Worth a Shot: Experience and Lessons From an Unsuccessful Pediatric Immunization Quality Improvement Effort in a Large Health System During the COVID-19 Pandemic.

INTRODUCTION: During the coronavirus disease of 2019 (COVID-19) pandemic, routine childhood immunization rates dropped dramatically across the world, and the Military Health System (MHS) was no exception. In the MHS, which is a large, universally covered, low-to-no-cost health system, the immunization rates with the measles, mumps, and rubella (MMR) vaccine remain below the rate necessary to prevent community transmission of measles. We aimed to improve childhood immunization rates in the MHS with an expansive quality improvement project. MATERIALS AND METHODS: Measles, mumps, and rubella immunization rates served as proxy outcome measures for routine immunization rates tracked by the Center for Disease Control multi-immunization combination measures. The tracked measure was the percentage of 16- to 18-month olds and 6-year olds who had received MMR #1 and MMR #2, respectively. Various countermeasures were implemented throughout the study period, and standard quality improvement analyses informed the effect of countermeasures. RESULTS: By January 2023, the percentage of 16- to 18-month olds and 6-year olds who had received MMR #1 and MMR #2 was 85% and 91%, respectively, with no positive shift in immunization rates despite various countermeasures introduced during the study period. For reference, the MMR immunization rates of commercial health maintenance organization and commercial preferred provider organization for 24-month-old populations were 92% and 90.3%, respectively. On chart review, the most common cause for under-immunization (55%) was vaccine abandonment. MMR #1 rates rose to 92% in 24-month olds. CONCLUSIONS: Measles, mumps, and rubella immunization rates within the MHS remained below commercial health system rates and below public health standards required for herd immunity despite various countermeasures throughout the COVID-19 pandemic. Immunization rates increased with age, suggesting that children within the MHS eventually catch up despite potential barriers.

Carprofen Attenuates Postoperative Mechanical and Thermal Hypersensitivity after Plantar Incision in Immunodeficient NSG Mice.

Immunodeficient NSG mice are reported to be less responsive to buprenorphine analgesia. Here, we used NSG mice to compare the efficacy of the commonly used dose of carprofen (5 mg/kg) with 5 and 10 times that dose (25 and 50 mg/kg) for attenuating postoperative mechanical and thermal hypersensitivity following an incisional pain model. Male and female NSG mice (n = 45) were randomly assigned to one of 4 groups and received daily subcutaneous injections for 3 d: saline (5 mL/kg), 5 mg/kg carprofen (Carp5), 25 mg/kg carprofen (Carp25), and 50 mg/kg carprofen (Carp50). Mechanical and thermal hypersensitivity were assessed 24 h before and at 4, 24, and 48 h after surgery. Plasma carprofen concentrations were measured in a separate group of mice (n = 56) on days 0 (at 2, 4, 12, and 23 h), 1, and 2 after the first, second, and third doses, respectively. Toxicity was assessed through daily fecal occult blood testing (n = 27) as well as gross and histopathologic evaluation (n = 15). Our results indicated that the saline group showed both mechanical and thermal hypersensitivity throughout the study. Carp5 did not attenuate mechanical or thermal hypersensitivity at any time point. Carp25 attenuated mechanical and thermal (except for the 4-h time point) hypersensitivity. Carp50 attenuated only thermal hypersensitivity at 24 h. Fecal occult blood was detected in 1 of 8 Carp25-treated mice at 48 and 72 h. Histopathologic abnormalities (gastric ulceration, ulcerative enteritis, and renal lesions) were observed in some Carp50-treated mice. Plasma carprofen concentrations were dose and time dependent. Our results indicate that Carp25 attenuated postoperative mechanical and thermal hypersensitivity more effectively than Carp5 or Carp50 in NSG mice with incisional pain. Therefore, we recommend providing carprofen at 25 mg/kg SID for incisional pain procedures using immunodeficient NSG mouse.

A Novel Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth in Mouse Models of GI Cancer.

Here, we describe a novel pan-RAS inhibitor, ADT-007, that potently inhibited the growth of RAS mutant cancer cells irrespective of the RAS mutation or isozyme. RAS WT cancer cells with activated RAS from upstream mutations were equally sensitive. Conversely, cells from normal tissues or RAS WT cancer cells harboring downstream BRAF mutations were insensitive. Insensitivity to ADT-007 was attributed to low activated RAS levels and metabolic deactivation by UDP-glucuronosyltransferases expressed in normal cells but repressed in RAS mutant cancer cells. Cellular, biochemical, and biophysical experiments show ADT-007 binds nucleotide-free RAS to block GTP activation of RAS and MAPK/AKT signaling. Local administration of ADT-007 strongly inhibited tumor growth in syngeneic immune-competent and xenogeneic immune-deficient mouse models of colorectal and pancreatic cancer while activating innate and adaptive immunity in the tumor immune microenvironment. Oral administration of ADT-007 prodrug inhibited tumor growth, supporting further development of this novel class of pan-RAS inhibitors for treating RAS-driven cancers. SIGNIFICANCE: ADT-007 is a 1 st -in-class pan-RAS inhibitor with ultra-high potency and unique selectivity for cancer cells with mutant or activated RAS capable of circumventing resistance and activating antitumor immunity. Further development of ADT-007 analogs or prodrugs with oral bioavailability as a generalizable monotherapy or combined with immunotherapy is warranted.

Comparing Three Formulations of Buprenorphine in an Incisional Pain Model in Mice.

This study compared the therapeutic effects in mice of 3 different formulations of buprenorphine. These formulations were standard buprenorphine hydrochloride (Bup-HCL) and 2 different extended-release buprenorphine formulations (Bup-ER and Ethiqa-XR [Bup-XR]). Drugs were evaluated based on their ability to attenuate thermal hypersensitivity in a mouse plantar incisional pain model. We hypothesized that Bup-HCL would attenuate postoperative thermal hypersensitivity at 20 min after administration, and that Bup-ER and Bup-XR would attenuate thermal hypersensitivity at 40 min after administration. Male C57BL6/J mice were randomly assigned to 1 of 4 treatment groups: 1) saline, 5 mL/kg SC, once; 2) Bup-HCL, 0.1 mg/kg SC, once; 3) Bup-ER, 1 mg/kg, SC, once; and 4) Bup-XR, 3.25 mg/kg, SC, once. Thermal hypersensitivity was assessed on the day before surgery and again on the day of surgery at 20, 40, 60, 90, and 120 min after drug administration. Thermal hypersensitivity after surgery was not different among the Bup-HCL, Bup-ER and Bup-XR groups at any timepoint. In addition, all buprenorphine treatment groups showed significantly less thermal hypersensitivity after surgery than did the saline group. Subjective observations suggested that mice that received Bup-ER or Bup-XR became hyperactive after drug administration (83 and 75% of mice tested, respectively). Our results indicate that Bup-HCL, Bup-ER, or Bup-XR attenuate thermal hyper- sensitivity related to foot incision by 20 min after administration.

Interaction between buprenorphine and norbuprenorphine in neonatal opioid withdrawal syndrome.

Buprenorphine (BUP) is the preferred treatment for opioid use disorder during pregnancy but can cause neonatal opioid withdrawal syndrome (NOWS). Norbuprenorphine (NorBUP), an active metabolite of BUP, is implicated in BUP-associated NOWS. We hypothesized that BUP, a low-efficacy agonist of mu opioid receptors, will not antagonize NorBUP, a high-efficacy agonist of mu opioid receptors, in producing NOWS. To test this hypothesis, we treated pregnant Long-Evans rats with BUP (0, 0.01, 0.1 or 1mg/kg/day) ± NorBUP (1mg/kg/day) from gestation day 9 until pup delivery, and tested pups for opioid dependence using our established NOWS model. We used LC-MS-MS to quantify brain concentrations of BUP, NorBUP, and their glucuronide conjugates. BUP had little effect on NorBUP-induced NOWS, with the exception of 1mg/kg/day BUP significantly increasing NorBUP-induced NOWS by 58% in females. BUP and NorBUP brain concentrations predicted NOWS in multiple linear regression models. Interestingly, NorBUP contributed more to NOWS in females (ßNorBUP = 51.34, p = 0.0001) than in males (ßNorBUP = 19.21, P = 0.093), while BUP was similar for females (ßBUP = 10.62, P = 0.0017) and males (ßBUP = 11.38, P = 0.009). We are the first to report that NorBUP induces NOWS in the presence of BUP and it is more influential in females than males in the contribution of NorBUP to BUP-associated NOWS. These findings suggest that females are more susceptible to NorBUP-induced NOWS, and that treatment strategies that reduce prenatal NorBUP exposure may be more effective for females than males.

Deuterated buprenorphine retains pharmacodynamic properties of buprenorphine and resists metabolism to the active metabolite norbuprenorphine in rats.

Introduction: An active metabolite of buprenorphine (BUP), called norbuprenorphine (NorBUP), is implicated in neonatal opioid withdrawal syndrome when BUP is taken during pregnancy. Therefore, reducing or eliminating metabolism of BUP to NorBUP is a novel strategy that will likely lower total fetal exposure to opioids and thus improve offspring outcomes. Precision deuteration alters pharmacokinetics of drugs without altering pharmacodynamics. Here, we report the synthesis and testing of deuterated buprenorphine (BUP-D2). Methods: We determined opioid receptor affinities of BUP-D2 relative to BUP with radioligand competition receptor binding assays, and the potency and efficacy of BUP-D2 relative to BUP to activate G-proteins via opioid receptors with [35S]GTPγS binding assays in homogenates containing the human mu, delta, or kappa opioid receptors. The antinociceptive effects of BUP-D2 and BUP were compared using the warm-water tail withdrawal assay in rats. Blood concentration versus time profiles of BUP, BUP-D2, and NorBUP were measured in rats following intravenous BUP-D2 or BUP injection. Results: The synthesis provided a 48% yield and the product was ≥99% deuterated. Like BUP, BUP-D2 had sub-nanomolar affinity for opioid receptors. BUP-D2 also activated opioid receptors and induced antinociception with equal potency and efficacy as BUP. The maximum concentration and the area under the curve of NorBUP in the blood of rats that received BUP-D2 were over 19- and 10-fold lower, respectively, than in rats that received BUP. Discussion: These results indicate that BUP-D2 retains key pharmacodynamic properties of BUP and resists metabolism to NorBUP and therefore holds promise as an alternative to BUP.

The brain-penetrant cell-cycle inhibitor p28 sensitizes brain metastases to DNA-damaging agents.

Background: Brain metastases (BMs), the most common tumors of the central nervous system, are life-threatening with a dismal prognosis. The major challenges to developing effective treatments for BMs are the limited abilities of drugs to target tumors and to cross the blood-brain barrier (BBB). We aimed to investigate the efficacy of our therapeutic approach against BMs in mouse models that recapitulate the clinical manifestations of BMs. Methods: BMs mouse models were constructed by injecting human breast, lung cancer, and melanoma intracardially, which allowed the BBB to remain intact. We investigated the ability of the cell-penetrating peptide p28 to cross the BBB in an in vitro 3D model and in the BMs animal models. The therapeutic effects of p28 in combination with DNA-damaging agents (radiation and temozolomide) on BMs were also evaluated. Results: p28 crossed the intact BBB more efficiently than the standard chemotherapeutic agent, temozolomide. Upon crossing the BBB, p28 localized preferentially to tumor lesions and enhanced the efficacy of DNA-damaging agents by activating the p53-p21 axis. In the BMs animal models, radiation in combination with p28 significantly reduced the tumor burden of BMs. Conclusions: The cell-cycle inhibitor p28 can cross the BBB localize to tumor lesions in the brain and enhance the inhibitory effects of DNA-damaging agents on BMs, suggesting the potential therapeutic benefits of this molecule in BMs.

From the Defense Health Board: Military Accessions and the Continuum of Mental Health Research.

The Defense Health Board conducted a year-long examination of mental health accession screening and related issues. In its August 2020 report, Examination of Mental Health Accession Screening: Predictive Value of Current Measures and Processes, the Board recommends a paradigm shift in how mental health impacts on readiness are understood and addressed. This shift can only occur with the development and implementation of a research plan that follows cohorts of military personnel from recruitment through their military career. The following article describes this research plan as an excerpt of the larger report.

Indomethacin-induced oxidative stress enhances death receptor 5 signaling and sensitizes tumor cells to adoptive T-cell therapy.

BACKGROUND: Adoptive cell therapy (ACT) using genetically modified T cells has evolved into a promising treatment option for patients with cancer. However, even for the best-studied and clinically validated CD19-targeted chimeric antigen receptor (CAR) T-cell therapy, many patients face the challenge of lack of response or occurrence of relapse. There is increasing need to improve the efficacy of ACT so that durable, curative outcomes can be achieved in a broad patient population. METHODS: Here, we investigated the impact of indomethacin (indo), a non-steroidal anti-inflammatory drug (NSAID), on the efficacy of ACT in multiple preclinical models. Mice with established B-cell lymphoma received various combinations of preconditioning chemotherapy, infusion of suboptimal dose of tumor-reactive T cells, and indo administration. Donor T cells used in the ACT models included CD4+ T cells expressing a tumor-specific T cell receptor (TCR) and T cells engineered to express CD19CAR. Mice were monitored for tumor growth and survival. The effects of indo on donor T cell phenotype and function were evaluated. The molecular mechanisms by which indo may influence the outcome of ACT were investigated. RESULTS: ACT coupled with indo administration led to improved tumor growth control and prolonged mouse survival. Indo did not affect the activation status and tumor infiltration of the donor T cells. Moreover, the beneficial effect of indo in ACT did not rely on its inhibitory effect on the immunosuppressive cyclooxygenase 2 (COX2)/prostaglandin E2 (PGE2) axis. Instead, indo-induced oxidative stress boosted the expression of death receptor 5 (DR5) in tumor cells, rendering them susceptible to donor T cells expressing TNF-related apoptosis-inducing ligand (TRAIL). Furthermore, the ACT-potentiating effect of indo was diminished against DR5-deficient tumors, but was amplified by donor T cells engineered to overexpress TRAIL. CONCLUSION: Our results demonstrate that the pro-oxidative property of indo can be exploited to enhance death receptor signaling in cancer cells, providing rationale for combining indo with genetically modified T cells to intensify tumor cell killing through the TRAIL-DR5 axis. These findings implicate indo administration, and potentially similar use of other NSAIDs, as a readily applicable and cost-effective approach to augment the efficacy of ACT.

Nontoxic Tumor-Targeting Optical Agents for Intraoperative Breast Tumor Imaging.

Precise identification of the tumor margins during breast-conserving surgery (BCS) remains a challenge given the lack of visual discrepancy between malignant and surrounding normal tissues. Therefore, we developed a fluorescent imaging agent, ICG-p28, for intraoperative imaging guidance to better aid surgeons in achieving negative margins in BCS. Here, we determined the pharmacokinetics (PK), biodistribution, and preclinical toxicity of ICG-p28. The PK and biodistribution of ICG-p28 indicated rapid tissue uptake and localization at tumor lesions. There were no dose-related effect and no significant toxicity in any of the breast cancer and normal cell lines tested. Furthermore, ICG-p28 was evaluated in clinically relevant settings with transgenic mice that spontaneously developed invasive mammary tumors. Intraoperative imaging with ICG-p28 showed a significant reduction in the tumor recurrence rate. This simple, nontoxic, and cost-effective method can offer a new approach that enables surgeons to intraoperatively identify tumor margins and potentially improves overall outcomes by reducing recurrence rates.

A Career Life-Cycle Perspective on Women's Health and Safety: Insights From the Defense Health Board Report on Military Women's Health.

OBJECTIVE: Women's health has demanded more attention from employers as women integrated into the workforce. Traditionally male-dominant fields and occupations require special attention to workplace design, physical standards for entry, employment practices, equipment, and health monitoring. This editorial summarizes the Defense Health Board's (DHB) review of Active Duty Women's Health and its recommendations grounded in a woman's career life-cycle. METHODS: The DHB reviewed the Department of Defense and foreign militaries' current women's health services, relevant policies and practices, peer-reviewed scientific literature, and subject matter expert interviews. RESULTS: The DHB's recommendations centered on a comprehensive approach to education, health care access and treatment, professional workforce development, workplace standards and equipment, and accountable outcomes metrics to guide improvement. CONCLUSIONS: Employers can learn how to reduce morbidity, leading to a healthier and more productive female workforce.

Urine Single-Cell RNA Sequencing in Focal Segmental Glomerulosclerosis Reveals Inflammatory Signatures.

INTRODUCTION: Individuals with focal segmental glomerular sclerosis (FSGS) typically undergo kidney biopsy only once, which limits the ability to characterize kidney cell gene expression over time. METHODS: We used single-cell RNA sequencing (scRNA-seq) to explore disease-related molecular signatures in urine cells from subjects with FSGS. We collected 17 urine samples from 12 FSGS subjects and captured these as 23 urine cell samples. The inflammatory signatures from renal epithelial and immune cells were evaluated in bulk gene expression data sets of FSGS and minimal change disease (MCD) (The Nephrotic Syndrome Study Network [NEPTUNE] study) and an immune single-cell data set from lupus nephritis (Accelerating Medicines Partnership). RESULTS: We identified immune cells, predominantly monocytes, and renal epithelial cells in the urine. Further analysis revealed 2 monocyte subtypes consistent with M1 and M2 monocytes. Shed podocytes in the urine had high expression of marker genes for epithelial-to-mesenchymal transition (EMT). We selected the 16 most highly expressed genes from urine immune cells and 10 most highly expressed EMT genes from urine podocytes as immune signatures and EMT signatures, respectively. Using kidney biopsy transcriptomic data from NEPTUNE, we found that urine cell immune signature and EMT signature genes were more highly expressed in FSGS biopsies compared with MCD biopsies. CONCLUSION: The identification of monocyte subsets and podocyte expression signatures in the urine samples of subjects with FSGS suggests that urine cell profiling might serve as a diagnostic and prognostic tool in nephrotic syndrome. Furthermore, this approach may aid in the development of novel biomarkers and identifying personalized therapies targeting particular molecular pathways in immune cells and podocytes.

Design and Assessment of a Mobile Health Care Solution for the Military Pediatrician: The DHA Pediatrics App.

INTRODUCTION: Mobile health technology design and use by patients and clinicians have rapidly evolved in the past 20 years. Nevertheless, the technology has remained in silos of practices, patients, and individual institutions. Uptake across integrated health systems has lagged. MATERIALS AND METHODS: In 2015, the authors designed a mobile health application (App) aimed at augmenting the capabilities of clinicians who care for children within the Military Health System (MHS). This App incorporated a curated, system-based collection of Clinical Practice Guidelines, access to emergency resuscitation cards, call buttons for local market subspecialty and inpatient teams, links to residency academic calendars, and other web-based resources. Over the next 5 years, three Plan-Do-Study-Act cycles facilitated multiple enhancements for the App which eventually transitioned from the Android/iOS stores to a web browser. The "People At the Centre of Mobile Application Development" tool which has validity evidence captured user experience. The team assessed the App's global effectiveness using Google Analytics. A speed test measured time saved and accuracy of task completion for clinicians using the App compared to non-users. Finally, MHS medical librarians critiqued the App using a questionnaire with validity evidence. The Walter Reed National Military Medical Center Institutional Review Board reviewed the study and deemed it exempt. RESULTS: Clinician respondents (n = 68 complete responses across six MTFs, 51% graduate medical trainees representing a 7.4% response rate of active duty pediatrician forces) perceived the App to have appropriate qualities of efficiency, effectiveness, learnability, memorability, errors, satisfaction, and cognitive properties following App use in clinical practice. Google Analytics demonstrated more than 1,000 unique users on the App from May 1, 2020 to January 20, 2021. There were 746 instances (26% of all sessions) when a user navigated between more than one military treatment facility. App users were faster and more accurate at task completion during a digital scavenger hunt. Medical librarians measured the App to have acceptable usefulness, accuracy, authority, objectivity, timeliness, functionality, design, security, and value. CONCLUSIONS: The App appears to be an effective tool to extend a clinician's capabilities and inter-professional communication between world-wide users and six MHS markets. This App was designed-and used-for a large health care network across a wide geographic footprint. Next steps are establishing an enduring chain of App champions for continued updates and sharing the App's code with other military medical disciplines and interested civilian centers.

Mobilizing the U.S. Military's TRICARE Program for Value-Based Care: A Report From the Defense Health Board.

The U.S. Military Health System spends about $50 billion annually to provide care to 9.6 million active duty service members, retirees, and their families through its TRICARE health plans. TRICARE follows the predominant payment model in the USA-fee-for-service-although the Department of Defense (DoD) and Congress encourage and mandate a move toward alternative payment models-mainly, fee-for-value. For the next TRICARE contracts which will begin in 2023, the DoD asked its health-focused federal advisory committee, the Defense Health Board (DHB), to recommend how best to assess and prioritize leading value-based healthcare initiatives identified from private, public, and employer-based health plans. The November 2020 report, 'Modernization of the TRICARE Benefit', specifies a rubric to evaluate these value-based care initiatives not only in traditional measures of effectiveness but also in terms of the Defense Health Agency's Quadruple Aim with its focus on readiness. The goal of TRICARE's move toward value-based care is to leverage its size and focus on prevention of disease and injury to maintain the readiness of the U.S. Armed Forces in addition to delivering great outcomes and value to the DoD's nearly 10 million beneficiaries. The DHB emphasizes that TRICARE's size and focus on providing quality care at lower cost will incentivize providers to participate in the shift toward value-based care despite the potential challenges in transitioning to this system. This shift also aims to motivate other large government and private payors to accelerate the adoption of value-based care through TRICARE's example.

Probiotic Releasing Angiotensin (1-7) in a Drosophila Model of Alzheimer's Disease Produces Sex-Specific Effects on Cognitive Function.

BACKGROUND: While extensive research on the brain has failed to identify effective therapies, using probiotics to target the gut microbiome has shown therapeutic potential in Alzheimer's disease (AD). Genetically modified probiotics (GMP) are a promising strategy to deliver key therapeutic peptides with high efficacy and tissue specificity. Angiotensin (Ang)-(1-7) levels inversely correlate to AD severity, but its administration is challenging. Our group has successfully established a GMP-based method of Ang-(1-7) delivery. OBJECTIVE: Since Drosophila represents an excellent model to study the effect of probiotics on complex disorders in a high throughput manner, we tested whether oral supplementation with Lactobacillus paracasei releasing Ang-(1-7) (LP-A) delays memory loss in a Drosophila AD model. METHODS: Flies overexpressing the human amyloid-ß protein precursor and its ß-site cleaving enzyme in neurons were randomized to receive four 24-h doses of Lactobacillus paracasei alone (LP), LP-A or sucrose over 14 days. Memory was assessed via an aversive phototaxic suppression assay. RESULTS: Optimal dilution,1:2, was determined based on palatability. LP-A improved memory in trained AD males but worsened cognition in AD females. LP-supplementation experiments confirmed that Ang-(1-7) conferred additional cognitive benefits in males and was responsible for the deleterious cognitive effects in females. Sex-specific differences in the levels of angiotensin peptides and differential activation of the kynurenine pathway of tryptophan metabolism in response to supplementation may underlie this male-only therapeutic response. CONCLUSION: In summary, LP-A ameliorated the memory deficits of a Drosophila AD model, but effects were sex-specific. Dosage optimization may be required to address this differential response.

The usability and applicability of knowledge translation theories, models, and frameworks for research in the context of a national health service.

BACKGROUND: Translating research findings into service improvements for patients and/or policy changes is a key challenge for health service organizations. The Health Service Executive (HSE) in Ireland launched the Action Plan for Health Research 2019-2029, as reported by Terrés (HSE, Dublin, 2019), one of the goals of which is to maximize the impact of the research that takes place within the service to achieve improvements in patient care, services, or policy change. The purpose of this research is to review the literature on knowledge translation theories, models, and frameworks (TMFs) and to assess the suitability of the TMFs for HSE use, selecting one or more for this purpose. The aim is to produce guidance for HSE researchers and other health services staff, validate the usability of the framework(s) with researchers, and review and implement the guidance. It was hoped that identifying a suitable methodology would provide the means to increase the uptake and application of research findings, and reduce research wastage. This paper reports on the first part of the study: the review, assessment, and selection of knowledge translation TMFs for a national health service. METHODS: An interdisciplinary working group of academic experts in implementation science, research wastage, and knowledge translation, along with key representatives from research funders (Health Research Board) and HSE personnel with expertise in quality improvement and research management, undertook a three-stage review and selection process to identify a knowledge translation TMF that would be suitable and usable for HSE purposes. The process included a literature review, consensus exercise, and a final consensus workshop. The review group adopted the Theory Comparison and Selection Tool (T-CaST) developed by Birken et al. (Implement Sci 13: 143, 2018) to review knowledge translation theories, models, and frameworks. RESULTS: From 247 knowledge translation TMFs initially identified, the first stage of the review identified 18 that met the criteria of validity, applicability, relevance, usability, and ability to be operationalized in the local context. A further review by a subgroup of the working group reduced this number to 11. A whole-group review selected six of these to be reviewed at a facilitated consensus workshop, which identified three that were suitable and applicable for HSE use. These were able to be mapped onto the four components of the HSE knowledge translation process: knowledge creation, knowledge into action, transfer and exchange of knowledge, and implementation and sustainability. CONCLUSION: The multiplicity of knowledge translation TMFs presents a challenge for health service researchers in making decisions about the appropriate methods for disseminating their research. Building a culture that uses research knowledge and evidence is important for organizations seeking to maximize the benefits from research. Supporting researchers with guidance on how to disseminate and translate their research can increase the uptake and application of research findings. The use of robust selection criteria enabled the HSE to select relevant TMFs and develop a process for increasing the dissemination and translation of research knowledge. The guidance developed to inform and educate researchers and knowledge users is expected to increase organizational capacity to promote a culture of research knowledge and evidence use within the HSE.

Pharmacokinetic and Histopathologic Study of an Extended-Release, Injectable Formulation of Buprenorphine in Sprague-Dawley Rats.

A novel buprenorphine (BUP) extended-release formulation (BUP-XR) produced as a lipid-encapsulated, low viscosity BUP suspension for SC injection to control pain was evaluated for pharmacokinetics and safety in Sprague-Dawley rats given either 0.65 mg/kg (low dose) or 1.30 mg/kg (high dose). The 2 dosage groups each contained 6 male and 6 female rats to determine whether BUP-XR behaved differently in male or female animals. Blood samples were obtained from each animal before BUP-XR administration and at 6, 24, 48, 72, 96, and 168 h after administration. For necropsy and injection-site histopathology evaluation, 3 animals of each sex from each test group were euthanized on day 8, with the remaining animals euthanized on day 15. Mean plasma BUP concentration peaked from 6 to 24 h in all test groups, then declined in a linear fashion. Quantifiable plasma BUP was measured in all male rats at all time points except for one low dose group sample taken at 168 h. Female rats had quantifiable plasma BUP at all time points except for 1 low dose group sample at 72 and 96 h, and 2 low dose group samples at 168 h. The low dose groups, whether male or female, had lower mean plasma BUP levels at all time points as compared with their high dose counterparts, and female rats had lower mean plasma BUP levels than male rats at all time points. Results indicate that a single BUP-XR dose at either dose concentration can reliably provide plasma levels of BUP reported in the literature to be therapeutically relevant for up to 72 h, although lower plasma BUP levels can be anticipated in female rats compared with male counterparts. Mild to moderate injection-site granulomatous inflammation was observed in 6 of 12 rats in the low dose group and 7 of 12 in the high dose group. This reaction is characteristic of lipid material designed to persist in situ.

Fidelity of Interventions to Reduce or Prevent Stress and/or Anxiety from Pregnancy up to Two Years Postpartum: A Systematic Review.

INTRODUCTION: Intervention fidelity refers to whether an intervention is delivered as intended and can enhance interpretation of trial outcomes. Fidelity of interventions to reduce or prevent stress and anxiety during pregnancy and postpartum has yet to be examined despite inconsistent findings for intervention effects. This study systematically reviews use and/or reporting of intervention fidelity strategies in trials of interventions, delivered to (expectant) parents during pregnancy and postpartum, to reduce or prevent stress and/or anxiety. METHODS: MEDLINE, Embase, CINAHL, PsychINFO, and Maternity and Infant Care were searched from inception to March 2019. Studies were included if they were randomised controlled trials including pregnant women, expectant fathers and/or partners during pregnancy, and/ or parents within the first two years postpartum. The National Institutes of Health Behavior Change Consortium checklist was used to assess fidelity across five domains (study design, provider training, delivery, receipt, enactment). RESULTS: Sixteen papers (14 interventions) were identified. Average reported use of fidelity strategies was 'low' (45%), ranging from 17.5 to 76%. Fidelity ratings ranged from 22% for provider training to 54% for study design. CONCLUSIONS: Low levels of intervention fidelity may explain previous inconsistent effects of stress and anxiety reduction interventions. Important methodological areas for improvement include intervention provider training, fidelity of comparator conditions, and consideration of non-specific treatment effects. Increased methodological rigour in fidelity enhancement and assessment will improve intervention implementation and enhance examination of stress and anxiety reduction and prevention interventions delivered during pregnancy and the postpartum.

The Angiotensin-Converting Enzyme Inhibitor Lisinopril Mitigates Memory and Motor Deficits in a Drosophila Model of Alzheimer's Disease.

The use of angiotensin-converting enzyme inhibitors (ACEis) has been reported to reduce symptoms of cognitive decline in patients with Alzheimer's disease (AD). Yet, the protective role of ACEis against AD symptoms is still controversial. Here, we aimed at determining whether oral treatment with the ACEi lisinopril has beneficial effects on cognitive and physical functions in a Drosophila melanogaster model of AD that overexpresses the human amyloid precursor protein and the human ß-site APP-cleaving enzyme in neurons. We found a significant impairment in learning and memory as well as in climbing ability in young AD flies compared to control flies. After evaluation of the kynurenine pathway of tryptophan metabolism, we also found that AD flies displayed a >30-fold increase in the levels of the neurotoxic 3-hydroxykynurenine (3-HK) in their heads. Furthermore, compared to control flies, AD flies had significantly higher levels of the reactive oxygen species (ROS) hydrogen peroxide in their muscle-enriched thoraces. Lisinopril significantly improved deficits in learning and memory and climbing ability in AD flies. The positive impact of lisinopril on physical function might be, in part, explained by a significant reduction in ROS levels in the thoraces of the lisinopril-fed AD flies. However, lisinopril did not affect the levels of 3-HK. In conclusion, our findings provide novel and relevant insights into the therapeutic potential of ACEis in a preclinical AD model.