Adapting IAPT services to support frontline NHS staff during the Covid-19 pandemic: the Homerton Covid Psychological Support (HCPS) pathway.

The Coronavirus (Covid-19) pandemic is exerting unprecedented pressure on NHS Health and Social Care provisions, with frontline staff, such as those of critical care units, encountering vast practical and emotional challenges on a daily basis. Although staff are being supported through organisational provisions, facilitated by those in leadership roles, the emergence of mental health difficulties or the exacerbation of existing ones amongst these members of staff is a cause for concern. Acknowledging this, academics and healthcare professionals alike are calling for psychological support for frontline staff, which not only addresses distress during the initial phases of the outbreak but also over the months, if not years, that follow. Fortunately, mental health services and psychology professional bodies across the United Kingdom have issued guidance to meet these needs. An attempt has been made to translate these sets of guidance into clinical provisions via the recently established Homerton Covid Psychological Support (HCPS) pathway delivered by Talk Changes (Hackney & City IAPT). This article describes the phased, stepped-care and evidence-based approach that has been adopted by the service to support local frontline NHS staff. We wish to share our service design and pathway of care with other Improving Access to Psychological Therapies (IAPT) services who may also seek to support hospital frontline staff within their associated NHS Trusts and in doing so, lay the foundations of a coordinated response. KEY LEARNING AIMS: (1)To understand the ways staff can be psychologically and emotionally impacted by working on the frontline of disease outbreaks.(2)To understand the ways in which IAPT services have previously supported populations exposed to crises.(3)To learn ways of delivering psychological support and interventions during a pandemic context based on existing guidance and research.

Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model.

BACKGROUND: The pan-histone deacetylase inhibitor panobinostat is a potential therapy for malignant glioma, but it is water insoluble and does not cross the blood-brain barrier when administered systemically. In this article, we describe the in vitro and in vivo efficacy of a novel water-soluble nano-micellar formulation of panobinostat designed for administration by convection enhanced delivery (CED). MATERIALS AND METHODS: The in vitro efficacy of panobinostat-loaded nano-micelles against rat F98, human U87-MG and M059K glioma cells and against patient-derived glioma stem cells was measured using a cell viability assay. Nano-micelle distribution in rat brain was analyzed following acute CED using rhodamine-labeled nano-micelles, and toxicity was assayed using immunofluorescent microscopy and synaptophysin enzyme-linked immunosorbent assay. We compared the survival of the bioluminescent syngenic F98/Fischer344 rat glioblastoma model treated by acute CED of panobinostat-loaded nano-micelles with that of untreated and vehicle-only-treated controls. RESULTS: Nano-micellar panobinostat is cytotoxic to rat and human glioma cells in vitro in a dose-dependent manner following short-time exposure to drug. Fluorescent rhodamine-labelled nano-micelles distribute with a volume of infusion/volume of distribution (Vi/Vd) ratio of four and five respectively after administration by CED. Administration was not associated with any toxicity when compared to controls. CED of panobinostat-loaded nano-micelles was associated with significantly improved survival when compared to controls (n=8 per group; log-rank test, P<0.001). One hundred percent of treated animals survived the 60-day experimental period and had tumour response on post-mortem histological examination. CONCLUSION: CED of nano-micellar panobinostat represents a potential novel therapeutic option for malignant glioma and warrants translation into the clinic.

Integrative mRNA profiling comparing cultured primary cells with clinical samples reveals PLK1 and C20orf20 as therapeutic targets in cutaneous squamous cell carcinoma.

Identifying therapeutic targets for cancer treatment relies on consistent changes within particular types or sub-types of malignancy. The ability to define either consistent changes or sub-types of malignancy is often masked by tumor heterogeneity. To elucidate therapeutic targets in cutaneous squamous cell carcinoma (cSCC), the most frequent skin neoplasm with malignant potential, we have developed an integrated approach to gene expression profiling beginning with primary keratinocytes in culture. Candidate drivers of cSCC development were derived by first defining a set of in vitro cancer genes and then comparing their expression in a range of clinical data sets containing normal skin, cSCC and the benign hyper-proliferative condition psoriasis. A small interfering RNA (siRNA) screen of the resulting 21 upregulated genes has yielded targets capable of reducing xenograft tumor volume in vivo. Small-molecule inhibitors for one target, Polo-like kinase-1 (PLK1), are already in clinical trials for other malignancies, and our data show efficacy in cSCC. Another target, C20orf20, is identified as being overexpressed in cSCC, and siRNA-mediated knockdown induces apoptosis in vitro and reduces tumor growth in vivo. Thus, our approach has shown established and uncharacterized drivers of tumorigenesis with potent efficacy as therapeutic targets for the treatment of cSCC.

Rapid, femtomolar bioassays in complex matrices combining microfluidics and magnetoelectronics.

A significant challenge for all biosensor systems is to achieve high assay sensitivity and specificity while minimizing sample preparation requirements, operational complexity, and sample-to-answer time. We have achieved multiplexed, unamplified, femtomolar detection of both DNA and proteins in complex matrices (including whole blood, serum, plasma, and milk) in minutes using as few as two reagents by labeling conventional assay schemes with micrometer-scale magnetic beads, and applying fluidic force discrimination (FFD). In FFD assays, analytes captured onto a microarray surface are labeled with microbeads, and a controlled laminar flow is then used to apply microfluidic forces sufficient to preferentially remove only nonspecifically bound bead labels. The density of beads that remain bound is proportional to the analyte concentration and can be determined with either optical counting or magnetoelectronic detection of the magnetic labels. Combining FFD assays with chip-based magnetoelectronic detection enables a simple, potentially handheld, platform capable of both nucleic acid hybridization assays and immunoassays, including orthogonal detection and identification of bacterial and viral pathogens, and therefore suitable for a wide range of biosensing applications.

Heparan sulphate synthetic and editing enzymes in ovarian cancer.

Several angiogenic growth factors including fibroblast growth factors 1 and 2 (FGF1 and FGF2) depend on heparan sulphate (HS) for biological activity. We previously showed that all cellular elements in ovarian tumour tissue synthesised HS but biologically active HS (i.e. HS capable of binding FGF2 and its receptor) was confined to ovarian tumour endothelium. In this study, we have sought to explain this observation. Heparan sulphate sulphotransferases 1 and 2 (HS6ST1 and HS6ST2) attach sulphate groups to C-6 of glucosamine residues in HS that are critical for FGF2 activation. These enzymes were strongly expressed by tumour cells, but only HS6ST1 was found in endothelial cells. Immunostaining with the 3G10 antibody of tissue sections pretreated with heparinases indicated that HS proteoglycans were produced by tumour and endothelial cells. These results indicated that, in contrast to the endothelium, HS produced by tumour cells may be modified by cell-surface heparanase (HPA1) or endosulphatase (SULF). Protein and RNA analysis revealed that HPA1 was strongly expressed by ovarian tumour cells in eight of ten specimens examined. HSULF-1, which removes specific 6-O-sulphate groups from HS, was abundant in tumour cells but weakly expressed in the endothelium. If this enzyme was responsible for the lack of biologically active HS on the tumour cell surface, we would expect exogenous FGF2 binding to be preserved; we showed previously that this was indeed the case although FGF2 binding was reduced compared to the endothelium and stroma. Thus, the combined effects of heparanase and HSULF could account for the lack of biologically active HS in tumour cells rather than deficiencies in the biosynthetic enzymes.

The lobster shaw gene: cloning, sequence analysis and comparison to fly shaw.

We cloned and sequenced the cDNA for the shaw gene, encoding a voltage-dependent potassium (K+) channel, from the spiny lobster, Panulirus interruptus. The deduced amino acid sequence has a high degree of homology to the Drosophila melanogaster Shaw protein. In addition, lobster Shaw has several putative sites for post-translational modifications.

Lobster shal: comparison with Drosophila shal and native potassium currents in identified neurons.

The transient potassium (K+) current, or A-current (IA), plays an essential role in shaping the firing properties of identified neurons in the 14-cell pyloric network in the stomatogastric ganglion of the spiny lobster, Panulirus interruptus. The different cells in the pyloric network have distinct IAs. To begin to understand the molecular basis for IA heterogeneity, we examined the relationship between the Panulirus shal current, the IAs in the lateral pyloric (LP) and pyloric dilator (PY) cells, and the Drosophila shal current. After isolating a complete open reading frame for lobster shal 1, which shows significant sequence homology to the fly, mouse, and rat shal homologs, we used a single-cell reverse transcription polymerase chain reaction method to demonstrate that the shal 1 gene was expressed in the LP and PY cells. Next, we compared the lobster shal 1 current generated in a Xenopus oocyte expression system to the IAs in the LP and PY neurons as well as to the Drosophila shal current in Xenopus oocytes. While the transient K+ lobster shal 1 current was similar to the IAs in pyloric neurons, a detailed comparison shows that they are not identical and differ in kinetic and voltage-dependent parameters. The highly homologous lobster and fly shal genes also produce currents with some significant similarities and differences in an oocyte expression system.

RT-PCR analysis of shaker, shab, shaw, and shal gene expression in single neurons and glial cells.

We have developed a reverse transcription-polymerase chain reaction (RT-PCR) method to examine single neurons and glial cells in the stomatogastric ganglion of the spiny lobster Panulirus interruptus for the expression of four members of the Shaker family of potassium channel genes. Using this technique we found that shaker, shab, shaw, and shal are expressed in 100%, 78%, 100%, and 94% of stomatogastric neurons. Furthermore, neuronal shab, shaw, and shal transcript levels vary among cells in a manner which is independent of cell size. We also detected Shaker family gene expression in glial cells. Shaker, shaw, and shal are detectably expressed in 100%, 63%, and 100% of the glial caps examined, respectively, while shab gene expression could not be detected in glial cells.

Shab gene expression in identified neurons of the pyloric network in the lobster stomatogastric ganglion.

A single shab gene exists in the lobster, Panulirus interruptus, and undergoes alternate splicing to produce multiple transcripts. Using in situ hybridization we have determined the expression pattern of the shab gene in identified neurons of the pyloric network. The shab gene is consistently expressed at a low level in the Ventricular Dilator cell, a high level in the Pyloric Dilator cell, and is not detectably expressed in the Lateral Pyloric or Inferior Cardiac cells. Shab gene expression in the Anterior Burster cell varies from animal to animal. The electrophysiologically heterogeneous group of eight Pyloric Constrictor cells also shows differences in shab gene expression. These results support the idea that differences in shab gene expression contribute to the unique electrophysiological phenotypes displayed by each cell type.

Self-management training of mentally retarded adults presenting severe conduct difficulties.

Chronic and clinically significant conduct difficulties of mildly and moderately mentally retarded adults in a vocational setting were reduced with a multicomponent self-management package. Skills of self-monitoring, self-evaluation, self-consequation, and self-instruction were trained and practiced in vivo. Positive effects on behaviors not specifically treated also were noted for some subjects. A combined treatment withdrawal and multiple baseline design was used to assess changes. Nine-month follow-up under different work conditions revealed continued maintenance of treatment gains.

Self-management of disruptive verbal ruminations by a mentally retarded adult.

Chronic and high-rate disruptive verbal ruminations of a mentally retarded adult in a vocational training setting were successfully reduced following introduction of a multi-component, self-management intervention program. Self-management skills of self-monitoring, self-evaluation, self-consequation, and self-instruction were trained and then practiced in vivo. In addition to influencing the specific dependent disruptive rumination behaviors targeted for intervention, three collateral behaviors not specifically treated showed positive effects. A combined treatment withdrawal and modified changing criterion design was used to assess changes throughout phases of the study. Follow-up data obtained 6 months and again 12 months after termination of the program revealed durability of intervention effects. The practical, conceptual, and philosophic significance of these findings are noted.

Mate swapping: Perceptions, value orientations, and participation in a midwestern community.

This article attempts to illuminate the understanding of swinging, or mate swapping, an increasingly common form of extramarital sexual activity. A theoretical formulation argues that swinging is a form of extramarital sexual activity which serves to define as good and acceptable a behavior that in other forms and in the past has been considered deviant or immoral. A stratified area probability sample of 579 married adults was drawn from a Midwestern community of 40,000. Areas investigated included community knowledge and perception of swinging, values of respondents with regard to participation in and acceptance of swinging, and the incidence of swinging in the community. Most respondents dispproved of mate swapping as well as other forms of extramarital sex. Over half of the respondents knew about mate swapping, although less than 7% of the sample would consider participating. Swinging was found to exist in the community, but less than 2% of the respondents had ever participted. The data analysis is descriptive and exploratory, focusing on social correlates and characterisitics.