Intranasal Prime-Boost with Spike Vectors Generates Antibody and T-Cell Responses at the Site of SARS-CoV-2 Infection.

BACKGROUND: Long-lived, re-activatable immunity to SARS-CoV-2 and its emerging variants will rely on T cells recognizing conserved regions of viral proteins across strains. Heterologous prime-boost regimens can elicit elevated levels of circulating CD8+ T cells that provide a reservoir of first responders upon viral infection. Although most vaccines are currently delivered intramuscularly (IM), the initial site of infection is the nasal cavity. METHODS: Here, we tested the hypothesis that a heterologous prime and boost vaccine regimen delivered intranasally (IN) will generate improved immune responses locally at the site of virus infection compared to intramuscular vaccine/booster regimens. RESULTS: In a transgenic human ACE2 murine model, both a Spike-expressing single-cycle adenovirus (SC-Ad) and an IFNß safety-enhanced replication-competent Vesicular Stomatitis Virus (VSV) platform generated anti-Spike antibody and T-cell responses that diminished with age. Although SC-Ad-Spike boosted a prime with VSV-Spike-mIFNß, SC-Ad-Spike alone induced maximal levels of IgG, IgA, and CD8+ T-cell responses. CONCLUSIONS: There were significant differences in T-cell responses in spleens compared to lungs, and the intranasal boost was significantly superior to the intramuscular boost in generating sentinel immune effectors at the site of the virus encounter in the lungs. These data show that serious consideration should be given to intranasal boosting with anti-SARS-CoV-2 vaccines.

APOBEC3B expression in 293T viral producer cells drives mutations in chimeric antigen receptors and reduces CAR T cell efficacy.

Chimeric antigen receptor (CAR) T cells are a clinically approved therapy for blood cancers. To produce clinical-grade CAR T cells, a retroviral or lentiviral vector is used to deliver the CAR and associated genes to patient T cells. Apolipoprotein B editing enzyme, catalytic polypeptide 3 (APOBEC3) enzymes are known to be upregulated after transfection and retroviral infection and to deaminate cytidine to uracil in nucleic acids, resulting in cytidine-to-thymine mutations in DNA. Here, we hypothesized that APOBEC3 enzymes, induced during the production of CAR T cells, impact the efficacy of the resulting CAR T cells. We demonstrated that APOBEC3 family member APOBEC3B was upregulated at the RNA and protein levels after transfection of HEK293T cells with plasmids to make lentivirus, and that APOBEC3 signature mutations were present in the CAR construct. APOBEC3B overexpression in HEK293T cells led to further mutations in the resulting CAR T cells, and significantly decreased CAR T cell killing. APOBEC3B knockout in HEK293T cells led to reduced mutations in the CAR construct and significantly increased in CAR T cell killing. These results suggest that generation of CAR-expressing viruses from producer cell lines deficient in genome-modifying proteins such as APOBEC3B could enhance the quality of CAR T cell production.

Smoldering oncolysis by foamy virus carrying CD19 as a CAR target escapes CAR T detection by genomic modification.

Chimeric antigen receptor (CAR) T cells have had limited success against solid tumors. Here, we used an oncolytic foamy virus (oFV) to display a model CAR target antigen (CD19) on tumors in combination with anti-CD19 CAR T cells. We generated oFV-Δbel2 and oFV-bel2 vectors to test the efficiency and stability of viral/CD19 spread. While both viruses conferred equal CAR T killing in vitro, the oFV-Δbel2 virus acquired G-to-A mutations, whereas oFV-bel2 virus had genome deletions. In subcutaneous tumor models in vivo, CAR T cells led to a significant decrease in oFV-specific bioluminescence, confirming clearance of oFV-infected tumor cells. However, the most effective therapy was with high-dose oFV in the absence of CAR T cells, indicating that CAR T clearance of oFV was detrimental. Moreover, in tumors that escaped CAR T cell treatment, resurgent virus contained deletions within the oFV-CD19 transgene, allowing the virus to escape CAR T elimination. Therefore, oFV represents a slow smoldering type of oncolytic virus, whose chronic spread through tumors generates anti-tumor therapy, which is abolished by CAR T therapy. These results suggest that further development of this oncolytic platform, with additional immunotherapeutic arming, may allow for an effective combination of chronic oncolysis.

Measuring the effect of the anti-nerve growth factor antibodies bedinvetmab and frunevetmab on quality of life in dogs and cats with osteoarthritis using a validated health-related quality of life outcome measure: an observational real-world study.

Background: Osteoarthritis causes chronic pain, impaired joint function, decreased mobility and negatively impacts quality of life (QOL). Anti-nerve growth factor antibodies bedinvetmab for dogs and frunevetmab for cats are licensed for the alleviation of osteoarthritis pain but their QOL impact is unreported. Our aim was to determine if these therapeutics improve QOL using a validated health-related QOL measure that generates scores in four domains of QOL-energetic and enthusiastic (E/E), happy and content (H/C), active and comfortable (A/C) and calm and relaxed (C/R)-in the dog and three in the cat-vitality, comfort and emotional wellbeing (EWB). Summary scores for physical wellbeing (PWB) and emotional wellbeing (EWB) for dogs and PWB for cats are calculated from the domain scores. Methods: Animals received bedinvetmab (dogs) at 0.5-1 mg/kg or frunevetmab (cats) at 1-2.8 mg/kg by subcutaneous injection on days 0, 28 and 56 and owners completed QOL assessments within 48 hours of day 0 and on days 14, 28, 56, 63 and 70 using a study-specific app. Results: Assessments were completed by 75 dog and 56 cat owners. By day 14 there was a statistically significant improvement (p ≤ 0.001) in PWB, EWB and all domains except C/R (p = 0.005) in dogs and in all domains and PWB in the cat. Subsequently there was a continued improvement in all domains and summary scores (p ≤ 0.001) except for H/C in the dog and EWB in the cat, which were excluded from the statistical model. The overall improvement in all domain scores in the cat and E/E and A/C in the dog exceeded the previously reported minimum important difference scores for the QOL measure, indicating a clinically significant change. Conclusion: Treatment with bedinvetmab and frunevetmab produced a significant improvement in the QOL of dogs and cats. This latest evidence for the use of these OA pain medications could be helpful in the clinical management of osteoarthritis and post-marketing clinical trials.

Expression of tumor antigens within an oncolytic virus enhances the anti-tumor T cell response.

Although patients benefit from immune checkpoint inhibition (ICI) therapy in a broad variety of tumors, resistance may arise from immune suppressive tumor microenvironments (TME), which is particularly true of hepatocellular carcinoma (HCC). Since oncolytic viruses (OV) can generate a highly immune-infiltrated, inflammatory TME, OVs could potentially restore ICI responsiveness via recruitment, priming, and activation of anti-tumor T cells. Here we find that on the contrary, an oncolytic vesicular stomatitis virus, expressing interferon-ß (VSV-IFNß), antagonizes the effect of anti-PD-L1 therapy in a partially anti-PD-L1-responsive model of HCC. Cytometry by Time of Flight shows that VSV-IFNß expands dominant anti-viral effector CD8 T cells with concomitant relative disappearance of anti-tumor T cell populations, which are the target of anti-PD-L1. However, by expressing a range of HCC tumor antigens within VSV, combination OV and anti-PD-L1 therapeutic benefit could be restored. Our data provide a cautionary message for the use of highly immunogenic viruses as tumor-specific immune-therapeutics by showing that dominant anti-viral T cell responses can inhibit sub-dominant anti-tumor T cell responses. However, through encoding tumor antigens within the virus, oncolytic virotherapy can generate anti-tumor T cell populations upon which immune checkpoint blockade can effectively work.

Development and validation of a quality of life and treatment satisfaction measure in canine osteoarthritis.

Introduction: Canine osteoarthritis (OA) causes pain and mobility impairment. This can reduce dog quality of life (QoL), owner QoL and owners' satisfaction with, and adherence to, treatments. No existing canine OA-specific instrument assesses all three impacts. This study aimed to develop and psychometrically evaluate an owner-completed canine OA-specific measure of dog QoL, owner QoL and owner treatment satisfaction; the "Canine OA Quality of Life and Treatment Satisfaction Questionnaire" (CaOA-QoL-TS). Methods: The CaOA-QoL-TS was developed using a conceptual model derived from a meta-synthesis of published literature followed by cognitive interviews with ten owners of dogs with OA, to evaluate content validity. Results: Based on interview findings, ten items were reworded, four removed, and two added; resulting in 26 items that all owners understood and considered relevant. The recall period and response options were well understood and appropriate to almost all owners. To evaluate its psychometric properties, the CaOA-QoL-TS (draft 26-item version) was administered, across six timepoints in a phase 4 field study, to owners of OA treated dogs, recruited from veterinary practices (N = 93). Inter-item correlations suggested items clustered into three distinct domains: Dog QoL, Owner QoL and Treatment Satisfaction, as hypothesized. Confirmatory factor analysis supported deletion of two items and calculation of the three domain scores, with acceptable model fit. The resulting 24-item CaOA-QoL-TS instrument demonstrated strong internal consistency and good to excellent test-retest reliability. Convergent validity was supported by moderate to strong correlations with concurrent measures. Known groups validity was supported by statistically significant differences between groups categorized by owner global impression of QoL. Ability to detect change was demonstrated through statistically significant improvements over time in Owner and Dog QoL, with larger within-group effect sizes reported for the mean of 'improved' dogs compared to the mean of 'stable' dogs. Only a small sample of dogs worsened throughout the study. Anchor-based analyses supported-0.9 and-1.0-point within-group responder definitions for dog and owner QoL domains, respectively. Discussion: Findings support the content validity of the CaOA-QoL-TS in canine OA. The 24-item CaOA-QoL-TS is a reliable and valid instrument to measure owner and canine QoL and TS and is sensitive to improvements following OA treatment.

Damage to tropical forests caused by cyclones is driven by wind speed but mediated by topographical exposure and tree characteristics.

Each year, an average of 45 tropical cyclones affect coastal areas and potentially impact forests. The proportion of the most intense cyclones has increased over the past four decades and is predicted to continue to do so. Yet, it remains uncertain how topographical exposure and tree characteristics can mediate the damage caused by increasing wind speed. Here, we compiled empirical data on the damage caused by 11 cyclones occurring over the past 40 years, from 74 forest plots representing tropical regions worldwide, encompassing field data for 22,176 trees and 815 species. We reconstructed the wind structure of those tropical cyclones to estimate the maximum sustained wind speed (MSW) and wind direction at the studied plots. Then, we used a causal inference framework combined with Bayesian generalised linear mixed models to understand and quantify the causal effects of MSW, topographical exposure to wind (EXP), tree size (DBH) and species wood density (ρ) on the proportion of damaged trees at the community level, and on the probability of snapping or uprooting at the tree level. The probability of snapping or uprooting at the tree level and, hence, the proportion of damaged trees at the community level, increased with increasing MSW, and with increasing EXP accentuating the damaging effects of cyclones, in particular at higher wind speeds. Higher ρ decreased the probability of snapping and to a lesser extent of uprooting. Larger trees tended to have lower probabilities of snapping but increased probabilities of uprooting. Importantly, the effect of ρ decreasing the probabilities of snapping was more marked for smaller than larger trees and was further accentuated at higher MSW. Our work emphasises how local topography, tree size and species wood density together mediate cyclone damage to tropical forests, facilitating better predictions of the impacts of such disturbances in an increasingly windier world.

Inflammatory and tissue injury marker dynamics in pediatric acute respiratory distress syndrome.

BACKGROUNDThe molecular signature of pediatric acute respiratory distress syndrome (ARDS) is poorly described, and the degree to which hyperinflammation or specific tissue injury contributes to outcomes is unknown. Therefore, we profiled inflammation and tissue injury dynamics over the first 7 days of ARDS, and associated specific biomarkers with mortality, persistent ARDS, and persistent multiple organ dysfunction syndrome (MODS).METHODSIn a single-center prospective cohort of intubated pediatric patients with ARDS, we collected plasma on days 0, 3, and 7. Nineteen biomarkers reflecting inflammation, tissue injury, and damage-associated molecular patterns (DAMPs) were measured. We assessed the relationship between biomarkers and trajectories with mortality, persistent ARDS, or persistent MODS using multivariable mixed effect models.RESULTSIn 279 patients (64 [23%] nonsurvivors), hyperinflammatory cytokines, tissue injury markers, and DAMPs were higher in nonsurvivors. Survivors and nonsurvivors showed different biomarker trajectories. IL-1α, soluble tumor necrosis factor receptor 1, angiopoietin 2 (ANG2), and surfactant protein D increased in nonsurvivors, while DAMPs remained persistently elevated. ANG2 and procollagen type III N-terminal peptide were associated with persistent ARDS, whereas multiple cytokines, tissue injury markers, and DAMPs were associated with persistent MODS. Corticosteroid use did not impact the association of biomarker levels or trajectory with mortality.CONCLUSIONSPediatric ARDS survivors and nonsurvivors had distinct biomarker trajectories, with cytokines, endothelial and alveolar epithelial injury, and DAMPs elevated in nonsurvivors. Mortality markers overlapped with markers associated with persistent MODS, rather than persistent ARDS.FUNDINGNIH (K23HL-136688, R01-HL148054).

'Moving on' for Adults With a Learning Disability and Their Families: A Constructivist Grounded Theory Study.

Ending familial co-residence, termed 'moving on' by participants, is an increasingly relevant life transition for people with a learning disability due to increasing life expectancy and policy developments. Nevertheless, there is an absence of research exploring this transition experience in a United Kingdom (UK) context. This constructivist grounded theory study therefore aimed to explore, conceptualise, and theorise the 'moving on' experiences of adults with a learning disability and their families. This article reports the experiences of five adults with a learning disability and nine family members in England, UK. Narrative interviews and creative storybook methods were used to collect data between April 2015 and May 2016. Constant comparative methods, theoretical sampling, and memo writing were used throughout data collection and analysis. Participants with a learning disability presented personal growth and greater life fulfilment over the course of the transition; they flourished. In parallel, family members relinquished their care responsibilities. Importantly, the iterative and reciprocal relationship between flourishing and relinquishing shows that ongoing family member involvement is crucial during and following relocation. Family members identified factors that potentially inhibit relinquishing: pressure to 'let go', different perceptions of independence between family members and service providers, inadequate future investment, and rapport with professional carers. These novel insights led to the generation of the first known mid-range theory concerning this transition, entitled 'Moving on: flourishing and relinquishing'. Findings will guide future research in this field and facilitate the design of appropriate support for people with a learning disability and their families.

Silvopastoral systems benefit invertebrate biodiversity on tropical livestock farms in Caquetá, Colombia.

In the Colombian Amazon, there has been long-term and sustained loss of primary forest threatening biodiversity and climate change mitigation. Silvopastoral practices that integrate trees into livestock production could help address both local economic and wider environmental challenges.We aimed to assess the effects of silvopastoral practices on invertebrate communities on smallholder farms in Caquetá, Colombia. Using sweep nets and malaise trapping, invertebrate communities were compared between traditional pasture, silvopasture and forest edge habitats.Invertebrate communities collected using sweep nets were contrasting among habitat types, communities were significantly different between traditional pasture and forest edge habitats and diversity and evenness were greatest in forest edges compared to traditional pastures. It appears that silvopasture areas, by supporting similar invertebrate assemblages to both traditional pasture and forest edges, may be acting as an intermediate habitat.When individual invertebrate orders were compared, Lepidoptera and Coleoptera were found in greater abundance in the forest edge habitats, while Hemiptera were more abundant in traditional pasture. Hemipterans are often pests of forage plants in pasture systems and these differences in abundance may have implications for ecosystem services and disservices.Silvopastoral approaches cannot replace the unique biodiversity supported by native forests but could deliver benefits for invertebrate conservation and ecosystem services if integrated into landscapes.

Resumen: En la Amazonía colombiana ha habido una pérdida sostenida y a largo plazo de bosque primario que amenaza la biodiversidad y la mitigación del cambio climático. Las prácticas silvopastoriles que integran los árboles en la producción ganadera podrían ayudar a abordar tanto los desafíos económicos locales como los ambientales.Nuestro objetivo fue evaluar los efectos de las prácticas silvopastoriles en comunidades de invertebrados en pequeñas fincas en Caquetá, Colombia. Las comunidades de invertebrados se compararon entre las pasturas nativas, el sistema silvopastoril y los hábitats del borde del bosque mediante el uso redes entomológicas de barrido y trampas Malaise.Las comunidades de invertebrados recolectadas usando redes entomológicas de barrido contrastaban entre los tipos de hábitat. Las comunidades eran significativamente diferentes entre las pasturas nativas y el borde de bosque. Pareciera que las áreas de silvopastoreo, al soportar conjuntos de invertebrados similares tanto a las pasturas nativas como a los bordes del bosque, pueden estar actuando como un hábitat intermedio.Cuando se compararon los órdenes individuales de invertebrados, los lepidópteros y los coleópteros se encontraron en mayor abundancia en los hábitats del borde del bosque, mientras que los hemípteros eran más abundantes en las pasturas nativas. Los hemípteros son a menudo plagas de plantas forrajeras en sistemas de pastoreo y estas diferencias en abundancia pueden tener implicaciones y perjuicios para los servicios ecosistémicos.Los sistemas silvopastoriles no pueden reemplazar la biodiversidad única apoyada por los bosques nativos, pero podrían ofrecer beneficios para la conservación de invertebrados y los servicios ecosistémicos si se integran en los paisajes.

Transgender and non-binary peoples experiences of cervical cancer screening: A scoping review.

AIM(S): To synthesise the literature about transgender and non-binary people's experiences of cervical cancer screening and identify ways to improve screening. BACKGROUND: Transgender people often face barriers to accessing health services including cervical screening, where transgender people have a lower uptake than cisgender women. DESIGN: A scoping review was undertaken following the Arksey and O'Malley (2005) framework and the PRISMA-ScR checklist. Following database searching of Medline via PubMed, Web of Science, Scopus and CINHAL, 23 papers published between 2008 and 2003 were included. Papers were included if they shared trans and non-binary people's experiences of cervical screening and were written in English. There were no date or geographical data restrictions due to the paucity of research. RESULTS: Transgender people experience barriers to cervical screening including gender dysphoria, a history of sexual trauma, and mistrust in health professionals or health services, which can result in having negative experiences of screening or avoiding screening. Health professionals can help to create a positive experience by informing themselves about best practices for trans+ health. CONCLUSION: Changes are required to improve transgender people's experiences and uptake of cervical screening. Improving medical education about trans health and updating health systems would help to combat issues discussed. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: Having an understanding of the reasons why accessing health services can be more difficult for transgender people will help health professionals to provide appropriate care for transgender patients. This paper details this in the context of cervical cancer screening and can be applied to other areas of healthcare. REPORTING METHOD: We have adhered to relevant EQUATOR guidelines and used the PRISMA-ScR reporting method. No Patient or Public Contribution.

Latitudinal patterns in stabilizing density dependence of forest communities.

Numerous studies have shown reduced performance in plants that are surrounded by neighbours of the same species1,2, a phenomenon known as conspecific negative density dependence (CNDD)3. A long-held ecological hypothesis posits that CNDD is more pronounced in tropical than in temperate forests4,5, which increases community stabilization, species coexistence and the diversity of local tree species6,7. Previous analyses supporting such a latitudinal gradient in CNDD8,9 have suffered from methodological limitations related to the use of static data10-12. Here we present a comprehensive assessment of latitudinal CNDD patterns using dynamic mortality data to estimate species-site-specific CNDD across 23 sites. Averaged across species, we found that stabilizing CNDD was present at all except one site, but that average stabilizing CNDD was not stronger toward the tropics. However, in tropical tree communities, rare and intermediate abundant species experienced stronger stabilizing CNDD than did common species. This pattern was absent in temperate forests, which suggests that CNDD influences species abundances more strongly in tropical forests than it does in temperate ones13. We also found that interspecific variation in CNDD, which might attenuate its stabilizing effect on species diversity14,15, was high but not significantly different across latitudes. Although the consequences of these patterns for latitudinal diversity gradients are difficult to evaluate, we speculate that a more effective regulation of population abundances could translate into greater stabilization of tropical tree communities and thus contribute to the high local diversity of tropical forests.

Tropical tree ectomycorrhiza are distributed independently of soil nutrients.

Mycorrhizae, a form of plant-fungal symbioses, mediate vegetation impacts on ecosystem functioning. Climatic effects on decomposition and soil quality are suggested to drive mycorrhizal distributions, with arbuscular mycorrhizal plants prevailing in low-latitude/high-soil-quality areas and ectomycorrhizal (EcM) plants in high-latitude/low-soil-quality areas. However, these generalizations, based on coarse-resolution data, obscure finer-scale variations and result in high uncertainties in the predicted distributions of mycorrhizal types and their drivers. Using data from 31 lowland tropical forests, both at a coarse scale (mean-plot-level data) and fine scale (20 × 20 metres from a subset of 16 sites), we demonstrate that the distribution and abundance of EcM-associated trees are independent of soil quality. Resource exchange differences among mycorrhizal partners, stemming from diverse evolutionary origins of mycorrhizal fungi, may decouple soil fertility from the advantage provided by mycorrhizal associations. Additionally, distinct historical biogeographies and diversification patterns have led to differences in forest composition and nutrient-acquisition strategies across three major tropical regions. Notably, Africa and Asia's lowland tropical forests have abundant EcM trees, whereas they are relatively scarce in lowland neotropical forests. A greater understanding of the functional biology of mycorrhizal symbiosis is required, especially in the lowland tropics, to overcome biases from assuming similarity to temperate and boreal regions.

Identification of molecular subphenotypes in two cohorts of paediatric ARDS.

BACKGROUND: Two subphenotypes of acute respiratory distress syndrome (ARDS), hypoinflammatory and hyperinflammatory, have been reported in adults and in a single paediatric cohort. The relevance of these subphenotypes in paediatrics requires further investigation. We aimed to identify subphenotypes in two large observational cohorts of paediatric ARDS and assess their congruence with prior descriptions. METHODS: We performed latent class analysis (LCA) separately on two cohorts using biomarkers as inputs. Subphenotypes were compared on clinical characteristics and outcomes. Finally, we assessed overlap with adult cohorts using parsimonious classifiers. FINDINGS: In two cohorts from the Children's Hospital of Philadelphia (n=333) and from a multicentre study based at the University of California San Francisco (n=293), LCA identified two subphenotypes defined by differential elevation of biomarkers reflecting inflammation and endotheliopathy. In both cohorts, hyperinflammatory subjects had greater illness severity, more sepsis and higher mortality (41% and 28% in hyperinflammatory vs 11% and 7% in hypoinflammatory). Both cohorts demonstrated overlap with adult subphenotypes when assessed using parsimonious classifiers. INTERPRETATION: We identified hypoinflammatory and hyperinflammatory subphenotypes of paediatric ARDS from two separate cohorts with utility for prognostic and potentially predictive, enrichment. Future paediatric ARDS trials should identify and leverage biomarker-defined subphenotypes in their analysis.

Chimerization of the Anti-Viral CD8+ T Cell Response with A Broad Anti-Tumor T Cell Response Reverses Inhibition of Checkpoint Blockade Therapy by Oncolytic Virotherapy.

Although immune checkpoint inhibition (ICI) has produced profound survival benefits in a broad variety of tumors, a proportion of patients do not respond. Treatment failure is in part due to immune suppressive tumor microenvironments (TME), which is particularly true of hepatocellular carcinoma (HCC). Since oncolytic viruses (OV) can generate a highly immune-infiltrated, inflammatory TME, we developed a vesicular stomatitis virus expressing interferon-ß (VSV-IFNß) as a viro-immunotherapy against HCC. Since HCC standard of care atezolizumab/bevacizumab incorporates ICI, we tested the hypothesis that pro-inflammatory VSV-IFNß would recruit, prime, and activate anti-tumor T cells, whose activity anti-PD-L1 ICI would potentiate. However, in a partially anti-PD-L1-responsive model of HCC, addition of VSV-IFNß abolished anti-PD-L1 therapy. Cytometry by Time of Flight showed that VSV-IFNß expanded dominant anti-viral effector CD8 T cells with concomitant, relative disappearance of anti-tumor T cell populations which are the target of anti-PD-L1. However, by expressing a range of HCC tumor antigens within VSV, the potent anti-viral response became amalgamated with an anti-tumor T cell response generating highly significant cures compared to anti-PD-L1 ICI alone. Our data provide a cautionary message for the use of highly immunogenic viruses as tumor-specific immune-therapeutics by showing that dominant anti-viral T cell responses can inhibit sub-dominant anti-tumor T cell responses. However, by chimerizing anti-viral and anti-tumor T cell responses through encoding tumor antigens within the virus, oncolytic virotherapy can be purposed for very effective immune driven tumor clearance and can generate anti-tumor T cell populations upon which immune checkpoint blockade can effectively work.

Explanation of context, mechanisms and outcomes in adult community mental health crisis care: the MH-CREST realist evidence synthesis.

Background: Mental health crises cause significant disruption to individuals and families and can be life-threatening. The large number of community crisis services operating in an inter-agency landscape complicates access to help. It is unclear which underpinning mechanisms of crisis care work, for whom and in which circumstances. Aim: The aim was to identify mechanisms to explain how, for whom and in what circumstances adult community crisis services work. Objectives: The objectives were to develop, test and synthesise programme theories via (1) stakeholder expertise and current evidence; (2) a context, intervention, mechanism and outcome framework; (3) consultation with experts; (4) development of pen portraits; (5) synthesis and refinement of programme theories, including mid-range theory; and (6) identification and dissemination of mechanisms needed to trigger desired context-specific crisis outcomes. Design: This study is a realist evidence synthesis, comprising (1) identification of initial programme theories; (2) prioritisation, testing and refinement of programme theories; (3) focused realist reviews of prioritised initial programme theories; and (4) synthesis to mid-range theory. Main outcome: The main outcome was to explain context, mechanisms and outcomes in adult community mental health crisis care. Data sources: Data were sourced via academic and grey literature searches, expert stakeholder group consultations and 20 individual realist interviews with experts. Review methods: A realist evidence synthesis with primary data was conducted to test and refine three initial programme theories: (1) urgent and accessible crisis care, (2) compassionate and therapeutic crisis care and (3) inter-agency working. Results: Community crisis services operate best within an inter-agency system. This requires compassionate leadership and shared values that enable staff to be supported; retain their compassion; and, in turn, facilitate compassionate interventions for people in crisis. The complex interface between agencies is best managed through greater clarity at the boundaries of services, making referral and transition seamless and timely. This would facilitate ease of access and guaranteed responses that are trusted by the communities they serve. Strengths and limitations: Strengths include the identification of mechanisms for effective inter-agency community crisis care and meaningful stakeholder consultation that grounded the theories in real-life experience. Limitations include the evidence being heavily weighted towards England and the review scope excluding full analysis of ethnic and cultural diversity. Conclusions: Multiple interpretations of crises and diverse population needs present challenges for improving the complex pathways to help in a crisis. Inter-agency working requires clear policy guidance with local commissioning. Seamless transitions between services generate trust through guaranteed responses and ease of navigation. This is best achieved where there is inter-agency affiliation that supports co-production. Compassionate leaders engender staff trust, and outcomes for people in crisis improve when staff are supported to retain their compassion. Future work: Further work might explore inter-agency models of crisis delivery, particularly in rural communities. Future work could focus on evaluating outcomes across crisis care provider agencies and include evaluation of individual, as well as service-level, outcomes. The implementation and effect of mental health triage could be explored further, including via telehealth. Barriers to access for marginalised populations warrant a specific focus in future research. Study registration: The study is registered as PROSPERO CRD42019141680. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme and will be published in full in Health and Social Care Delivery Research; Vol. 11, No. 15. See the NIHR Journals Library website for further project information.

A mental health crisis can be traumatic for individuals and families. There are a lot of different agencies delivering crisis care. This can make getting the right help from services difficult, confusing and slow. It is not clear which services work best or who they work best for. This research explored community mental health crisis services for adults. We focused on what is working, who it is working for and in what situations it is working. Service users, carers, mental health professionals and service managers formed an 'expert stakeholder group' to guide the project by helping the researchers make sense of what we learned. We gathered information from research reports, other documents and interviews with experts (i.e. service users, carers, professionals, managers). We focused on three questions: How can services make sure that people in crisis can get the right help, quickly? What makes crisis care compassionate? Does it help if different crisis services work together? Community crisis services are most compassionate and effective when staff from different organisations share information. When leaders of crisis care help staff to work together across services, they find better ways to help people. Close working across teams gives professionals a better understanding of what other services do and makes it easier for them to give people the right help at the right time. When leaders are kind and supportive to staff, they feel better at work and provide better crisis care. It would be useful to explore if the most effective crisis services are the same ones that service users like best. We need to know more about mental health triage, inter-agency working and telehealth. Our project did not explore diversity, but this is an important topic to investigate.

Skeletal Muscle Transcriptome Alterations Related to Declining Physical Function in Older Mice.

One inevitable consequence of aging is the gradual deterioration of physical function and exercise capacity, driven in part by the adverse effect of age on muscle tissue. We hypothesized that relationships exist between age-related differentially expressed genes (DEGs) in skeletal muscle and age-associated declines in physical function and exercise capacity. Previously, male C57BL/6mice (6m, months old, 24m, and 28m) were tested for physical function using a composite scoring system (comprehensive functional assessment battery, CFAB) comprised of five well-validated tests of physical function. In this study, total RNA was isolated from tibialis anterior samples (n = 8) randomly selected from each age group in the parent study. Using Next Generation Sequencing RNAseq to determine DEGs during aging (6m vs. 28m, and 6m vs. 24m), we found a greater than five-fold increase in DEGs in 28m compared to the 24m. Furthermore, regression of the normalized expression of each DEG with the CFAB score of the corresponding mouse revealed many more DEGs strongly associated (R ≥ |0.70|) with functional status in the older mice. Gene ontology results indicate highly enriched axon guidance and acetyl choline receptor gene sets, suggesting that denervation/reinnervation flux might potentially play a critical role in functional decline. We conclude that specific age-related DEG patterns are associated with declines in physical function, and the data suggest accelerated aging occurring between 24 and 28 months.

"Survive, learn to live with it or not": A narrative analysis of women's repeat victimization using a lifecourse perspective.

Violence against women is a global public health concern, with high levels of prevalence and debilitating consequences for victims, including a higher risk of revictimization. Quantitative evidence shows a strong association between previous experiences of sexual victimization, particularly in childhood, and future victimization. However, there is limited rigorous qualitative scholarship that advances understanding about revictimization experienced from childhood into adulthood. In this study, we address this gap offering a novel contribution to qualitative insights on revictimization using a life-course perspective. We conducted a rigorous qualitative secondary analysis, adopting a feminist narrative approach, to explore how individuals make sense of their experiences of abuse. Findings showed five main themes about survivors' experiences of repeat victimization across the life-course including: abuse experiences in childhood and adolescence; mental health and 'risky' coping mechanisms; naming abuse in early adulthood; seeking support in adulthood; surviving and a life beyond abuse. Most participants experienced multiple incidents of sexual abuse in childhood, which led to helplessness, shame, blame, and normalization of their experiences, creating a vulnerability to repeat victimization. Childhood abuse had later mental health impacts. Many participants used risky coping mechanisms, such as substance use. Survivors tended to be seen through the lens of their mental health diagnosis and addiction rather than through the lens of how abuse caused complex trauma. To address the impacts of revictimization and complex trauma affecting women across the globe, healthcare policy and services need a narrative and trauma-informed approach, over the short-, medium- or longer-term, enabling survivors to make sense of the connected nature of their experiences and accumulated vulnerability resulting from the abuse by others, rather than factors associated with the individual (their mental ill health, for example, or substance use). This is important as women's individual understanding is critical to processing trauma and abuse, and to longer-term recovery.

Explaining context, mechanism and outcome in adult community mental health crisis care: A realist evidence synthesis.

Mental health crises cause significant distress and disruption to the lives of individuals and their families. Community crisis care systems are complex, often hard to navigate and poorly understood. This realist evidence synthesis aimed to explain how, for whom and in what circumstances community mental health crisis services for adults work to resolve crises and is reported according to RAMESES guidelines. Using realist methodology, initial programme theories were identified and then tested through iterative evidence searching across 10 electronic databases, four expert stakeholder consultations and n = 20 individual interviews. 45 relevant records informed the three initial programme theories, and 77 documents, were included in programme theory testing. 39 context, mechanism, outcome configurations were meta-synthesized into three themes: (1) The gateway to urgent support; (2) Values based crisis interventions and (3) Leadership and organizational values. Fragmented cross-agency responses exacerbated staff stress and created barriers to access. Services should focus on evaluating interagency working to improve staff role clarity and ensure boundaries between services are planned for. Organizations experienced as compassionate contributed positively to perceived accessibility but relied on compassionate leadership. Attending to the support needs of staff and the proximity of leaders to the front line of crisis care are key. Designing interventions that are easy to navigate, prioritize shared decision-making and reduce the risk of re-traumatizing people is a priority.

Trap and ambush therapy using sequential primary and tumor escape-selective oncolytic viruses.

In multiple models of oncolytic virotherapy, it is common to see an early anti-tumor response followed by recurrence. We have previously shown that frontline treatment with oncolytic VSV-IFN-ß induces APOBEC proteins, promoting the selection of specific mutations that allow tumor escape. Of these mutations in B16 melanoma escape (ESC) cells, a C-T point mutation in the cold shock domain-containing E1 (CSDE1) gene was present at the highest frequency, which could be used to ambush ESC cells by vaccination with the mutant CSDE1 expressed within the virus. Here, we show that the evolution of viral ESC tumor cells harboring the escape-promoting CSDE1C-T mutation can also be exploited by a virological ambush. By sequential delivery of two oncolytic VSVs in vivo, tumors which would otherwise escape VSV-IFN-ß oncolytic virotherapy could be cured. This also facilitated the priming of anti-tumor T cell responses, which could be further exploited using immune checkpoint blockade with the CD200 activation receptor ligand (CD200AR-L) peptide. Our findings here are significant in that they offer the possibility to develop oncolytic viruses as highly specific, escape-targeting viro-immunotherapeutic agents to be used in conjunction with recurrence of tumors following multiple different types of frontline cancer therapies.