Safety and Feasibility of a Fast-Track Pathway for Neurosurgical Craniotomy Patients: Bypassing the Intensive Care Unit.

Objective: To describe the safety and feasibility of a fast-track pathway for neurosurgical craniotomy patients receiving care in a neurosciences progressive care unit (NPCU). Patients and Methods: Traditionally, most craniotomy patients are admitted to the neurosciences intensive care unit (NSICU) for postoperative follow-up. Decreased availability of NSICU beds during the coronavirus disease-2019 delta surge led our team to establish a de-novo NPCU to preserve capacity for patients requiring high level of care and would bypass routine NSICU admissions. Patients were selected a priori by treating neurosurgeons on the basis of the potential need for high-level ICU services. After operation, selected patients were transferred to the postoperative care unit, where suitability for NPCU transfer was reassessed with checklist-criteria. This process was continued after the delta surge. Results: From July 1, 2021 to September 30, 2022, 57 patients followed the NPCU protocol. Thirty-four (59.6%) were women, and the mean age was 56 years. Fifty-seven craniotomies for 34 intra-axial and 23 extra-axial lesions were performed. After assessment and application of the checklist-criteria, 55 (96.5%) were transferred to NPCU, and only 2 (3.5%) were transferred to ICU. All 55 patients followed in NPCU had good safety outcomes without requiring NSICU transfer. This saved $143,000 and led to 55 additional ICU beds for emergent admissions. Conclusion: This fast-track craniotomy protocol provides early experience that a surgeon-selected group of patients may be suitably monitored outside the traditional NSICU. This system has the potential to reduce overall health care expenses, increase capacity for NSICU bed availability, and change the paradigm of NSICU admission.

EBV+ tumors exploit tumor cell-intrinsic and -extrinsic mechanisms to produce regulatory T cell-recruiting chemokines CCL17 and CCL22.

The Epstein-Barr Virus (EBV) is involved in the etiology of multiple hematologic and epithelial human cancers. EBV+ tumors employ multiple immune escape mechanisms, including the recruitment of immunosuppressive regulatory T cells (Treg). Here, we show some EBV+ tumor cells express high levels of the chemokines CCL17 and CCL22 both in vitro and in vivo and that this expression mirrors the expression levels of expression of the EBV LMP1 gene in vitro. Patient samples from lymphoblastic (Hodgkin lymphoma) and epithelial (nasopharyngeal carcinoma; NPC) EBV+ tumors revealed CCL17 and CCL22 expression of both tumor cell-intrinsic and -extrinsic origin, depending on tumor type. NPCs grown as mouse xenografts likewise showed both mechanisms of chemokine production. Single cell RNA-sequencing revealed in vivo tumor cell-intrinsic CCL17 and CCL22 expression combined with expression from infiltrating classical resident and migratory dendritic cells in a CT26 colon cancer mouse tumor engineered to express LMP1. These data suggest that EBV-driven tumors employ dual mechanisms for CCL17 and CCL22 production. Importantly, both in vitro and in vivo Treg migration was effectively blocked by a novel, small molecule antagonist of CCR4, CCR4-351. Antagonism of the CCR4 receptor may thus be an effective means of activating the immune response against a wide spectrum of EBV+ tumors.

Tumors establish resistance to immunotherapy by regulating Treg recruitment via CCR4.

BACKGROUND: Checkpoint inhibitors (CPIs) such as anti-PD(L)-1 and anti-CTLA-4 antibodies have resulted in unprecedented rates of antitumor responses and extension of survival of patients with a variety of cancers. But some patients fail to respond or initially respond but later relapse as they develop resistance to immune therapy. One of the tumor-extrinsic mechanisms for resistance to immune therapy is the accumulation of regulatory T cells (Treg) in tumors. In preclinical and clinical studies, it has been suggested that tumor trafficking of Treg is mediated by CC chemokine receptor 4 (CCR4). Over 90% of human Treg express CCR4 and migrate toward CCL17 and CCL22, two major CCR4 ligands that are either high at baseline or upregulated in tumors on CPI treatment. Hence, CCR4 antagonism has the potential to be an effective antitumor treatment by reducing the accumulation of Treg into the tumor microenvironment (TME). METHODS: We developed in vitro and in vivo models to assess Treg migration and antitumor efficacy using a potent and selective CCR4 antagonist, CCR4-351. We used two separate tumor models, Pan02 and CT26 mouse tumors, that have high and low CCR4 ligand expression, respectively. Tumor growth inhibition as well as the frequency of tumor-infiltrating Treg and effector T cells was assessed following the treatment with CCR4 antagonist alone or in combination with CPI. RESULTS: Using a selective and highly potent, novel small molecule inhibitor of CCR4, we demonstrate that migration of CCR4+ Treg into the tumor drives tumor progression and resistance to CPI treatment. In tumor models with high baseline levels of CCR4 ligands, blockade of CCR4 reduced the number of Treg and enhanced antitumor immune activity. Notably, in tumor models with low baseline level of CCR4 ligands, treatment with immune CPIs resulted in significant increases of CCR4 ligands and Treg numbers. Inhibition of CCR4 reduced Treg frequency and potentiated the antitumor effects of CPIs. CONCLUSION: Taken together, we demonstrate that CCR4-dependent Treg recruitment into the tumor is an important tumor-extrinsic mechanism for immune resistance. Blockade of CCR4 led to reduced frequency of Treg and resulted in increased antitumor activity, supporting the clinical development of CCR4 inhibitors in combination with CPI for the treatment of cancer. STATEMENT OF SIGNIFICANCE: CPI upregulates CCL17 and CCL22 expression in tumors and increases Treg migration into the TME. Pharmacological antagonism of the CCR4 receptor effectively inhibits Treg recruitment and results in enhanced antitumor efficacy either as single agent in CCR4 ligandhigh tumors or in combination with CPIs in CCR4 ligandlow tumors.

Novel, Selective Inhibitors of USP7 Uncover Multiple Mechanisms of Antitumor Activity In Vitro and In Vivo.

The deubiquitinase USP7 regulates the levels of multiple proteins with roles in cancer progression and immune response. Thus, USP7 inhibition may decrease oncogene function, increase tumor suppressor function, and sensitize tumors to DNA-damaging agents. We have discovered a novel chemical series that potently and selectively inhibits USP7 in biochemical and cellular assays. Our inhibitors reduce the viability of multiple TP53 wild-type cell lines, including several hematologic cancer and MYCN-amplified neuroblastoma cell lines, as well as a subset of TP53-mutant cell lines in vitro Our work suggests that USP7 inhibitors upregulate transcription of genes normally silenced by the epigenetic repressor complex, polycomb repressive complex 2 (PRC2), and potentiate the activity of PIM and PI3K inhibitors as well as DNA-damaging agents. Furthermore, oral administration of USP7 inhibitors inhibits MM.1S (multiple myeloma; TP53 wild type) and H526 (small cell lung cancer; TP53 mutant) tumor growth in vivo Our work confirms that USP7 is a promising, pharmacologically tractable target for the treatment of cancer.

Co-creation of the Safewards Model in a Forensic Mental Health Care Facility.

Violence and aggression are highly complex problems in mental health care facilities; thus, multi-faceted conflict-reduction strategies are required to mitigate and reduce violence. Safewards is an evidence-informed model aimed at preventing events that have the capacity to trigger aggression and violence. Effectiveness studies of the implementation of Safewards have shown mixed results, including that implementation strategies failed to engage staff and fidelity was low. The objective of this study was to examine the effectiveness of implementing the Safewards model with an approach that embedded co-creation principles in the staff training. Overall, results showed high staff engagement. The average rate of attendance at the classroom-based, staff champion training (n = 108) was 79% (SD = 23). Additionally, online training modules were available to all staff and were completed by 238 of 259 forensic program staff (92%). Overall, staff perceived co-creation to be a positive strategy; staff liked being asked to be involved in the planning, felt that their voices were heard, and believed that it contributed to the success of the Safewards implementation. This study showed that the inclusion of co-creation principles in the implementation strategy enhanced staff adherence to the Safewards model as demonstrated by the high fidelity scores, and effectively led to increased buy-in and engagement of staff.

CCR4 Antagonists Inhibit Treg Trafficking into the Tumor Microenvironment.

Recruitment of naturally occurring suppressive CD4+, CD25+, and FOXP3+ regulatory T cells (Treg) to the tumor microenvironment (TME) has the potential to weaken the antitumor response in patients receiving treatment with immuno-oncology (IO) agents. Human Treg express CCR4 and can be recruited to the TME through the C-C chemokines CCL17 and CCL22. We have recently developed a series of potent, orally bioavailable small molecule antagonists of CCR4 that can block recruitment of Treg into the TME.

The assessment of dynamic risk among forensic psychiatric patients transitioning to the community.

Individuals with serious mental illness (SMI; i.e., psychotic or major mood disorders) are vulnerable to experiencing multiple forms of adverse safety events in community settings, including violence perpetration and victimization. This study investigates the predictive validity and clinical utility of modifiable risk factors for violence in a sample of 87 forensic psychiatric patients found Not Criminally Responsible on Account of Mental Disorder (NCRMD) transitioning to the community. Using a repeated-measures prospective design, we assessed theoretically based dynamic risk factors (e.g., insight, psychiatric symptoms, negative affect, treatment compliance) before hospital discharge, and at 1 and 6 months postdischarge. Adverse outcomes relevant to this population (e.g., violence, victimization, hospital readmission) were measured at each community follow-up, and at 12 months postdischarge. The base rate of violence (23%) was similar to prior studies of discharged psychiatric patients, but results also highlighted elevated rates of victimization (29%) and hospital readmission (28%) characterizing this sample. Many of the dynamic risk indicators exhibited significant change across time and this change was related to clinically relevant outcomes. Specifically, while controlling for baseline level of risk, fluctuations in dynamic risk factors predicted the likelihood of violence and hospital readmission most consistently (hazard ratios [HR] = 1.35-1.84). Results provide direct support for the utility of dynamic factors in the assessment of violence risk and other adverse community outcomes, and emphasize the importance of incorporating time-sensitive methodologies into predictive models examining dynamic risk. (PsycINFO Database Record

A front line police perspective of mental health issues and services.

BACKGROUND: Changes in mental health service provision in most western countries have been associated with an increasing role of the police in the community management of people with mental health problems, but little is known about how the police perceive this in the UK. OBJECTIVES: To investigate police officers' views on their roles in dealings with people with mental health problems and with mental health services. METHODS: Nine in-depth semi-structured interviews were conducted with front line police officers. These interviews were analysed for recurrent themes using interpretative phenomenological analysis. RESULTS: The recurrent themes identified were: emotional aspects of dealing with people with mental health problems and with services, impact of incidents on police resources and on people with mental health problems, success through collaborative working with health services and failure in its absence. CONCLUSIONS: Police officers' experiences of work with people with mental disorder in the community in Scotland had much in common with those previously reported in the USA and in Australia. Development of more collaborative approaches and mutual respect between the police and mental health service providers would resolve many of the currently perceived difficulties.

Significant gene content variation characterizes the genomes of inbred mouse strains.

The contribution to genetic diversity of genomic segmental copy number variations (CNVs) is less well understood than that of single-nucleotide polymorphisms (SNPs). While less frequent than SNPs, CNVs have greater potential to affect phenotype. In this study, we have performed the most comprehensive survey to date of CNVs in mice, analyzing the genomes of 42 Mouse Phenome Consortium priority strains. This microarray comparative genomic hybridization (CGH)-based analysis has identified 2094 putative CNVs, with an average of 10 Mb of DNA in 51 CNVs when individual mouse strains were compared to the reference strain C57BL/6J. This amount of variation results in gene content that can differ by hundreds of genes between strains. These genes include members of large families such as the major histocompatibility and pheromone receptor genes, but there are also many singleton genes including genes with expected phenotypic consequences from their deletion or amplification. Using a whole-genome association analysis, we demonstrate that complex multigenic phenotypes, such as food intake, can be associated with specific copy number changes.

Barriers to effective drug addiction treatment for women involved in street-level prostitution: a qualitative investigation.

OBJECTIVES: To examine barriers to effective drug addiction treatment for women involved in street-level prostitution. METHODS: A qualitative approach was selected to enable a detailed exploration, in an informal and unthreatening manner, of the barriers to drug addiction treatment from the women's perspective. Nine in-depth interviews were conducted with women who were involved in street-level prostitution. Transcripts of one-to-one interviews were analysed for recurrent themes using Interpretative Phenomenological Analysis. RESULTS: Barriers to effective addiction treatment are present at psychological, interpersonal, and wider societal levels. Themes identified included: an impoverished sense of self-worth, a lack of trust and consistency in treatment, and the absence of a comprehensive treatment package. CONCLUSION: Current services could be improved by the provision of a structured treatment programme designed to target the specific physical and psychological requirements of this population. Also, efforts to correct the fictitious, negative portrayals of women involved in prostitution are required, if treatment efficacy is to be improved.

Increased lysosomal uptake of methotrexate-polyglutamates in two methotrexate-resistant cell lines with distinct mechanisms of resistance.

Methotrexate (MTX) resistance in mitoxantrone-selected MCF7/MX cells and in MTX-selected CEM/MTX cells is associated with reduced drug accumulation, albeit caused by different mechanisms. In addition, in both resistant cell lines the proportion of active long-chain MTX-polyglutamate (MTX-PG) metabolites is reduced relative to that in the respective parental cell line. Previous studies by others have implied that increased lysosomal uptake could affect the rate of MTX-PG hydrolysis, and hence the length distribution of the polyglutamate chains. However, in the two cell line pairs studied, the number of lysosomes per cell was not different between the corresponding parental and resistant cells. Instead, we observed a two- to three-fold increased facilitative uptake of MTX-Glu4 by the lysosomes from these two independently derived MTX-resistant cell lines, compared to uptake by lysosomes from their corresponding parental cells. Enhanced lysosomal uptake of MTX-Glu4 was reflected in an increased maximal uptake velocity, without a change in the apparent substrate affinity. In addition, the rate of MTX efflux from lysosomes from CEM/MTX cells was two-fold faster than from lysosomes from CEM cells. Consistent with this observation, the relative amount of short-chain MTX-Glu(1+2) species, as a fraction of the total amount of all MTX-Glu(1-4) species combined, was only half as large in lysosomes from CEM/MTX cells as in lysosomes from CEM cells. Together, these results suggest the possibility that increased lysosomal uptake, and hence enhanced sequestration of MTX-PGs in resistant cells, contributes to the development of high-level MTX resistance by decreasing the cytosolic levels of MTX-PGs.

Protective factors for youth considered at risk of criminal behaviour: does participation in extracurricular activities help?

BACKGROUND: There is a lack of research investigating the potential protective effect of participation in extracurricular activities on youth who are at risk of engaging in delinquent activity. AIM: This study examined the potential for participation in extracurricular activities to act as a protective factor for youth deemed at risk of engaging in delinquent activity. METHOD: One hundred and sixty-nine secondary students from Glasgow, Scotland completed two questionnaires (the Youth Self-Report and an additional information sheet) requesting information about their participation in extracurricular and delinquent activities as well as their possible risk factors. Activities included sports, non-sports (hobbies and games), current activities (youth clubs and other organisations) and previous involvement in activities. Risk factors included residing in a broken home, having four or more siblings, academic failure and lacking a non-parental very important person. Delinquent activities included rule-breaking and aggressive behaviours. RESULTS: Independent samples t-tests found that females participated in significantly more non-sports and previous activities than males and that males participated in significantly more rule-breaking behaviour than females. Hierarchical multiple regression analyses found that gender and participation in sports were strong predictors of rule-breaking behaviour. A significant positive correlation was found between participation in sports and involvement in aggressive behaviour. CONCLUSION: The results suggest that participation in extracurricular activities does not act as a protective factor for youth, regardless of whether or not they are considered to be at risk of engaging in delinquent activity. The significant correlation found between participation in sports and involvement in aggressive behaviour suggests that youth participation in sports may act as a risk factor.

A potent and selective nonpeptide antagonist of CXCR2 inhibits acute and chronic models of arthritis in the rabbit.

Much evidence implicates IL-8 as a major mediator of inflammation and joint destruction in rheumatoid arthritis. The effects of IL-8 and its related ligands are mediated via two receptors, CXCR1 and CXCR2. In the present study, we demonstrate that a potent and selective nonpeptide antagonist of human CXCR2 potently inhibits (125)I-labeled human IL-8 binding to, and human IL-8-induced calcium mobilization mediated by, rabbit CXCR2 (IC(50) = 40.5 and 7.7 nM, respectively), but not rabbit CXCR1 (IC(50) = >1000 and 2200 nM, respectively). These data suggest that the rabbit is an appropriate species in which to examine the anti-inflammatory effects of a human CXCR2-selective antagonist. In two acute models of arthritis in the rabbit induced by knee joint injection of human IL-8 or LPS, and a chronic Ag (OVA)-induced arthritis model, administration of the antagonist at 25 mg/kg by mouth twice a day significantly reduced synovial fluid neutrophils, monocytes, and lymphocytes. In addition, in the more robust LPS- and OVA-induced arthritis models, which were characterized by increased levels of proinflammatory mediators in the synovial fluid, TNF-alpha, IL-8, PGE(2), leukotriene B(4), and leukotriene C(4) levels were significantly reduced, as was erythrocyte sedimentation rate, possibly as a result of the observed decreases in serum TNF-alpha and IL-8 levels. In vitro, the antagonist potently inhibited human IL-8-induced chemotaxis of rabbit neutrophils (IC(50) = 0.75 nM), suggesting that inhibition of leukocyte migration into the knee joint is a likely mechanism by which the CXCR2 antagonist modulates disease.

The identification and characterization of the marine natural product scytonemin as a novel antiproliferative pharmacophore.

Marine natural products provide a rich source of chemical diversity that can be used to design and develop new, potentially useful therapeutic agents. We report here that scytonemin, a pigment isolated from cyanobacteria, is the first described small molecule inhibitor of human polo-like kinase, a serine/threonine kinase that plays an integral role in regulating the G(2)/M transition in the cell cycle. Scytonemin inhibited polo-like kinase 1 activity in a concentration-dependent manner with an IC(50) of 2 microM against the recombinant enzyme. Biochemical analysis showed that scytonemin reduced GST-polo-like kinase 1 activity in a time-independent fashion, suggesting reversibility, and with a mixed-competition mechanism with respect to ATP. Although scytonemin was less potent against protein kinase A and Tie2, a tyrosine kinase, it did inhibit other cell cycle-regulatory kinases like Myt1, checkpoint kinase 1, cyclin-dependent kinase 1/cyclin B, and protein kinase Cbeta2 with IC(50) values similar to that seen for polo-like kinase 1. Consistent with these effects, scytonemin effectively attenuated, without chemical toxicity, the growth factor- or mitogen-induced proliferation of three cell types commonly implicated in inflammatory hyperproliferation. Similarly, scytonemin (up to 10 microM) was not cytotoxic to nonproliferating endotoxin-stimulated human monocytes. In addition, Jurkat T cells treated with scytonemin were induced to undergo apoptosis in a non-cell cycle-dependent manner consistent with its activities on multiple kinases. Here we propose that scytonemin's dimeric structure, unique among natural products, may be a valuable template for the development of more potent and selective kinase inhibitors used for the treatment of hyperproliferative disorders.