c-Rel-dependent Chk2 signaling regulates the DNA damage response limiting hepatocarcinogenesis.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. The NF-κB transcription factor family subunit c-Rel is typically protumorigenic; however, it has recently been reported as a tumor suppressor. Here, we investigated the role of c-Rel in HCC. APPROACH AND RESULTS: Histological and transcriptional studies confirmed expression of c-Rel in human patients with HCC, but low c-Rel expression correlated with increased tumor cell proliferation and mutational burden and was associated with advanced disease. In vivo , global ( Rel-/- ) and epithelial specific ( RelAlb ) c-Rel knockout mice develop more tumors, with a higher proliferative rate and increased DNA damage, than wild-type (WT) controls 30 weeks after N-diethylnitrosamine injury. However, tumor burden was comparable when c-Rel was deleted in hepatocytes once tumors were established, suggesting c-Rel signaling is important for preventing HCC initiation after genotoxic injury, rather than for HCC progression. In vitro , Rel-/- hepatocytes were more susceptible to genotoxic injury than WT controls. ATM-CHK2 DNA damage response pathway proteins were suppressed in Rel-/- hepatocytes following genotoxic injury, suggesting that c-Rel is required for effective DNA repair. To determine if c-Rel inhibition sensitizes cancer cells to chemotherapy, by preventing repair of chemotherapy-induced DNA damage, thus increasing tumor cell death, we administered single or combination doxorubicin and IT-603 (c-Rel inhibitor) therapy in an orthotopic HCC model. Indeed, combination therapy was more efficacious than doxorubicin alone. CONCLUSION: Hepatocyte c-Rel signaling limits genotoxic injury and subsequent HCC burden. Inhibiting c-Rel as an adjuvant therapy increased the effectiveness of DNA damaging agents and reduced HCC growth.

Implementing a Social Needs Screening and Referral Program Among Veterans: Assessing Circumstances & Offering Resources for Needs (ACORN).

BACKGROUND: The Department of Veterans Affairs (VA) healthcare system routinely screens Veterans for food insecurity, housing instability, and intimate partner violence, but does not systematically screen for other health-related social needs (HRSNs). OBJECTIVES: To (1) develop a process for systematically identifying and addressing Veterans' HRSNs, (2) determine reported prevalence of HRSNs, and (3) assess the acceptability of HRSN screening among Veterans. DESIGN: "Assessing Circumstances and Offering Resources for Needs" (ACORN) is a Veteran-tailored HRSN screening and referral quality improvement initiative. Veterans were screened via electronic tablet for nine HRSNs (food, housing, utilities, transportation, legal needs, social isolation, interpersonal violence, employment, and education) and provided geographically tailored resource guides for identified needs. Two-week follow-up interviews with a purposive sample of Veterans explored screening experiences. PARTICIPANTS: Convenience sample of Veterans presenting for primary care at a VA urban women's health clinic and suburban community-based outpatient clinic (October 2019-May 2020). MAIN MEASURES: Primary outcomes included prevalence of HRSNs, Veteran-reported acceptability of screening, and use of resources guides. Data were analyzed using descriptive statistics, chi-square tests, and rapid qualitative analysis. KEY RESULTS: Of 268 Veterans screened, 50% reported one or more HRSNs. Social isolation was endorsed most frequently (29%), followed by educational needs (19%), interpersonal violence (12%), housing instability (9%), and utility concerns (7%). One in five Veterans reported at least one form of material hardship. In follow-up interviews (n = 15), Veterans found screening acceptable and felt VA should continue screening. No Veterans interviewed had contacted recommended resources at two-week follow-up, although several planned to use resource guides in the future. CONCLUSION: In a VA HRSN screening and referral program, Veterans frequently reported HRSNs, felt screening was important, and thought VA should continue to screen for these needs. Screening for HRSNs is a critical step towards connecting patients with services, identifying gaps in service delivery, and informing future resource allocation.

Cooking behaviours after Diabetes Prevention Program (DPP) participation among DPP participants in Baltimore, MD.

OBJECTIVE: The Diabetes Prevention Program (DPP) is a widely implemented 12-month behavioural weight loss programme for individuals with prediabetes. The DPP covers nutrition but does not explicitly incorporate cooking skills education. The objective of the current study is to describe food and cooking skills (FACS) and strategies of recent DPP participants. DESIGN: Photo-elicitation in-depth interviews were conducted from June to August, 2021. SETTING: Baltimore, MD, USA. PARTICIPANTS: Thirteen Black women who participated in DPP. RESULTS: The DPP curriculum influenced participants' healthy cooking practices. Many participants reported shifting from frying foods to air-frying and baking foods to promote healthier cooking and more efficient meal preparation. Participants also reported that their participation in DPP made them more mindful of consuming fruits and vegetables and avoiding foods high in carbohydrates, fats, sugars and Na. With respect to food skills, participants reported that they were more attentive to reading labels and packaging on foods and assessing the quality of ingredients when grocery shopping. CONCLUSIONS: Overall, participants reported changing their food preferences, shopping practices and cooking strategies to promote healthier eating after completing the DPP. Incorporating hands-on cooking skills and practices into the DPP curriculum may support sustained behaviour change to manage prediabetes and prevent development of type 2 diabetes among participants.

The synthetic cathinone 3,4-methylenedioxypyrovalerone increases impulsive action in rats.

A previous study from our laboratory has shown that the selective catecholamine reuptake inhibitor 3,4-methylenedioxypyrovalerone (MDPV) persistently alters impulsive choice as measured by delay discounting. To further understand the proimpulsive effects of MDPV, we examined its capacity to modulate a different impulsive measure - impulsive action - using a differential reinforcement of low rates of responding task with an inter-response time of 20 s. Three groups of male, Sprague-Dawley rats (n = 6) were first tested in daily sessions to understand the acute effects of cocaine (1.0-30.0 mg/kg), MDPV (0.1-3.0 mg/kg), or saline (1.0 ml/kg) on impulsive action. Both cocaine and MDPV increased impulsive action, most notably by decreasing timing error responses and response efficiency, but MDPV was more effective than cocaine. Additionally, MDPV suppressed operant responding in two of six animals at the highest dose tested. Next, the same animals received 10 postsession injections, once every other day, of either 30.0 mg/kg cocaine, 3.0 mg/kg MDPV, or 1.0 ml/kg saline based on their treatment group. An acute dose-effect redetermination was completed following the repeated administration studies, and once again MDPV and cocaine demonstrated proimpulsive effects. Interestingly, timing error responses were decreased in both MDPV and cocaine groups after an acute saline injection, potentially indicating persistent impulsive changes following the repeated administration phase of the experiment. These studies indicate that MDPV increases impulsive action acutely and that this increase may be potentiated following a series of repeated administrations.

Arkansas community's attitudes toward the regulation of medical cannabis and the pharmacist's involvement in Arkansas medical cannabis.

OBJECTIVES: This study explored the attitudes of the Arkansas community toward medical cannabis (MC) regulation and the role of pharmacists in dispensing MC before the product became available and examined whether participants' demographics (e.g., age, gender) and characteristics (e.g., history of cannabis use) were associated with these attitudes. DESIGN: Cross-sectional survey. SETTING AND PARTICIPANTS: Using social media, a university research registry, and posted flyers, we invited residents of Arkansas to participate in the self-administered online survey study during a 3-month period, February to April, in 2018. OUTCOME MEASURES: Five questions that inquired about participants' attitudes toward MC regulation and pharmacists' roles regarding MC use. RESULTS: Participants (n = 1343) who completed at least 1 of the 5 questions were included. The majority were aged 40-64 years (52.2%), female (69.1%), and white (88.7%). Most participants reported a history of cannabis use (81.8%) and possession or intention to apply for an MC card (52.9%). Among the conditions approved for MC use, pain (20.3%), arthritis (15.4%), and posttraumatic stress disorder (14.5%) were reported frequently. Likewise, prescription use for mood disorders (46.1%) and pain (37.4%) were also reported. In multivariable regression analyses, participants' history of cannabis use was associated with a preference for lesser oversight of MC, disagreement with MC being available through a pharmacy only, and disagreement on whether MC should be regulated before it is legalized for recreational use (all P < 0.001). It was also associated with a decrease in agreement that pharmacists are well-trained to improve patient safety (P < 0.001) and counsel patients regarding appropriate MC use (P = 0.032). CONCLUSION: Participants who had previously used cannabis were in favor of fewer restrictions and negatively perceived pharmacists' involvement in ensuring appropriate dispensing and MC use. The findings may highlight the need for Arkansas pharmacists to explore alternative ways to promote the safe and proper MC use.

In Utero Exposure to Norbuprenorphine, a Major Metabolite of Buprenorphine, Induces Fetal Opioid Dependence and Leads to Neonatal Opioid Withdrawal Syndrome.

Buprenorphine is the preferred treatment of opioid use disorder during pregnancy but can cause fetal opioid dependence and neonatal opioid withdrawal syndrome (NOWS). Notably, withdrawal severity is independent of maternal buprenorphine dose, suggesting that interindividual variance in pharmacokinetics may influence risk and severity of NOWS. Using a rat model of NOWS, we tested the hypothesis that clinically relevant doses of the active metabolite norbuprenorphine (NorBUP) can induce in utero opioid dependence, manifested as naltrexone-precipitated withdrawal signs in the neonate. Pregnant Long-Evans rats were implanted with 14-day osmotic minipumps containing vehicle, morphine (positive control), or NorBUP (0.3-10 mg/kg per day) on gestation day 9. By 12 hours post-delivery, an intraperitoneal injection of the opioid antagonist naltrexone (1 or 10 mg/kg) or saline was administered to pups. Precipitated withdrawal signs were graded by raters blinded to treatment conditions. In a separate group, NorBUP concentrations in maternal and fetal blood and brain on gestation day 20 were determined by liquid chromatography-tandem mass spectrometry. Steady-state maternal blood concentrations of NorBUP in dams infused with 1 or 3 mg/kg per day were comparable to values reported in pregnant humans treated with buprenorphine (1.0 and 9.6 ng/ml, respectively), suggesting a clinically relevant dosing regimen. At these doses, NorBUP increased withdrawal severity in the neonate as shown by an evaluation of 10 withdrawal indicators. These findings support the possibility that NorBUP contributes to fetal opioid dependence and NOWS following maternal buprenorphine treatment during pregnancy.

Repeated administration of synthetic cathinone 3,4-methylenedioxypyrovalerone persistently increases impulsive choice in rats.

3,4-Methylenedioxypyrovalerone (MDPV) is a selective catecholamine reuptake inhibitor abused for its psychostimulant properties. This study examined if MDPV administration alters impulsive choice measured by delay discounting in rats. Three groups of rats were tested in daily delay discounting sessions to determine the effects of acute cocaine (1.0-30.0 mg/kg), MDPV (0.1-3.0 mg/kg), or saline on mean adjusted delay (MAD). Dose-dependent decreases in MAD were elicited only by acute MDPV, which also suppressed operant responding at the highest dose. Next, rats received post-session injections (30.0 mg/kg cocaine, 3.0 mg/kg MDPV, or saline) every other day for a total of 10 injections. MAD increased during saline treatment, did not change during cocaine treatment, and was reduced during MDPV treatment. In dose-effect re-determinations, no acute drug effects on MAD were observed, but compared to the initial dose-effect determination, MDPV suppressed operant responding in more animals, with zero animals completing trials at the highest dose. All saline and MDPV-treated subjects were sacrificed, and striatal and cortical dopamine levels were quantified by HPLC. These studies indicate that administration of MDPV may increase impulsive choice acutely and persistently. These proimpulsive effects are possibly mediated by increases in striatal dopamine turnover.

Engineering Biomaterials to Influence Oligodendroglial Growth, Maturation, and Myelin Production.

Millions of people suffer from damage or disease to the nervous system that results in a loss of myelin, such as through a spinal cord injury or multiple sclerosis. Diminished myelin levels lead to further cell death in which unmyelinated neurons die. In the central nervous system, a loss of myelin is especially detrimental because of its poor ability to regenerate. Cell therapies such as stem or precursor cell injection have been investigated as stem cells are able to grow and differentiate into the damaged cells; however, stem cell injection alone has been unsuccessful in many areas of neural regeneration. Therefore, researchers have begun exploring combined therapies with biomaterials that promote cell growth and differentiation while localizing cells in the injured area. The regrowth of myelinating oligodendrocytes from neural stem cells through a biomaterials approach may prove to be a beneficial strategy following the onset of demyelination. This article reviews recent advancements in biomaterial strategies for the differentiation of neural stem cells into oligodendrocytes, and presents new data indicating appropriate properties for oligodendrocyte precursor cell growth. In some cases, an increase in oligodendrocyte differentiation alongside neurons is further highlighted for functional improvements where the biomaterial was then tested for increased myelination both in vitro and in vivo.

Acute pancreatitis following granulosa cell tumor removal in a mare.

Acute pancreatitis is a rare disease in horses and is often associated with gastrointestinal disorders. Accurate diagnosis is challenging due to the presence of nonspecific clinical signs. This case represents the first documentation of acute pancreatitis in a horse following surgery of the reproductive tract.

Pancréatite aiguë consécutive à l'enlèvement d'une tumeur de la granulosa chez une jument. La pancréatite aiguë est une maladie rare chez les chevaux et est souvent associée aux troubles gastro-intestinaux. Un diagnostic exact est difficile en raison de la présence de signes cliniques non spécifiques. Ce cas représente la première fois qu'une pancréatite aiguë est documentée chez un cheval après la chirurgie de l'appareil reproducteur.(Traduit par Isabelle Vallières).

Variation in identifying children and adolescents with disability and developmental disability in population-based public health surveys.

BACKGROUND: The term "developmental disability" (DD) is inconsistently defined and applied depending on purpose and across sources, including in legislation. OBJECTIVE: This project aimed to identify existing definitions of disability and DD and to determine the extent to which each definition could be operationalized to produce prevalence estimates using data from U.S. national surveys. METHODS: Using data among children <18 years from the 2016-2018 National Health Interview Survey (NHIS) and National Survey of Children's Health (NSCH), we estimated the prevalence of two definitions of disability (Washington Group Short Set on Functioning, American Community Survey) and seven definitions of DD [Health and Human Services (ever/current), Developmental Disabilities Assistance and Bill of Rights Act of 2000 (1+, 2+, or 3+ components), and Diagnostic and Statistical Manual of Mental Disorders, 5th ed (ever/current)]. Complex sample design variables and weights were used to calculate nationally representative prevalence. RESULTS: Disability (NHIS: 5.2-6.3%; NSCH: 9.2-11.9%) and DD prevalence (NHIS: 0.6-18.0% and NSCH: 0.2-22.2%) varied depending on the definition and data source. For the same definition, NSCH prevalence estimates tended to be higher than NHIS estimates. CONCLUSIONS: The substantial variability in estimated prevalence of disability and DD among children in the United States may be in part due to the surveys not representing all components of each definition. Different or additional questions in national surveys may better capture existing definitions of disability and DD. Considering the data collection goals may help determine the optimal definition to provide useful information for public health action.

Addressing Veteran Health-Related Social Needs: How Joint Commission Standards Accelerated Integration and Expansion of Tools and Services in the Veterans Health Administration.

BACKGROUND: The Joint Commission recently named reduction of health care disparities and improvement of health care equity as quality and safety priorities (Leadership [LD] Standard LD.04.03.08 and National Patient Safety Goal [NPSG] Standard NPSG.16.01.01). As the largest integrated health system, the Veterans Health Administration (VHA) sought to leverage these new accreditation standards to further integrate and expand existing tools and initiatives to reduce health care disparities and address health-related social needs (HRSNs). INITIATIVES AND TOOLS: A combination of existing data tools (for example, Primary Care Equity Dashboard), resource tools (for example, Assessing Circumstances and Offering Resources for Needs tool), and a care delivery approach (for example, Whole Health) are discussed as quality improvement opportunities to further integrate and expand how VHA addresses health care disparities and HRSNs. The authors detail the development timeline, building, limitations, and future plans for these tools and initiatives. COORDINATION OF INITIATIVES: Responding to new health care equity Joint Commission standards led to new implementation strategies and deeper partnerships across VHA that facilitated expanded dissemination, technical assistance activities, and additional resources for VHA facilities to meet new standards and improve health care equity for veterans. Health care systems may learn from VHA's experiences, which include building actionable data platforms, employing user-centered design for initiative development and iteration, designing wide-reaching dissemination strategies for tools, and recognizing the importance of providing technical assistance for stakeholders. FUTURE DIRECTIONS: VHA continues to expand implementation of a diverse set of tools and resources to reduce health care disparities and identify and address unmet individual veteran HRSNs more widely and effectively.

Health-care organization characteristics in cancer care delivery: an integrated conceptual framework with content validation.

Context can influence cancer-related outcomes. For example, health-care organization characteristics, including ownership, leadership, and culture, can affect care access, communication, and patient outcomes. Health-care organization characteristics and other contextual factors can also influence whether and how clinical discoveries reduce cancer incidence, morbidity, and mortality. Importantly, policy, market, and technology changes are transforming health-care organization design, culture, and operations across the cancer continuum. Consequently, research is essential to examine when, for whom, and how organizational characteristics influence person-level, organization-level, and population-level cancer outcomes. Understanding organizational characteristics-the structures, processes, and other features of entities involved in health care delivery-and their dynamics is an important yet understudied area of care delivery research across the cancer continuum. Research incorporating organizational characteristics is critical to address health inequities, test care delivery models, adapt interventions, and strengthen implementation. The field lacks conceptual grounding, however, to help researchers identify germane organizational characteristics. We propose a framework identifying organizational characteristics relevant for cancer care delivery research based on conceptual work in health services, organizational behavior, and management science and refined using a systematic review and key informant input. The proposed framework is a tool for organizing existing research and enhancing future cancer care delivery research. Following a 2012 Journal of the National Cancer Institute monograph, this work complements National Cancer Institute efforts to stimulate research addressing the relationship between cancer outcomes and contextual factors at the patient, provider, team, delivery organization, community, and health policy levels.

Building Tailored Resource Guides to Address Social Risks and Advance Health Equity in the Veterans Health Administration.

Background: Health care organizations, including the Veterans Health Administration (VHA), are increasingly adopting programs to address social determinants of health. As part of a comprehensive social risk screening and referral model, tailored resource guides can support efforts to address unmet social needs. However, limited guidance is available on best practices for the development of resource guides in health care settings. Observations: This article describes the development of geographically tailored resource guides for a national VHA quality improvement initiative, Assessing Circumstances and Offering Resources for Needs (ACORN), which aims to systematically screen for and address social needs among veterans. We outline the rationale for using resource guides as a social needs intervention and provide a pragmatic framework for resource guide development and maintenance. We offer guidance based on lessons learned from the development of ACORN resource guides, emphasizing a collaborative approach with VHA social workers and other frontline clinical staff, as well as with community-based organizations. Our how-to guide provides steps for identifying high-yield resources along with formatting considerations to maximize accessibility and usability among patients. Conclusions: Resource guides can serve as a valuable cross-cutting component of health care organizations' efforts to address social needs. We provide a practical approach to resource guide development that may support successful implementation within the VHA and other clinical settings.

Developing a brief assessment of social risks for the Veterans Health Administration Survey of Healthcare Experiences of Patients.

OBJECTIVE: To determine whether a 6- or 12-month look-back period affected rates of reported social risks in a social risk survey for use in the Veterans Health Administration and to assess associations of social risks with overall health and mental health. STUDY DESIGN: Cross-sectional survey of respondents randomized to 6- or 12-month look-back period. DATA SOURCES AND STUDY SETTING: Online survey with a convenience sample of Veterans in June and July 2021. DATA COLLECTION/EXTRACTION METHODS: Veteran volunteers were recruited by email to complete a survey assessing social risks, including financial strain, adult caregiving, childcare, food insecurity, housing, transportation, internet access, loneliness/isolation, stress, discrimination, and legal issues. Outcomes included self-reported overall health and mental health. Chi-squared tests compared the prevalence of reported social risks between 6- and 12-month look-back periods. Spearman correlations assessed associations among social risks. Bivariate and multivariable logistic regression models estimated associations between social risks and fair/poor overall and mental health. PRINCIPAL FINDINGS: Of 3418 Veterans contacted, 1063 (31.10%) responded (87.11% male; 85.61% non-Hispanic White; median age = 70, interquartile range [IQR] = 61-74). Prevalence of most reported social risks did not significantly differ by look-back period. Most social risks were weakly intercorrelated (median |r| = 0.24, IQR = 0.16-0.31). Except for legal issues, all social risks were associated with higher odds of fair/poor overall health and mental health in bivariate models. In models containing all significant social risks from bivariate models, adult caregiving and stress remained significant predictors of overall health; food insecurity, housing, loneliness/isolation, and stress remained significant for mental health. CONCLUSIONS: Six- and 12-month look-back periods yielded similar rates of reported social risks. Although most individual social risks are associated with fair/poor overall and mental health, when examined together, only adult caregiving, stress, loneliness/isolation, food, and housing remain significant.

Assessing an electronic self-report method for improving quality of ethnicity and race data in the Veterans Health Administration.

Objective: Evaluate self-reported electronic screening (eScreening) in a VA Transition Care Management Program (TCM) to improve the accuracy and completeness of administrative ethnicity and race data. Materials and Methods: We compared missing, declined, and complete (neither missing nor declined) rates between (1) TCM-eScreening (ethnicity and race entered into electronic tablet directly by patient using eScreening), (2) TCM-EHR (Veteran-completed paper form plus interview, data entered by staff), and (3) Standard-EHR (multiple processes, data entered by staff). The TCM-eScreening (n = 7113) and TCM-EHR groups (n = 7113) included post-9/11 Veterans. Standard-EHR Veterans included all non-TCM Gulf War and post-9/11 Veterans at VA San Diego (n = 92 921). Results: Ethnicity: TCM-eScreening had lower rates of missingness than TCM-EHR and Standard-EHR (3.0% vs 5.3% and 8.6%, respectively, P < .05), but higher rates of "decline to answer" (7% vs 0.5% and 1.2%, P < .05). TCM-EHR had higher data completeness than TCM-eScreening and Standard-EHR (94.2% vs 90% and 90.2%, respectively, P < .05). Race: No differences between TCM-eScreening and TCM-EHR for missingness (3.5% vs 3.4%, P > .05) or data completeness (89.9% vs 91%, P > .05). Both had better data completeness than Standard-EHR (P < .05), which despite the lowest rate of "decline to answer" (3%) had the highest missingness (10.3%) and lowest overall completeness (86.6%). There was strong agreement between TCM-eScreening and TCM-EHR for ethnicity (Kappa = .92) and for Asian, Black, and White Veteran race (Kappas = .87 to .97), but lower agreement for American Indian/Alaska Native (Kappa = .59) and Native Hawaiian/Other Pacific Islander (Kappa = .50) Veterans. Conculsions: eScreening is a promising method for improving ethnicity and race data accuracy and completeness in VA.

Increased migration and motility in XIAP-null cells mediated by the C-RAF protein kinase.

The product encoded by the X-linked inhibitor of apoptosis (XIAP) gene is a multi-functional protein which not only controls caspase-dependent cell death, but also participates in inflammatory signalling, copper homeostasis, response to hypoxia and control of cell migration. Deregulation of XIAP, either by elevated expression or inherited genetic deletion, is associated with several human disease states. Reconciling XIAP-dependent signalling pathways with its role in disease progression is essential to understand how XIAP promotes the progression of human pathologies. In this study we have created a panel of genetically modified XIAP-null cell lines using TALENs and CRISPR/Cas9 to investigate the functional outcome of XIAP deletion. Surprisingly, in our genetically modified cells XIAP deletion had no effect on programmed cell death, but instead the primary phenotype we observed was a profound increase in cell migration rates. Furthermore, we found that XIAP-dependent suppression of cell migration was dependent on XIAPdependent control of C-RAF levels, a protein kinase which controls cell signalling pathways that regulate the cytoskeleton. These results suggest that XIAP is not necessary for control of the apoptotic signalling cascade, however it does have a critical role in controlling cell migration and motility that cannot be compensated for in XIAP-knockout cells.

Metabolites of Synthetic Cannabinoid 5F-MDMB-PINACA Retain Affinity, Act as High Efficacy Agonists and Exhibit Atypical Pharmacodynamic Properties at CB1 Receptors.

Synthetic cannabinoid receptor agonists (SCRAs) are a large group of abused psychoactive compounds that elicit numerous toxic effects not observed with cannabis, including death. Abuse of third-generation SCRA 5F-MDMB-PINACA (also known as 5F-ADB) has been associated with over 40 fatalities. This SCRA is metabolized to several active phase I metabolites, including excessively high post-mortem serum concentrations of an ester hydrolysis metabolite, 5F-MDMB-PINACA-M7 (M7). Although high serum concentrations of M7 (and other active metabolites) have been suggested to contribute to 5F-MDMB-PINACA toxicity, the affinity of M7 for CB1 receptors is unknown and more complete pharmacodynamic characterization of 5F-MDMB-PINACA and its active metabolites is needed. Competition binding and G-protein modulation studies presented here confirm reports that 5F-MDMB-PINACA and a second N-5-hydroxypentyl metabolite (M2) exhibit nM affinity and act as high efficacy agonists at CB1 receptors. Also as previously published, M7 exhibits high efficacy at CB1 receptors; however, demonstrated here for the first time, M7 retains only low µΜ affinity. Empirically derived Kb values indicate rimonabant differentially antagonizes G-protein activation produced by 5F-MDMB-PINACA, relative to Δ9-THC (THC) or its metabolites. Chronic administration of 5F-MDMB-PINACA and metabolites results in CB1 down-regulation, but only 5F-MDMB-PINACA produces desensitization. Although low CB1 affinity/potency of M7 precluded in vivo studies, both M2 and THC produce locomotor suppression and CB1-mediated dose-dependent hypothermia and analgesia in mice. Collectively, these data confirm and extend previous studies suggesting that 5F-MDMB-PINACA is metabolized to active compounds exhibiting atypical pharmacodynamic properties at CB1 receptors, that may accumulate with parent drug to produce severe toxicity.

Adaptation of a social risk screening and referral initiative across clinical populations, settings, and contexts in the Department of Veterans Affairs Health System.

Identifying and addressing social risks and social needs in healthcare settings is an important step towards achieving health equity. Assessing Circumstances and Offering Resources for Needs (ACORN) is a Department of Veterans Affairs (VA) social risk screening and referral model that aims to systematically identify and address social needs. Since initial piloting in 2018, our team has collaborated with clinical and operations partners to implement ACORN across multiple VA clinical settings while adapting and tailoring the initiative to meet the needs of different populations, specialties, and individuals administering screening. Given ACORN's complexity as a growing initiative with multiple partners and frequent real-time modifications within a large national healthcare system, we recognized a need to systematically document the rationale and process of adaptations over time. We looked to three implementation frameworks-RE-AIM, the Adaptome, and FRAME-to describe the rationale for adaptations, the nature of and context within which adaptations were made, and the details of each adaptation. In this manuscript, we uniquely interweave these three frameworks to document adaptations to ACORN across diverse VA clinical settings, with a focus on how adaptations support the promotion of heath equity in the Veteran population.

Influence of Supraphysiologic Biomaterial Stiffness on Ventricular Mechanics and Myocardial Infarct Reinforcement.

Injectable intramyocardial biomaterials have promise to limit adverse ventricular remodeling through mechanical and biologic mechanisms. While some success has been observed by injecting materials to regenerate new tissue, optimal biomaterial stiffness to thicken and stiffen infarcted myocardium to limit adverse remodeling has not been determined. In this work, we present an in-vivo study of the impact of biomaterial stiffness over a wide range of stiffness moduli on ventricular mechanics. We utilized injectable methacrylated polyethylene glycol (PEG) hydrogels fabricated at 3 different mechanical moduli: 5 kPa (low), 25 kPa (medium/myocardium), and 250 kPa (high/supraphysiologic). We demonstrate that the supraphysiological high stiffness favorably alters post-infarct ventricular mechanics and prevents negative tissue remodeling. Lower stiffness materials do not alter mechanics and thus to be effective, must instead target biological reparative mechanisms. These results may influence rationale design criteria for biomaterials developed for infarct reinforcement therapy. STATEMENT OF SIGNIFICANCE: Acellular biomaterials for cardiac application can provide benefit via mechanical and biological mechanisms post myocardial infarction. We study the role of biomaterial mechanical characteristics on ventricular mechanics in myocardial infarcts. Previous studies have not measured the influence of injected biomaterials on ventricular mechanics, and consequently rational design criteria is unknown. By utilizing an in-vivo assessment of ventricular mechanics, we demonstrate that low stiffness biomaterial do not alter pathologic ventricular mechanics. Thus, to be effective, low stiffness biomaterials must target biological reparative mechanisms. Physiologic and supra-physiologic biomaterials favorably alter post-infarct mechanics and prevents adverse ventricular remodeling.

Quantitative microbial risk assessment associated with ready-to-eat salads following the application of farmyard manure and slurry or anaerobic digestate to arable lands.

Farmyard manure and slurry (FYM&S) and anaerobic digestate are potentially valuable soil conditioners providing important nutrients for plant development and growth. However, these organic fertilisers may pose a microbial health risk to humans. A quantitative microbial risk assessment (QMRA) model was developed to investigate the potential human exposure to pathogens following the application of FYM&S and digestate to agricultural land. The farm-to-fork probabilistic model investigated the fate of microbial indicators (total coliforms and enterococci) and foodborne pathogens in the soil with potential contamination of ready-to-eat salads (RTEs) at the point of human consumption. The processes examined included pathogen inactivation during mesophilic anaerobic digestion (M-AD), post-AD pasteurisation, storage, dilution while spreading, decay in soil, post-harvest washing processes, and finally, the potential growth of the pathogen during refrigeration/storage at the retail level in the Irish context. The QMRA highlighted a very low annual probability of risk (Pannual) due to Clostridium perfringens, norovirus, and Salmonella Newport across all scenarios. Mycobacterium avium may result in a very high mean Pannual for the application of raw FYM&S, while Cryptosporidium parvum and pathogenic E. coli showed high Pannual, and Listeria monocytogenes displayed moderate Pannual for raw FYM&S application. The use of AD reduces this risk; however, pasteurisation reduces the Pannual to an even greater extent posing a very low risk. An overall sensitivity analysis revealed that mesophilic-AD's inactivation effect is the most sensitive parameter of the QMRA, followed by storage and the decay on the field (all negatively correlated to risk estimate). The information generated from this model can help to inform guidelines for policymakers on the maximum permissible indicator or pathogen contamination levels in the digestate. The QMRA can also provide the AD industry with a safety assessment of pathogenic organisms resulting from the digestion of FYM&S.