Evaluating a psychological support service focused on the needs of critical care and theatres staff in the first wave of COVID-19.

BACKGROUND: In response to COVID-19, the authors used clinical psychology resources from their hospital's Pain Medicine Department to provide direct support to critical areas. AIMS: The degree to which the service met the needs of staff and managers between March and August 2020 was evaluated. METHODS: A total of 51 staff were referred. Most were nurses (43%), followed by theatre practitioners (36%), healthcare assistants (9%), consultants (8%), administrative (2%) and support staff (2%). Working status, reason for referral and presenting difficulties at first appointment and outcome were recorded. Staff were sent an anonymous survey following intervention. FINDINGS: Staff reported high rates of burnout, anxiety and low mood, with 22% experiencing exacerbation of pre-existing mental health problems. All staff reported benefit from the intervention and managers provided positive feedback. CONCLUSION: Establishing a supportive service that included psychology benefited both staff and managers at the peak of the pandemic. Recommendations are provided.

Blood phenylalanine reduction reverses gene expression changes observed in a mouse model of phenylketonuria.

Phenylketonuria (PKU) is a genetic deficiency of phenylalanine hydroxylase (PAH) in liver resulting in blood phenylalanine (Phe) elevation and neurotoxicity. A pegylated phenylalanine ammonia lyase (PEG-PAL) metabolizing Phe into cinnamic acid was recently approved as treatment for PKU patients. A potentially one-time rAAV-based delivery of PAH gene into liver to convert Phe into tyrosine (Tyr), a normal way of Phe metabolism, has now also entered the clinic. To understand differences between these two Phe lowering strategies, we evaluated PAH and PAL expression in livers of PAHenu2 mice on brain and liver functions. Both lowered brain Phe and increased neurotransmitter levels and corrected animal behavior. However, PAL delivery required dose optimization, did not elevate brain Tyr levels and resulted in an immune response. The effect of hyperphenylalanemia on liver functions in PKU mice was assessed by transcriptome and proteomic analyses. We observed an elevation in Cyp4a10/14 proteins involved in lipid metabolism and upregulation of genes involved in cholesterol biosynthesis. Majority of the gene expression changes were corrected by PAH and PAL delivery though the role of these changes in PKU pathology is currently unclear. Taken together, here we show that blood Phe lowering strategy using PAH or PAL corrects both brain pathology as well as previously unknown lipid metabolism associated pathway changes in liver.

Local delivery of mRNA-encoded cytokines promotes antitumor immunity and tumor eradication across multiple preclinical tumor models.

Local immunotherapy ideally stimulates immune responses against tumors while avoiding toxicities associated with systemic administration. Current strategies for tumor-targeted, gene-based delivery, however, are limited by adverse effects such as off-targeting or antivector immunity. We investigated the intratumoral administration of saline-formulated messenger (m)RNA encoding four cytokines that were identified as mediators of tumor regression across different tumor models: interleukin-12 (IL-12) single chain, interferon-α (IFN-α), granulocyte-macrophage colony-stimulating factor, and IL-15 sushi. Effective antitumor activity of these cytokines relied on multiple immune cell populations and was accompanied by intratumoral IFN-γ induction, systemic antigen-specific T cell expansion, increased granzyme B+ T cell infiltration, and formation of immune memory. Antitumor activity extended beyond the treated lesions and inhibited growth of distant tumors and disseminated tumors. Combining the mRNAs with immunomodulatory antibodies enhanced antitumor responses in both injected and uninjected tumors, thus improving survival and tumor regression. Consequently, clinical testing of this cytokine-encoding mRNA mixture is now underway.

An experimental model of anti-PD-1 resistance exhibits activation of TGFß and Notch pathways and is sensitive to local mRNA immunotherapy.

Immune checkpoint blockade elicits durable anti-cancer responses in the clinic, however a large proportion of patients do not benefit from treatment. Several mechanisms of innate and acquired resistance to checkpoint blockade have been defined and include mutations of MHC I and IFNγ signaling pathways. However, such mutations occur in a low frequency of patients and additional mechanisms have yet to be elucidated. In an effort to better understand acquired resistance to checkpoint blockade, we generated a mouse tumor model exhibiting in vivo resistance to anti-PD-1 antibody treatment. MC38 tumors acquired resistance to PD-1 blockade following serial in vivo passaging. Lack of sensitivity to PD-1 blockade was not attributed to dysregulation of PD-L1 or ß2M expression, as both were expressed at similar levels in parental and resistant cells. Similarly, IFNγ signaling and antigen processing and presentation pathways were functional in both parental and resistant cell lines. Unbiased gene expression analysis was used to further characterize potential resistance mechanisms. RNA-sequencing revealed substantial differences in global gene expression, with tumors resistant to anti-PD-1 displaying a marked reduction in expression of immune-related genes relative to parental MC38 tumors. Indeed, resistant tumors exhibited reduced immune infiltration across multiple cell types, including T and NK cells. Pathway analysis revealed activation of TGFß and Notch signaling in anti-PD-1 resistant tumors, and activation of these pathways was associated with poorer survival in human cancer patients. While pharmacological inhibition of TGFß and Notch in combination with PD-1 blockade decelerated tumor growth, a local mRNA-based immunotherapy potently induced regression of resistant tumors, resulting in complete tumor remission, and resensitized tumors to treatment with anti-PD-1. Overall, this study describes a novel anti-PD-1 resistant mouse tumor model and underscores the role of two well-defined signaling pathways in response to immune checkpoint blockade. Furthermore, our data highlights the potential of intratumoral mRNA therapy in overcoming acquired resistance to PD-1 blockade.

The voice of detainees in a high security setting on services for people with personality disorder.

BACKGROUND: British government Home and Health Departments have been consulting widely about service development for people with ' dangerous severe personality disorder' (DSPD). There has, however, been no consultation with service users, nor is there any user view literature in this area. METHODS: All people detained in one high security hospital under the legal classification of psychopathic disorder were eligible but those on the admission or intensive care wards were not approached. Views of service were elicited using a purpose designed semi-structured interview. The principal researcher was independent of all clinical teams. Confidentiality about patients' views was assured. AIMS: To establish views on services from one subgroup of people nominated by the government department as having 'DSPD'. RESULTS: Sixty-one of 89 agreed to interview. With security a given, about half expressed a preference for a high security hospital setting, 20% prison and 25% elsewhere, generally medium secure hospitals. Participants most valued caring, understanding and 'experience' among staff. An ideal service was considered to be one within small, domestic living units, providing group and individual therapies. Some found living with people with mental illness difficult, but some specified not wanting segregated units. Views were affected by gender and comorbidity. CONCLUSIONS: As the sample were all in hospital, the emphasis on treatment may reflect a placement bias. All but five participants, however, had had experience of both health and criminal justice services, so were well placed to talk with authority about preferences.