Pre-existing skin-resident CD8 and gd T cell circuits mediate immune response in Merkel cell carcinoma and predict immunotherapy efficacy.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with a ~50% response rate to immune checkpoint blockade (ICB) therapy. To identify predictive biomarkers, we integrated bulk and single-cell RNA-seq with spatial transcriptomics from a cohort of 186 samples from 116 patients, including bulk RNA-seq from 14 matched pairs pre- and post-ICB. In non-responders, tumors show evidence of increased tumor proliferation, neuronal stem cell markers, and IL-1. Responders have increased type I/II interferons and pre-existing tissue resident (Trm) CD8 or Vd1 gd T cells that functionally converge with overlapping antigen-specific transcriptional programs and clonal expansion of public TCRs. Spatial transcriptomics demonstrated co-localization of T cells with B and dendritic cells, which supply chemokines and co-stimulation. Lastly, ICB significantly increased clonal expansion or recruitment of Trm and Vd1 cells in tumors specifically in responders, underscoring their therapeutic importance. These data identify potential clinically actionable biomarkers and therapeutic targets for MCC.

Genomic Analysis of Aspergillus Section Terrei Reveals a High Potential in Secondary Metabolite Production and Plant Biomass Degradation.

Aspergillus terreus has attracted interest due to its application in industrial biotechnology, particularly for the production of itaconic acid and bioactive secondary metabolites. As related species also seem to possess a prosperous secondary metabolism, they are of high interest for genome mining and exploitation. Here, we present draft genome sequences for six species from Aspergillus section Terrei and one species from Aspergillus section Nidulantes. Whole-genome phylogeny confirmed that section Terrei is monophyletic. Genome analyses identified between 70 and 108 key secondary metabolism genes in each of the genomes of section Terrei, the highest rate found in the genus Aspergillus so far. The respective enzymes fall into 167 distinct families with most of them corresponding to potentially unique compounds or compound families. Moreover, 53% of the families were only found in a single species, which supports the suitability of species from section Terrei for further genome mining. Intriguingly, this analysis, combined with heterologous gene expression and metabolite identification, suggested that species from section Terrei use a strategy for UV protection different to other species from the genus Aspergillus. Section Terrei contains a complete plant polysaccharide degrading potential and an even higher cellulolytic potential than other Aspergilli, possibly facilitating additional applications for these species in biotechnology.

Prospective investigation of amino acid transport and PSMA-targeted positron emission tomography for metastatic lobular breast carcinoma.

PURPOSE: To explore the feasibility of imaging amino-acid transport and PSMA molecular pathways in the detection of metastatic breast invasive lobular carcinoma (ILC) and if there is superior detection compared to standard-of-care imaging [computed tomography (CT)/bone scan, or 18F-FDG positron-emission-tomography (PET)-CT]. METHODS: 20 women with de-novo or suspected metastatic ILC underwent two PET-CT scans with 18F-fluciclovine and 68Ga-PSMA-11 on separate days. Uptake per patient and in 3 regions per patient - ipsilateral axillary lymph node (LN), extra-axillary LN (ipsilateral supraclavicular or internal mammary), or distant sites of disease - was compared to standard-of-care imaging (CT/bone scan in 13 patients and 18F-FDG PET-CT in 7 patients). Results were correlated to a composite standard of truth. Confirmed detection rate (cDR) was compared using McNemar's test. Mean SUVmax of 18F-fluciclovine and 68Ga-PSMA-11 in the most avid lesion for each true positive metastatic region and intact primary lesion were compared by t-test. RESULTS: The cDR for standard-of-care imaging was 5/20 patients in 5/60 regions. 68Ga-PSMA-11 PET-CT detected metastasis in 7/20 patients in 7/60 regions. 18F-fluciclovine PET-CT detected metastasis in 9/20 patients in 12/60 regions. The cDR for 18F-fluciclovine PET-CT was significantly higher versus standard-of-care imaging on the patient and combined region levels, while there were no significant differences between 68Ga-PSMA-11 and standard-of care imaging. 18F-fluciclovine cDR was also significantly higher than 68Ga-PSMA-11 on the combined region level. Mean SUVmax for true positive metastatic and primary lesions with 18F-fluciclovine (n = 18) was significantly greater than for 68Ga-PSMA-11 (n = 11) [5.5 ± 1.8 versus 3.5 ± 2.7 respectively, p = 0.021]. CONCLUSION: In this exploratory trial, 18F-fluciclovine PET-CT has a significantly higher cDR for ILC metastases compared to standard-of-care imaging and to 68Ga-PSMA-11. Mean SUVmax for true positive malignancy was significantly higher with 18F-fluciclovine than for 68Ga-PSMA-11. Exploratory data from this trial suggests that molecular imaging of amino acid metabolism in patients with ILC deserves further study. CLINICAL TRIAL REGISTRATION: Early phase (I-II) clinical trial (NCT04750473) funded by the National Institutes of Health (R21CA256280).

Experience of care from the perspectives of inpatients with palliative care needs: a cross-sectional study using a patient reported experience measure (PREM).

BACKGROUND: Improving palliative care for inpatients is urgently needed. Data from patient-reported experience measures (PREM) can assist in identifying areas for focused improvement. This study aimed to describe patient reported experience of care in inpatients with palliative care needs, to inform a baseline understanding of care experience and identify key areas for improvement. METHODS: Cross-sectional study design where inpatients with palliative care needs were invited to complete 'consideRATE,' a patient reported experience measure of care, over six months in 2022. Inpatients with palliative care needs receiving care on an oncology, general medicine/renal and general medicine/respiratory ward (n = 3) at an Australian metropolitan hospital were screened for eligibility. Carers could provide proxy responses where inpatients were unable to participate. Descriptive statistics were used to analyse quantitative ratings, whilst free text responses were analysed using integrated thematic analysis. RESULTS: One-hundred and twenty participants (108 patients and 12 carers) completed consideRATE. The questions with the highest number of 'very good' responses were attention to symptoms, attention to feelings and attention to what matters most; the questions with the lowest number of 'very good' responses was attention to patients' affairs, what to expect, and the environment of care. Almost half (n = 57, 48%) indicated that attention to patients' affairs 'did not apply' to their inpatient stay. Analysis of 532 free text responses across 8 questions highlighted the importance of feeling supported, feeling informed, feeling heard and navigating the clinical environment. CONCLUSION: Enabling inpatients with palliative care needs to provide feedback about their experience of care is one method of ensuring improvements matter to patients. Supporting clinical teams to understand and use these data to make tailored improvements is the next step in this multi-phase research.

The impact of hindsight bias on the diagnosis of perioperative events by anesthesia providers: A multicenter randomized crossover study.

STUDY OBJECTIVE: Hindsight bias is the tendency to overestimate the predictability of an event after it has already occurred. We aimed to evaluate whether hindsight bias influences the retrospective interpretation of clinical scenarios in the field of anesthesiology, which relies on clinicians making rapid decisions in the setting of perioperative adverse events. DESIGN: Two clinical scenarios were developed (intraoperative hypotension and intraoperative hypoxia) with 3 potential diagnoses for each. Participants completed a crossover study reviewing one case without being informed of the supposed ultimate diagnosis (i.e., no 'anchor' diagnosis), referred to as their foresight case, and the other as a hindsight case wherein they were informed in the leading sentence of the scenario that 1 of the 3 conditions provided was the ultimate diagnosis (i.e., the diagnosis the participant might 'anchor' to if given this information at the start). Participants were randomly assigned to (1) which scenario (hypotension or hypoxia) was presented as the initial foresight case and (2) which of the 3 potential diagnoses for the second case (the hindsight case, which defaulted to whichever case the participant was not assigned for the first case) was presented as the ultimate diagnosis in the leading sentence in a 2 (scenario order) x 3 (hindsight case anchor) between-subjects factorial design (6 possible randomization assignments). SETTING: Two academic medical centers. PARTICIPANTS: Faculty, fellow, and resident anesthesiologists and certified nurse anesthetists (CRNAs). INTERVENTIONS: None. MEASUREMENTS: After reading each clinical scenario, participants were asked to rate the probability (%) of each of three potential diagnoses to have caused the hypotension or hypoxia. Compositional data analysis (CoDA) was used to compare whether diagnosis probabilities differ between the hindsight and the foresight case. MAIN RESULTS: 113 participants completed the study. 59 participants (52%) were resident anesthesiologists. Participants randomized to the hypotension scenario as a hindsight case were 2.82 times more likely to assign higher probability to the pulmonary embolus diagnosis if provided as an anchor (95% CI, 1.35-5.90; P = 0.006) and twice as likely to assign higher probability to the myocardial infarction diagnosis if provided as an anchor (95% CI, 1.12-3.58; P = 0.020). Participants randomized to the hypoxia scenario as a hindsight case were 1.78 times more likely to assign higher probability to the mainstem bronchus intubation diagnosis if provided in the anchor statement (95% CI, 1.00-3.14; P = 0.048) and 3.72 times more likely to assign higher probability to the pulmonary edema diagnosis if provided as an anchor (95% CI, 1.88-7.35; P < 0.001). CONCLUSIONS: Hindsight bias influences the clinical diagnosis probabilities assigned by anesthesia providers. Clinicians should be educated on hindsight bias in perioperative medicine and be cognizant of the effect of hindsight bias when interpreting clinical outcomes.

Aggressiveness, inhibitory control, and emotional states: A provocation paradigm.

The current study examines the effects of trait aggressiveness, inhibitory control and emotional states on aggressive behavior in a laboratory paradigm. One hundred and fifty-one adult participants took part (73 men, 71 women, and 7 nondisclosed). Event Related Potentials (ERPs) during a Go/No-Go task were utilized to capture the extent of inhibitory processing, with a laboratory provocation paradigm used to assess aggression. Contrary to the expectations, negative affective responses to provocation were negatively associated only with short-lived aggression and only among those with high past aggressiveness. Furthermore, past aggressiveness was related to a continuous increase in laboratory aggressive behavior regardless of the level of inhibitory control (P3 difference amplitude). However, feeling hostile was associated with short-lived aggressive behavior, only in those with lower levels of inhibitory control. These findings demonstrate the effect of distinct mechanisms on different patterns of aggressive behavior.

Support needs of Australians bereaved during the COVID-19 pandemic: A cross-sectional survey study.

BACKGROUND: COVID-19 disrupted access to bereavement support. The objective of this study was to identify the bereavement supports used by Australians during the COVID-19 pandemic, perceived helpfulness of supports used, prevalence and areas of unmet support need, and characteristics of those with unmet support needs. METHODS: A convenience sample of bereaved adults completed an online questionnaire (April 2021-April 2022) about their bereavement experiences including support use and perceived helpfulness, unmet support needs and mental health. Multiple logistic regression was conducted to determine sociodemographic correlates of unmet needs. Open-ended responses were examined using content analysis to determine key themes. RESULTS: 1,878 bereaved Australians completed the questionnaire. Participants were mostly women (94.9%) living in major cities (68%) and reported the death of a parent (45%), with an average age of 55.1 years (SD = 12.2). The five most used supports were family and friends, self-help resources, general practitioners, psychologists, and internet/online community groups. Notably, each was nominated as most helpful and most unhelpful by participants. Two-thirds (66%) reported specific unmet support needs. Those with unmet needs scored lower on mental health measures. Correlates of unmet needs included being of younger age, being a spouse or parent to the deceased; reporting more impacts from public health measures, and not reporting family and friends as supports. The most frequent unmet need was for social support after the death and during lockdown. CONCLUSIONS: This study demonstrates the complexity of bereavement support needs during a pandemic. Specialised grief therapy needs to be more readily available to the minority of grievers who would benefit from it. A clear recommendation for a bereavement support action plan is to bolster the ability of social networks to provide support in times of loss. The fostering of social support in the wake of bereavement is a major gap that needs to be addressed in practice, policy, and research.

Change in Patient Enrollment After Site Principal Investigator Turnover in Surgical Clinical Trials.

This cohort study examines the association of principal investigator (PI) turnover with patient enrollment in surgical clinical trials.

Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in Synovial Sarcoma.

Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF subunit SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-ncBAF-driven transcription, associated with DNA damage and cell death and resulting in tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, positioning the in-clinic TAK-981 to treat SS.

Effectiveness, experience, and usability of low-technology augmentative and alternative communication in intensive care: A mixed-methods systematic review.

BACKGROUND: Patients in the intensive care unit (ICU) are commonly on mechanical ventilation, either through endotracheal intubation or tracheostomy, which usually leaves them nonverbal. Low-technology augmentative and alternative communication (AAC) strategies are simple and effective ways to enhance communication between patients and their communication partners but are underutilised. AIM: The aim of this study was to systematically review current evidence regarding the effectiveness, experience of use, and usability of low-technology AAC with nonverbal patients and their communication partners in the ICU. METHODS: This review included quantitative, qualitative, and mixed-methods studies of adult ICU patients aged 18 or older who were nonverbal due to mechanical ventilation and their communication partners. Studies using low-technology AAC, such as communication boards and pen and paper, were included. Six databases were searched, and the review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A convergent segregated approach was used for data synthesis. RESULTS: Thirty-two studies were included. Low-technology AAC improved patient satisfaction, facilitated communication, and met patients' physical and psychological needs. Communication boards with mixed content (e.g., pictures, words, and letters) were preferred but were used less frequently than unaided strategies due to patients' medical status, tool availability, and staff attitudes. Boards should be user-friendly, tailored, include pen/paper, and introduced preoperation to increase patient's comfort when using them postoperatively. CONCLUSION: Existing evidence support low-technology AAC's efficacy in meeting patients' needs. Better usability hinges on proper implementation and addressing challenges. Further research is crucial for refining communication-board design, ensuring both user-friendliness and sophistication to cater to ICU patients' diverse needs. REGISTRATION: The review protocol was registered in the International Prospective Register of Systematic Reviews, with registration number CRD42022331566.

In silico predicted compound targeting the IQGAP1-GRD domain selectively inhibits growth of human acute myeloid leukemia.

Acute myeloid leukemia (AML) is fatal in the majority of adults. Identification of new therapeutic targets and their pharmacologic modulators are needed to improve outcomes. Previous studies had shown that immunization of rabbits with normal peripheral WBCs that had been incubated with fluorodinitrobenzene elicited high titer antibodies that bound to a spectrum of human leukemias. We report that proteomic analyses of immunoaffinity-purified lysates of primary AML cells showed enrichment of scaffolding protein IQGAP1. Immunohistochemistry and gene-expression analyses confirmed IQGAP1 mRNA overexpression in various cytogenetic subtypes of primary human AML compared to normal hematopoietic cells. shRNA knockdown of IQGAP1 blocked proliferation and clonogenicity of human leukemia cell-lines. To develop small molecules targeting IQGAP1 we performed in-silico screening of 212,966 compounds, selected 4 hits targeting the IQGAP1-GRD domain, and conducted SAR of the 'fittest hit' to identify UR778Br, a prototypical agent targeting IQGAP1. UR778Br inhibited proliferation, induced apoptosis, resulted in G2/M arrest, and inhibited colony formation by leukemia cell-lines and primary-AML while sparing normal marrow cells. UR778Br exhibited favorable ADME/T profiles and drug-likeness to treat AML. In summary, AML shows response to IQGAP1 inhibition, and UR778Br, identified through in-silico studies, selectively targeted AML cells while sparing normal marrow.

Donor Types and Outcomes of Transplantation in Myelofibrosis: A CIBMTR Study.

We aim to evaluate impact of donor types on outcomes of hematopoietic cell transplantation (HCT) in myelofibrosis, using CIBMTR registry data for HCTs done between 2013 and 2019. In all 1597 undergoing HCT for myelofibrosis, the use of haploidentical donors increased from 3% in 2013 to 19% in 2019. In study eligible, 1032 patients who received peripheral blood grafts for chronic phase myelofibrosis, 38% recipients of haploidentical-HCT were of non-White/Caucasian ethnicity. Matched sibling donor (MSD)-HCTs were independently associated with superior overall survival (OS) in the first 3 months [reference MSD, haploidentical HR 5.80 (95% CI 2.52-13.35), matched unrelated HR 4.50 (95% CI 2.24-9.03), and mismatched unrelated HR 5.13 (95% CI 1.44-18.31), P<0.001]. This difference in OS aligns with lower graft failure with MSD [haploidentical HR 6.11 (95%CI 2.98-12.54), matched unrelated HR 2.33 (95%CI 1.20-4.51), mismatched unrelated HR 1.82 (95%CI 0.58-5.72). There was no significant difference in OS among haploidentical, matched unrelated, and mismatched unrelated donor HCTs in the first 3 months. Donor type was not associated with differences in OS beyond 3 months post-HCT, relapse, disease-free survival or OS among patients who underwent HCT within 24 months of diagnosis. Patients who experienced graft failure had more advanced disease and commonly used nonmyeloablative conditioning. While MSDs remain a superior donor option due to improved engraftment, there is no significant difference in HCT outcomes from haploidentical and matched unrelated donors. These results establish haploidentical-HCT with posttransplantation cyclophosphamide as a viable option in myelofibrosis, especially for ethnic minorities underrepresented in the donor registries.

GD2 and its biosynthetic enzyme GD3 synthase promote tumorigenesis in prostate cancer by regulating cancer stem cell behavior.

While better management of loco-regional prostate cancer (PC) has greatly improved survival, advanced PC remains a major cause of cancer deaths. Identification of novel targetable pathways that contribute to tumor progression in PC could open new therapeutic options. The di-ganglioside GD2 is a target of FDA-approved antibody therapies in neuroblastoma, but the role of GD2 in PC is unexplored. Here, we show that GD2 is expressed in a small subpopulation of PC cells in a subset of patients and a higher proportion of metastatic tumors. Variable levels of cell surface GD2 expression were seen on many PC cell lines, and the expression was highly upregulated by experimental induction of lineage progression or enzalutamide resistance in CRPC cell models. GD2high cell fraction was enriched upon growth of PC cells as tumorspheres and GD2high fraction was enriched in tumorsphere-forming ability. CRISPR-Cas9 knockout (KO) of the rate-limiting GD2 biosynthetic enzyme GD3 Synthase (GD3S) in GD2high CRPC cell models markedly impaired the in vitro oncogenic traits and growth as bone-implanted xenograft tumors and reduced the cancer stem cell and epithelial-mesenchymal transition marker expression. Our results support the potential role of GD3S and its product GD2 in promoting PC tumorigenesis by maintaining cancer stem cells and suggest the potential for GD2 targeting in advanced PC.

Breeding Novel Chemistry in Willow: New Hetero Diels-Alder Cyclodimers from Arbusculoidin and Salicortin Suggest Parallel Biosynthetic Pathways.

An investigation of phenolic glycosides extracted from Salix germplasm revealed that arbusculoidin (benzyl 1-O-ß-d-glucopyranosyl-1-hydroxy-6-oxo-2-cyclohexenyl carboxylate) and its enolic 6-glycoside isomer, isoarbusculoidin, are widespread across the Salix family. An analysis of natural hybrid species and progeny from a willow breeding programme demonstrated that the putative biosynthetic pathway leading to the salicinoid family of phenolic glycosides runs in parallel to a "benzyl"-based pathway to arbusculoidin. The introduction of a known Diels-Alder reaction trait from Salix dasyclados, as well as an acylation trait, into progeny containing both salicyl- and benzyl- pathways caused the formation of all possible hetero-cyclodimers from mixtures of reactive dienone (acyl)glycosides that participated in cross-over reactions. In addition to providing access to new analogues of the anti-cancer dimer miyabeacin, the analysis of the breeding progeny also indicated that these dienone (acyl)glycosides are stable in planta. Although the immediate biosynthetic precursors of these compounds remain to be defined, the results suggest that the (acyl)glycosylation reactions may occur later in the pathway than previously suggested by in vitro work on cloned UGT enzymes.

Recommendations to Improve Neonatal Circumcision Training.

BACKGROUND: Although multiple specialties perform neonatal circumcision (NC), overall NC proceduralist availability is limited. The approach to training new practitioners varies. This study aims to describe NC training experiences, current practices, and make suggestions for future improvements. METHODS: Perinatal physicians across 11 hospitals in a large Midwestern United States city who perform NC or who conduct newborn examinations and provide circumcision counseling were recruited for semistructured interviews about NC care. Interviews were transcribed; training-related comments underwent inductive and deductive qualitative coding. Themes related to circumcision training and recommendations for improving the experience of future circumcision learners were summarized. RESULTS: Twenty-three physicians (10 family medicine, 8 pediatrics, and 5 obstetrics; 78% currently perform circumcision) participated. All participants conducted newborn examinations and provided circumcision counseling, but only 21/23 were trained to perform circumcision. Several themes related to training emerged: (1) personal training experience, (2) training others to perform circumcision, and (3) current training needs and barriers. Most reported learning in residency by a "see one, do one, teach one" approach with minimal formal didactic or structured training. Compared with their personal experience, participants noted a shift toward more direct supervision and preprocedure preparation for current trainees. However, most reported that circumcision learning continues to be "hands-on." Participants desired a more structured approach for future trainees. CONCLUSIONS: Perinatal physicians noted a shift in the current NC training to a more hands-on approach than they experienced personally. Development of a structured NC curriculum was recommended to improve training.

What do carers of people with high-grade glioma perceive could improve their preparedness to care, and what additional support do they require?

Background: Concerning levels of stress, strain, and poorer mental health are observed in family carers of patients diagnosed with high-grade glioma (HGG). Understanding the reported unmet needs of these carers will enable future interventions to address such needs to improve their preparedness for care and well-being. In this secondary analysis, we aimed to explore: (i) what carers of people with HGG perceive could improve their preparedness to care; and (ii) what needs carers reported they required additional support with. Methods: Responses from 188 carers of patients with HGG participating in a randomized controlled trial of the Care-IS intervention were analyzed to identify reported unmet needs. Of this larger sample, 92 participants answered a qualitative question seeking to identify perceived unmet needs in carer preparedness over 12 months. These responses comprised the data for the current secondary analysis. Content analysis was used to analyze the qualitative data and observe trends across participant responses. Results: Five overarching themes were identified: carer needs, providing emotional and practical care, coping with uncertainty, coping with the consequences of illness progression, and processing and supporting end-of-life care. Notably, the content analysis identified differences in response numbers between groups in the Care-IS trial, particularly with the control group having more needs regarding illness progression and end-of-life care. Conclusions: Future interventions aimed at improving the well-being and preparedness of carers of people with HGG should consider providing better support centered on carer needs, their changed circumstances, living with uncertainty, and care transition.

Adapting a Dutch Web-Based Intervention to Support Family Caregivers of People With Dementia in the UK Context: Accelerated Experience-Based Co-Design.

BACKGROUND: Around 700,000 family caregivers provide unpaid care for 900,000 people living with dementia in the United Kingdom. Few family caregivers receive support for their own psychological needs and funding for community respite services has declined. These trends are seen across Europe as demographic and budgetary pressures have intensified due to public spending cuts arising from the 2008 financial crisis and the COVID-19 pandemic. The World Health Organization has prioritized the need to expand the provision of support for caregivers and families of people with dementia by 2025. Web-based interventions have the potential for development as they require modest investment and can be accessed by family caregivers at home. Further cost benefits can be realized by adapting existing interventions with demonstrated effectiveness for new contexts. This paper reports initial findings from the CareCoach study, which is adapting Partner in Balance (PiB), a web-based coaching intervention developed in the Netherlands, for family caregivers in the United Kingdom. OBJECTIVE: This study aims to work with unpaid family caregivers and staff in adapting the Dutch web-based support tool PiB to improve its acceptability and usability for use in the United Kingdom. METHODS: Accelerated Experience-Based Co-Design (AEBCD) was used with caregivers, staff, and core stakeholders. Interviews, workshops, and stakeholder consultations were conducted. Data were analyzed iteratively. Recommendations for the redesign of PiB for use across the United Kingdom were adjudicated by the study Adaptation Working Party. RESULTS: Sixteen caregivers and 17 staff took part in interviews. Thirteen caregivers and 17 staff took part in workshops. Most (n=26) participants were White, female, and retired. All except 4 caregivers (2 male and 2 female) found the PiB's offer of web-based self-help learning acceptable. Caregivers identified complexity and lack of inclusivity in some wording and video resources as problematic. The staff took a stronger perspective on the lack of inclusivity in PiB video resources. Staff and caregivers coproduced new inclusive wording and recommended creating new videos to adapt PiB for the UK context. CONCLUSIONS: AEBCD methods facilitated the engagement of caregivers and staff and advanced the adaptation of the PiB complex intervention. An important addition to the AEBCD method in this process was the work of an Adaptation Working Party, which adjudicated and agreed to new wording where this could not be established in consultation with caregivers and staff. TRIAL REGISTRATION: ISRCTN Registry ISRCTN12540555; https://doi.org/10.1186/ISRCTN12540555.

Lower extremity woven and nonwoven venous stent morphology and luminal changes.

OBJECTIVE: Venous stents are a common treatment modality for obstructive venous disease. Venous stents differentiate themselves by either a woven or braided structure, open or closed cell arrangement or based on material composition (elgiloy vs nitinol). Changes in the morphology of venous stents over time may contribute to restenosis or thrombosis. Woven elgiloy stents are prone to proximal and distal edge deformation compared with dedicated venous stents, which offer increased radial force at stent edges. The objective of this study is to describe luminal morphological changes among various venous stents and between woven to nonwoven venous stent configuration, over time. METHODS: A retrospective review at a single institution between January 2014 and June 2021 identified patients treated with venous stents. Patients with iliac and/or femoral venous stents with intraoperative intravascular ultrasound and a postoperative computed tomography scan were included in the study. Cross-sectional diameters measurements were taken at proximal, middle, and distal portions of each stent from intravascular ultrasound examination at the time of initial stenting and compared with the cross-sectional diameter measurements taken from computed tomography imaging at follow-up. A paired t test was used to compare the luminal change with a D'Agostino-Pearson test used for normality. RESULTS: Fifty-four stents distributed among 38 patients were identified. The mean time to follow-up was 17.5 months. Stents were placed in the common iliac vein (n = 37, 68.5%), external iliac vein (n = 14, 25.9%), and common femoral vein (n = 3, 5.6%). Implanted stents included the Boston Scientific Wallstent (n = 23, 42.6%), Bard Venovo (n = 3, 5.6%), Boston Scientific Vici (n = 23, 42.6%), and Medtronic Abre (n = 5, 9.3%). The mean luminal loss was measured at 2.12 mm proximally (95% confidence interval [CI], 1.64-2.60; P<.001), 1.29 mm at the mid-stent (95% CI, 0.83-1.74, P<.001), and 1.56 mm distally (95% CI, 0.99-2.12; P<.001). There was no significant difference in luminal changes between woven and nonwoven stents at proximal (P = .374), middle (P = .179), and distal (P = .609) stent measurements. CONCLUSIONS: This study reports morphological changes within venous stents and between woven and nonwoven venous stents. Our findings demonstrate that the edge-stent luminal decrease traditionally attributed to woven configurations also occurs with the newer nonwoven stents. Additional factors such as anatomical location, pelvic curvature, and other external forces may be accountable for this change rather than geometrical configuration of the stent.

GZ17-6.02 kills PDX isolates of uveal melanoma.

GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525). The RP2D is 375 mg PO BID, with an uveal melanoma patient exhibiting a 15% reduction in tumor mass for 5 months at this dose. Studies in this manuscript have defined the biology of GZ17-6.02 in PDX isolates of uveal melanoma cells. GZ17-6.02 killed uveal melanoma cells through multiple convergent signals including enhanced ATM-AMPK-mTORC1 activity, inactivation of YAP/TAZ and inactivation of eIF2α. GZ17-6.02 significantly enhanced the expression of BAP1, predictive to reduce metastasis, and reduced the levels of ERBB family RTKs, predicted to reduce growth. GZ17-6.02 interacted with doxorubicin or ERBB family inhibitors to significantly enhance tumor cell killing which was associated with greater levels of autophagosome formation and autophagic flux. Knock down of Beclin1, ATG5 or eIF2α were more protective than knock down of ATM, AMPKα, CD95 or FADD, however, over-expression of FLIP-s provided greater protection compared to knock down of CD95 or FADD. Expression of activated forms of mTOR and STAT3 significantly reduced tumor cell killing. GZ17-6.02 reduced the expression of PD-L1 in uveal melanoma cells to a similar extent as observed in cutaneous melanoma cells whereas it was less effective at enhancing the levels of MHCA. The components of GZ17-6.02 were detected in tumors using a syngeneic tumor model. Our data support future testing GZ17-6.02 in uveal melanoma as a single agent, in combination with ERBB family inhibitors, in combination with cytotoxic drugs, or with an anti-PD1 immunotherapy.

Risk and protective factors in risk assessment: Predicting inpatient aggression in adult males detained in a forensic mental health setting.

Structured clinical risk assessments represent a preferred means of assessing levels of aggression risk at different times and in different individuals. Increasing attention has been given to capturing protective factors, with sound risk assessment critical to high-secure forensic mental health care. The aim was to assess the predictive value of the HCR-20v3 for aggression risk and the long-term care pilot version of the SAPROF (the SAPROF-LC-pilot) in a high-secure forensic mental health inpatient population and to determine the incremental value of protective over risk factors. Participants were adult males detained in a high secure forensic mental health service, with a primary diagnosis of schizophrenia and/or personality disorder. The focus was on examining hospital based aggression (self- and other-directed) at two time points; up to 6 months (T1) and between 7 and 12 months (T2). The HCR-20V3 and SAPROF-LC-pilot demonstrated good predictive validity but with variability across subscales and aggression types/periods. Historical factors of the HCR-20V3 and External factors of the SAPROF-LC-pilot failed to predict, aside from a medium effect at T1 for verbal aggression and self-harm, for Historical factors. There was evidence for protective factors adding to prediction over risk factors alone, with the integration of protective and risk factors into a risk judgement particularly helpful in improving prediction accuracy. Protective factors contributed to risk estimates and particularly if integrated with risk factors. Combining risk and protective factors has clear predictive advantages, ensuring that protective factors are not supplementary but important to the aggression assessment process.