorithm that incorporates multiple assays to evaluate host cellular and humoral immunity and antigen detection concerning Mycobacterium tuberculosis complex (MTBC) infection in captive nonhuman primates. ANIMALS: Cohorts of captive-bred and wild-caught macaques from 5 different geographic regions. PROCEDURES: Macaques were tested for MTBC infection by use of a γ interferon tuberculosis (GIFT) assay, an interferon-γ release assay, and other assays. In the first 2 cohorts (n = 15 and 181), initial validation of the GIFT assay was performed by use of experimentally infected and unexposed control macaques. In the next 3 cohorts (n = 59, 42, and 11), results were obtained for opportunistically collected samples from macaques exposed during spontaneous outbreaks. RESULTS: Sensitivity and specificity of the GIFT assay in the control cohorts were 100% and 97%, respectively, and were variable but enhanced by incorporating results from multiple assays in spontaneous outbreaks. CLINICAL RELEVANCE: The detection and management of MTBC infection in captive nonhuman primate populations is an ongoing challenge, especially with animal imports and transfers. Despite standardized practices of initial quarantine with regular intradermal tuberculin skin testing, spontaneous outbreaks continue to be reported. Since infection encompasses a range of disease manifestations over time, a testing algorithm that incorporates multiple assays, such as the GIFT assay, to evaluate host cellular and humoral immunity in addition to agent detection is needed. Testing a combination of samples from controlled studies and spontaneous outbreaks of MTBC infection in nonhuman primates would advance the development and validation of a functional algorithm that incorporates promising tools such as the GIFT assay.

Optimization of capsaicin-induced dermal blood flow measurement by laser Doppler imaging in cynomolgus macaque.

BACKGROUND: Capsaicin is used in several areas of non-human primate research including allodynia and dermal blood flow (DBF). The capsaicin-induced DBF increase was measured using laser Doppler imaging (LDI), but this response is known to diminish upon repeated topical applications. Refinement of the experimental procedures could improve the rigor and reproducibility of the DBF migraine model. METHODS: Optimal anatomical site in cynomolgus was determined, and conditions and experimental settings for DBF measurement using LDI were established. Then, two study design trial structures were compared. RESULTS: Medial thigh was the preferrable site, and an ethanol-Tween 20 formulation of capsaicin was desirable. A 1-week washout for contralateral side or 2-week washout for ipsilateral side was necessary to eradicate capsaicin desensitization. CONCLUSIONS: With the established technicality in DBF measurements in cynomolgus macaques, the capsaicin-induced DBF model may be utilized in translational medical research in developing migraine therapeutics.

Heritability and Pedigree Analyses of Hypertrophic Cardiomyopathy in Rhesus Macaques (Macaca Mulatta).

In a colony of rhesus macaques at California National Primate Research Center (CNPRC), naturally occurring hypertrophic cardiomyopathy (HCM) classified by left ventricular hypertrophy without obvious underlying diseases has been identified during necropsy over the last two decades. A preliminary pedigree analysis suggested a strong genetic predisposition of this disease with a founder effect. However, the mode of inheritance was undetermined due to insufficient pedigree data. Since 2015, antemortem examination using echocardiographic examination as well as other cardiovascular analyses have been performed on large numbers of rhesus macaques at the colony. Based on antemortem examination, HCM was diagnosed in additional 65 rhesus macaques. Using HCM cases diagnosed based on antemortem and postmortem examinations, the heritability (h2) was estimated to determine the degree of genetic and environmental contributions to the development of HCM in rhesus macaques at the CNPRC. The calculated mean and median heritability (h2) of HCM in this colony of rhesus macaques were 0.5 and 0.51 (95% confidence interval; 0.14-0.82), respectively. This suggests genetics influence development of HCM in the colony of rhesus macaques. However, post-translational modifications and environmental factors are also likely to contribute the variability of phenotypic expression. Based on the pedigree analysis, an autosomal recessive trait was suspected, but an autosomal dominant mode of inheritance with incomplete penetrance was also possible. Further investigation with more data from siblings, offspring, and parents of HCM-affected rhesus macaques are warranted. Importantly, the findings of the present study support conducting genetic investigations such as whole genome sequencing to identify the causative variants of inherited HCM in rhesus macaques.

Reflections on project ECHO: qualitative findings from five different ECHO programs.

Project ECHO (Extension for Community Healthcare Outcomes) was developed in 2003 as an innovative model to facilitate continuing education and professional development. ECHO emphasizes 'moving knowledge, not people.' To accomplish this, ECHO programs use virtual collaboration and case-based learning to allow practitioners, including those in rural and underserved areas, to receive specialist training. The ECHO model has expanded rapidly and is now used in 44 countries. Preliminary research on ECHO's efficacy and effectiveness has shown promising results, but evidence remains limited and appropriate research outcomes have not been clearly defined. To improve the evidence basis for ECHO, this study of 5 ECHO programs (cancer prevention/survivorship, integrated pain management, hepatitis C, HIV, and LGBTQ+ health care elucidated actionable insights about the ECHO programs and directions in which future evaluations and research might progress. This was a qualitative study following COREQ standards. A trained interviewer conducted 10 interviews and 5 focus groups with 25 unique, purposively sampled ECHO attendees (2 interviews and 1 focus group for each of the 5 programs). Data were transcribed verbatim and analyzed using the general inductive approach, then reviewed for reliability. We identified four major categories (reasons to join ECHO, value of participating in ECHO, ways to improve ECHO, and barriers to participation) composed of 23 primary codes. We suggest that thematic saturation was achieved, and a coherent narrative about ECHO emerged for discussion. Participants frequently indicated they received valuable learning experiences and thereby changed their practice; rigorous trials of learning and patient-level outcomes are warranted. This study also found support for the idea that the ECHO model should be studied for its role in convening communities of practice and reducing provider isolation as an outcome in itself. Additional implications, including for interprofessional education and model evolution, were also identified and discussed.

Effects of transdermal mirtazapine on hyporexic rhesus and cynomolgus macaques (Macaca mulatta and Macaca fascicularis).

BACKGROUND: Hyporexia and weight loss are important indicators of physical and psychological well-being in macaque colonies. An FDA-approved transdermal formulated Mirtazapine (MTZ) shows effectiveness in managing feline hyporexia. This study sought to determine its effectiveness as an appetite stimulant in macaques. METHODS: Fourteen macaques with idiopathic hyporexia, intractable to conventional management were treated with transdermal MTZ (0.5 mg/kg) topically administered to aural pinnae once daily for 14 days. Qualitative food consumption was monitored daily for 6 months. Body weights were collected prior to treatment, every 2 weeks for the first 6 weeks, 10 weeks, and 6 months post-treatment. RESULTS: Transdermal MTZ significantly reduced the frequency of hyporexia during treatment and monthly for 6 months. No significant increase in weight noted until approximately 6 months post-treatment. CONCLUSIONS: Results from this study indicate that a short course of transdermal MTZ is an effective way to increase food consumption in macaques chronically.