Carbon-based Flame Retardants for Polymers: A Bottom-up Review.

This state-of-the-art review is geared towards elucidating the molecular understanding of the carbon-based flame-retardant mechanisms for polymers via holistic characterisation combining detailed analytical assessments and computational material science. The use of carbon-based flame retardants, which include graphite, graphene, carbon nanotubes (CNTs), carbon dots (CDs) and fullerenes, in their pure and functionalised forms are initially reviewed to evaluate their flame retardancy performance and to determine their elevation of the flammability resistance on various types of polymers. The early transition metal carbides such as MXenes, regarded as next generation carbon-based flame retardants, are discussed with respect to their superior flame retardancy and multifunctional applications. At the core of this review is the utilisation of cutting-edge molecular dynamics (MD) simulations which sets a precedence of an alternative bottom-up approach to fill the knowledge gap through insights into the thermal resisting process of the carbon-based flame retardants, such as the formation of carbonaceous char and intermediate chemical reactions offered by the unique carbon bonding arrangements and microscopic in-situ architectures. Combining MD simulations with detailed experimental assessments and characterisation, a more targeted development as well as a systematic material synthesis framework can be realised for the future development of advanced flame-retardant polymers. This article is protected by copyright. All rights reserved.

The information seeking behaviors of caregivers in the management of childhood fever - A systematic literature review.

INTRODUCTION: Parents' and caregivers' non-evidence-based childhood fever management 'fever phobic' practices have remained relatively stable over more than 34 years despite successful educational interventions. This systematic review aimed to assess the information seeking behavior of caregivers managing fever in their children, as well as to compile the fever management practices undertaken by caregivers by investigating underlying factors influencing them. METHODS: The electronic databases Pubmed, CINAHL, Medline, and International Pharmaceutical Abstracts were searched using key terms including, fever, child, caregiver, and management. Studies were included if they were written in English, published between January 1980 and January 2021, explored generalized childhood fever management practices of caregivers, and factors which influence fever management. Data extracted included study year and design, location, dimensions of fever management explored (i.e., knowledge, beliefs, detection, and/or treatment of fever), factors influencing management, and information sources used by caregivers. RESULTS: In total, 36 studies were eligible for inclusion in the study. Twenty-nine of the studies were designed as a cross-sectional survey, six studies were interviews and the remainder were pre-post studies. The review of studies found that parents and caregivers sourced childhood fever management information most commonly from friends and family or their own personal experiences, however, participants most commonly sourced doctors/general practitioners as their first line of information when required. Over the years, trends showed that doctors as well as the internet were more frequently being used as a first line source of information by caregivers. CONCLUSIONS: Despite decades of research, education and development of evidence-based guidelines caregivers continue to exhibit 'fever phobia' when caring for febrile children. This is demonstrated by their continued use of non-evidence-based methods and increasing reliance on, and incorrect use of antipyretics, alternating antipyretics if fever is not sufficiently reduced or returns. There is an increasing need for the development of easy to access digital resources for caregiver as internet use is rising which mirrors best practice taught to professionals.

Recurrent Retinal Detachment in Stickler Syndrome.

Objective: To assess clinical factors leading to recurrent retinal detachment (RD) and characteristics of recurrence in patients with Stickler Syndrome. Methods: Retrospective case series study of patients with clinical diagnosis of Stickler Syndrome who underwent rhegmatogenous RD repair. Recurrent RD after initial surgery was categorized as "early" if the recurrence was within 1 year or "late" if greater than 1 year. Results: Thirty eyes from 22 patients underwent rhegmatogenous RD repair. For initial repair, 13 eyes underwent pars plana vitrectomy combined with scleral buckling (PPV/SB), 16 eyes underwent primary scleral buckling (SB), and 1 eye underwent pneumatic retinopexy (PnR). Recurrent RD occurred in 6 (46%) PPV/SB eyes (5 early and 1 late), 10 (63%) SB eyes (3 early and 7 late), and 0 (0%) PnR eyes (p = 0.61). PPV/SB was preferred for eyes presenting with total detachment (82%), giant retinal tears (100%), and proliferative vitreoretinopathy (PVR) (80%). For eyes with early recurrent RD, 6 (75%) developed PVR leading to recurrence. For eyes with late recurrent RD, 7 (87.5%) developed a new retinal break leading to recurrence, including 4 with a break posterior to the buckle indentation apex. At last follow-up, median LogMAR visual acuity was 0.68 for eyes with recurrent RD compared to 0.29 for eyes without recurrence (p = 0.27). Conclusions: Early recurrent RD was mostly caused by PVR, while late recurrent RD was mostly due to new retinal breaks. Eyes with seemingly uncomplicated rhegmatogenous RD repair with primary SB remained at high risk for late re-detachment.

Investigating Variations in Medicine Approvals for Attention-Deficit/Hyperactivity Disorder: A Cross-Country Document Analysis Comparing Drug Labeling.

OBJECTIVE: This study aimed to compare the approval of medicines for attention deficit/hyperactivity disorder (ADHD) for pediatric patients across five countries. METHOD: A document analysis was completed, using the drug labeling for ADHD medicines from five countries; United Kingdom, Australia, New Zealand, Canada and United States (US). Comparisons of available formulations and approval information for ADHD medicine use in pediatric patients were made. RESULTS: The US had the highest number of approved medicines and medicine forms across the studied countries (29 medicine forms for 10 approved medicines). Approved age and dosage variations across countries and missing dosage information were identified in several drug labeling. CONCLUSIONS: The discrepancies in approval information in ADHD medicine drug labeling and differing availability of medicine formulations across countries suggest variations in the management of ADHD across countries. The update of drug labeling and further research into reasons for variability and impact on practice are needed.

The Carer Assessment of MedicaTion Management GuidanCe for People With Dementia at Hospital Discharge (CATCH) Tool: Exploratory Factor Analysis.

PURPOSE: The Carer Assessment of medicaTion management guidanCe for people with dementia at Hospital discharge (CATCH) tool was developed to examine the carer's experiences of medication management guidance delivery at discharge. This study explored its factor structure, characterized carers' experiences at discharge, and identified predictors of carer preparedness to manage medications at discharge. METHODS: A cross-sectional survey of carers across Australia was distributed. Survey responses were analyzed descriptively, and exploratory factor and regression analyses were performed. RESULTS: A total of 185 survey responses were completed. Exploratory factor analysis revealed 2 factors in the CATCH tool: (1) shared and supported decision-making in medication management (16 items loading 0.47 to 0.93); 2) provision of medication management guidance that is easy to understand (4 items loading (0.48 to 0.82). Internal consistency was acceptable (Cronbach alpha >0.8). Almost 18% of participants stated that they were not included in decisions about medications for people with dementia. The carer reported that the measure of how guidance is provided was positively related to their confidence in the management of medications postdischarge and satisfaction ( P < 0.05 for both). CONCLUSIONS: The CATCH tool can give the patient and carer an opportunity to provide feedback on key elements of medication management guidance delivered at discharge.

Pharmaceutical Care Network Europe definition of quality indicators for pharmaceutical care: a systematic literature review and international consensus development.

BACKGROUND: Over the past 40 years, the tasks of pharmacists have shifted from logistic services to pharmaceutical care (PhC). Despite the increasing importance of measuring quality of care, there is no general definition of Quality Indicators (QIs) to measure PhC. Recognising this, a working group in a European association of PhC researchers, the Pharmaceutical Care Network Europe (PCNE), was established in 2020. AIM: This research aimed to review existing definitions of QIs and develop a definition of QIs for PhC. METHOD: A two-step procedure was applied. Firstly, a systematic literature review was conducted to identify existing QI definitions that were summarised. Secondly, an expert panel, comprised of 17 international experts from 14 countries, participated in two surveys and a discussion using a modified Delphi technique to develop the definition of QIs for PhC. RESULTS: A total of 182 QI definitions were identified from 174 articles. Of these, 63 QI definitions (35%) cited one of five references as the source. Sixteen aspects that construct QI definitions were derived from the identified definitions. As a result of the Delphi study, the panel reached an agreement on a one-sentence definition of QIs for PhC: "quality indicators for pharmaceutical care are validated measurement tools to monitor structures, processes or outcomes in the context of care provided by pharmacists". CONCLUSION: Building upon existing definition of QIs, an international expert panel developed the PCNE definition of QIs for PhC. This definition is intended for universal use amongst researchers and healthcare providers in PhC.

A study to assess the efficacy of enasidenib and risk-adapted addition of azacitidine in newly diagnosed IDH2-mutant AML.

ABSTRACT: Enasidenib (ENA) is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML substudy, we applied a risk-adapted approach to assess the efficacy of ENA monotherapy for patients aged ≥60 years with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated that mutant IDH2 was in the dominant leukemic clone. Patients for whom ENA monotherapy did not induce a complete remission (CR) or CR with incomplete blood count recovery (CRi) enrolled in a phase 1b cohort with the addition of azacitidine. The phase 2 portion assessing the overall response to ENA alone demonstrated efficacy, with a composite complete response (cCR) rate (CR/CRi) of 46% in 60 evaluable patients. Seventeen patients subsequently transitioned to phase 1b combination therapy, with a cCR rate of 41% and 1 dose-limiting toxicity. Correlative studies highlight mechanisms of clonal elimination with differentiation therapy as well as therapeutic resistance. This study demonstrates both efficacy of ENA monotherapy in the upfront setting and feasibility and applicability of a risk-adapted approach to the upfront treatment of IDH2-mutant AML. This trial is registered at www.clinicaltrials.gov as #NCT03013998.

Perinatal depression screening in community pharmacy: Exploring pharmacists' roles, training and resource needs using content analysis.

BACKGROUND: Perinatal depression (PND) screening is often recommended in primary care settings, which includes the community pharmacy setting. However, there is limited research exploring pharmacists' perspectives on their roles in screening for perinatal mental illness. AIM: This study aimed to explore pharmacists' views of pharmacists' roles in PND screening, as well as training and resource needs for PND screening in community pharmacy settings. METHOD: A questionnaire including three open-ended questions focusing on pharmacists' perspectives of their role in PND screening, their training, and resource needs in this area, was disseminated to pharmacists across Australia via professional organisations and social media. Each open-ended question was separately analysed by inductive content analysis. Subcategories were deductively mapped to the Theoretical Framework of Acceptability. RESULTS: Responses (N = 149) from the first open-ended question about pharmacists' roles in PND screening resulted in three categories (PND screening in primary care settings will support the community, community pharmacy environment, and system and policy changes) and ten subcategories. Responses to question two on training needs (n = 148) were categorised as: training content, training length, and training delivery while responses about resource needs (n = 147) fell into three categories: adapting community pharmacy operating structures, pharmacist-specific resources, and consumer-specific resources. CONCLUSION: While some pharmacists were accepting of a role in PND screening due to pharmacists' accessibility and positive relationships with consumers, others had concerns regarding whether PND screening was within pharmacists' scope of practice. Further training and resources are needed to facilitate pharmacists' roles in PND screening, referral and care.

Endothelial cells are a key target of IFN-g during response to combined PD-1/CTLA-4 ICB treatment in a mouse model of bladder cancer.

To explore mechanisms of response to combined PD-1/CTLA-4 immune checkpoint blockade (ICB) treatment in individual cell types, we generated scRNA-seq using a mouse model of invasive urothelial carcinoma with three conditions: untreated tumor, treated tumor, and tumor treated after CD4+ T cell depletion. After classifying tumor cells based on detection of somatic variants and assigning non-tumor cell types using SingleR, we performed differential expression analysis, overrepresentation analysis, and gene set enrichment analysis (GSEA) within each cell type. GSEA revealed that endothelial cells were enriched for upregulated IFN-g response genes when comparing treated cells to both untreated cells and cells treated after CD4+ T cell depletion. Functional analysis showed that knocking out IFNgR1 in endothelial cells inhibited treatment response. Together, these results indicated that IFN-g signaling in endothelial cells is a key mediator of ICB induced anti-tumor activity.

A pharmacist integrated into a general practice in Australia: an evolving model of care in medicines optimization.

The general practice pharmacist (GPP) role in Australia is evolving. A pilot GPP model of care developed to optimize medicines for patients at risk of medicine-related harm was evaluated. The aims of this study were 2-fold: to evaluate the GPP model of care on medicines optimization, with a focus on deprescribing, in a population at risk of harm due to their medicines, or clinical condition, and to explore the perspectives of study participants. This single practice study involved two phases. Phase 1 (September 2019-May 2020): at risk patients were referred to the GPP for medication reconciliation, recommendations for optimization, and when appropriate, deprescribing support, especially for opioids. Medication plans were developed with patients, GPs, and the GPP. Quantitative data collected from patient records included demographics, discrepancies, medicines reviewed, GPP recommendations and uptake, and medicines deprescribed. Opioid-related data included dose changes from baseline, at 6 and 9 months, standardized to oral morphine equivalents. Descriptive statistics were used for analysis. Phase 2 (7-21 September 2020): qualitative evaluation using semi-structured interviews was undertaken, to explore the perspectives of GP and patient participants of the GPP model of care. Interview data were thematically analysed. The study had ethical approval. Phase 1: 198 multimorbid patients with multiple medications [median = 13 (9-16)] had at least one GPP consultation (n = 243). Discrepancies were resolved through 88% of GPP consultations; deprescribing commenced or occurred in 54%. Acceptance of GPP recommendations was 86%. Opioids were the most common medicines deprescribed (42% ceased). The baseline median opioid dose [44.4 (30-90) mg] was significantly reduced at 6 months [13.5 (0-40) mg] and 9 months [7 (0-30) mg], P < .0001. Phase 2: Thematic analysis of 28 interviews (10 GPs, 3 practice personnel, 10 patients, 5 carers) identified four key themes: safer foundation for deprescribing, deprescribing opportunities recognition, benefits of embedded GPP, and a supported approach to shared decision-making. General practice provides opportunities for medicine optimization and deprescribing. This study has demonstrated a GPP model of care that achieved functional deprescribing to reduce potential harm in a population at risk and addressed recognized barriers.

Modeling the co-assembly of binary nanoparticles.

In this work, we present a binary assembly model that can predict the co-assembly structure and spatial frequency spectra of monodispersed nanoparticles with two different particle sizes. The approach relies on an iterative algorithm based on geometric constraints, which can simulate the assembly patterns of particles with two distinct diameters, size distributions, and at various mixture ratios on a planar surface. The two-dimensional spatial-frequency spectra of the modeled assembles can be analyzed using fast Fourier transform analysis to examine their frequency content. The simulated co-assembly structures and spectra are compared with assembled nanoparticles fabricated using transfer coating method are in qualitative agreement with the experimental results. The co-assembly model can also be used to predict the peak spatial frequency and the full-width at half-maximum bandwidth, which can lead to the design of the structure spectra by selection of different monodispersed particles. This work can find applications in fabrication of non-periodic nanostructures for functional surfaces, light extraction structures, and broadband nanophotonics.

The impact of social connections and discrimination to HIV risk among Asian gay and bisexual men in Australia.

BACKGROUND: Asian gay, bisexual, and other men who have sex with men (GBMSM) are overrepresented in new HIV diagnoses in Australia. Social engagement with other GBMSM has been associated with HIV testing and pre-exposure prophylaxis (PrEP) uptake. Asian GBMSM may be socially disconnected from LGBTQ+ people, which may increase their HIV risk. This analysis assessed the contribution of social connection on HIV risk among Asian GBMSM. METHODS: Using an online cross-sectional survey of Asian GBMSM in Australia, we measured condomless anal intercourse (CLAI) in the last 6months without PrEP or an undetectable viral load (UVL), i.e. CLAI with a risk of HIV transmission. Bivariable and multivariable logistic regression models were performed to compare demographic characteristics and social engagement of participants who had CLAI without PrEP or UVL to those who had not. Analyses were restricted to participants who reported sex with casual partners in the last 6months. RESULTS: Among 509 participants who had casual partners in the last 6months, 151 (29.7%) reported CLAI without PrEP or UVL. CLAI without PrEP or UVL was negatively associated with full-time employment, and recently being tested for HIV and was positively associated with experiencing discrimination based on sexual orientation. Social engagement with LGBTQ+ people was not associated with CLAI without PrEP or UVL. CONCLUSIONS: CLAI without PrEP or UVL was not related to social connections with LGBTQ+ people but was more likely among Asian men who had experienced sexuality-related discrimination, suggesting that mitigating homophobia and biphobia may assist in improving HIV prevention among Asian GBMSM who live in Australia.

Impact of a training program on hospital pharmacists' patient-centered communication attitudes and behaviors.

Background: Effective communication that integrates the value of patient-centered care is important in healthcare encounters. Communication skills training (CST) has been indicated as effective in improving patient-centered communication behaviors. However, there is a paucity of studies on the impact of CST among Malaysian hospital pharmacists. Objective: This study aimed to evaluate the effects of a patient-centered CST program on patient-centered communication scores, communication self-efficacy, and attitudes toward concordance among pharmacists in public hospitals. Methods: A communication skills training (CST) program was conducted among hospital pharmacists. This training intervention was developed based on patient-centered communication frameworks and techniques, namely the Four Habits Model and motivational interviewing. A pre-test/post-test quasi-experimental design was implemented for the evaluation. Pharmacists underwent pre-test/post-test audiotaped simulated consultations and completed questionnaires, including the Revised United States-Leeds Attitudes Toward Concordance scale (RUS-LATCon) and Communication Self-Efficacy scale. The Four Habits Coding Scheme (FHCS) was used to evaluate patient-centered communication scores from the audiotapes, and the Wilcoxon signed-rank test was used to analyze for differences in the pre- and post-intervention scores. Results: A total of 38 pharmacists from four tertiary hospitals participated in this study and completed the pre-test. However, due to the impact of COVID-19, only 23 pharmacists completed the post-test data collection. Improvements were noted in the FHCS scores post-training, including items related to exploring patients' concerns, acceptability, and barriers to treatment. Based on the questionnaire, there was an improvement in recognizing patients' needs and potential medication uncertainty and an increase in the overall communication self-efficacy scores after the training. Conclusions: CST may help improve the adoption of patient-centered communication in pharmacists' consultations with patients.

Aluminum foil negative electrodes with multiphase microstructure for all-solid-state Li-ion batteries.

Metal negative electrodes that alloy with lithium have high theoretical charge storage capacity and are ideal candidates for developing high-energy rechargeable batteries. However, such electrode materials show limited reversibility in Li-ion batteries with standard non-aqueous liquid electrolyte solutions. To circumvent this issue, here we report the use of non-pre-lithiated aluminum-foil-based negative electrodes with engineered microstructures in an all-solid-state Li-ion cell configuration. When a 30-µm-thick Al94.5In5.5 negative electrode is combined with a Li6PS5Cl solid-state electrolyte and a LiNi0.6Mn0.2Co0.2O2-based positive electrode, lab-scale cells deliver hundreds of stable cycles with practically relevant areal capacities at high current densities (6.5 mA cm-2). We also demonstrate that the multiphase Al-In microstructure enables improved rate behavior and enhanced reversibility due to the distributed LiIn network within the aluminum matrix. These results demonstrate the possibility of improved all-solid-state batteries via metallurgical design of negative electrodes while simplifying manufacturing processes.

Exploring stakeholders' perspectives on the quality of services provided through community pharmacies.

INTRODUCTION: It is important to understand the factors impacting the quality of services provided through community pharmacies. Exploring how key stakeholders perceive good quality in these services is a logical first step. This could also inform the development of quality measures, such as quality indicators (QIs). AIM: To identify key stakeholders' perspectives on the quality of services provided through community pharmacies in Norway, specifically by exploring their experiences and perceptions about what constitutes good service quality. METHODS: A convenient sampling approach was used to recruit participants for five semi-structured focus groups from Facebook, pharmacy chains, and patient organizations. The interviews with twenty-six participants were conducted via Microsoft Teams. Interviews were transcribed verbatim, and an inductive thematic analysis with a reflexive approach was used. RESULTS: Four main themes emerged from the analysis; 1) sufficient and substantively suitable information to cover individual needs, 2) communication skills and relationships with the pharmacy professionals, 3) customer satisfaction with knowledgeable employees and conveniently located pharmacies, and 4) factors that affect the pharmacy working environment. CONCLUSION: This study has identified areas that pharmacy professionals and customers regard as essential to define good quality of community pharmacy services. Effective communication skills, appropriate provision of information, customer satisfaction, and working environment are all essential factors when developing quality metrics for community pharmacies.

Direct observation of coherence transfer and rotational-to-vibrational energy exchange in optically centrifuged CO2 super-rotors.

Optical centrifuges are laser-based molecular traps that can rotationally accelerate molecules to energies rivalling or exceeding molecular bond energies. Here we report time and frequency-resolved ultrafast coherent Raman measurements of optically centrifuged CO2 at 380 Torr spun to energies beyond its bond dissociation energy of 5.5 eV (Jmax = 364, Erot = 6.14 eV, Erot/kB = 71, 200 K). The entire rotational ladder from J = 24 to J = 364 was resolved simultaneously which enabled a more accurate measurement of the centrifugal distortion constants for CO2. Remarkably, coherence transfer was directly observed, and time-resolved, during the field-free relaxation of the trap as rotational energy flowed into bending-mode vibrational excitation. Vibrationally excited CO2 (ν2 > 3) was observed in the time-resolved spectra to populate after 3 mean collision times as a result of rotational-to-vibrational (R-V) energy transfer. Trajectory simulations show an optimal range of J for R-V energy transfer. Dephasing rates for molecules rotating up to 5.5 times during one collision were quantified. Very slow decays of the vibrational hot band rotational coherences suggest that they are sustained by coherence transfer and line mixing.

Suppression of coherent interference to electric-field-induced second-harmonic (E-FISH) signals for the measurement of electric field in mesoscale confined geometries.

We present spatially enhanced electric-field-induced second-harmonic (SEEFISH) generation with a chirped femtosecond beam for measurements of electric field in mesoscale confined geometries subject to destructive spurious second-harmonic generation (SHG). Spurious SHG is shown to interfere with the measured E-FISH signal coherently, and thus simple background subtraction is not sufficient for single-beam E-FISH approaches, especially in a confined system with a large surface-to-volume ratio. The results show that a chirped femtosecond beam is effective in preventing higher-order mixing and white light generation in windows near the beam focal point which further contaminates the SEEFISH signal. The successful measurements of electric field of a nanosecond dielectric barrier discharge in a test cell demonstrated that spurious SHG detected with a congruent traditional E-FISH approach can be eliminated using the SEEFISH approach.

The PRESIDE (PhaRmacogEnomicS In DEpression) Trial: a double-blind randomised controlled trial of pharmacogenomic-informed prescribing of antidepressants on depression outcomes in patients with major depressive disorder in primary care.

BACKGROUND: The evidence for the clinical utility of pharmacogenomic (PGx) testing is growing, and guidelines exist for the use of PGx testing to inform prescribing of 13 antidepressants. Although previous randomised controlled trials of PGx testing for antidepressant prescribing have shown an association with remission of depression in clinical psychiatric settings, few trials have focused on the primary care setting, where most antidepressant prescribing occurs. METHODS: The PRESIDE Trial is a stratified double-blinded randomised controlled superiority trial that aims to evaluate the impact of a PGx-informed antidepressant prescribing report (compared with standard prescribing using the Australian Therapeutic Guidelines) on depressive symptoms after 12 weeks, when delivered in primary care. Six hundred seventy-two patients aged 18-65 years of general practitioners (GPs) in Victoria with moderate to severe depressive symptoms, measured using the Patient Health Questionnaire-9 (PHQ-9), will be randomly allocated 1:1 to each arm using a computer-generated sequence. Participants and GPs will be blinded to the study arm. The primary outcome is a difference between arms in the change of depressive symptoms, measured using the PHQ-9 after 12 weeks. Secondary outcomes include a difference between the arms in change in PHQ-9 score at 4, 8 and 26 weeks, proportion in remission at 12 weeks, a change in side effect profile of antidepressant medications, adherence to antidepressant medications, change in quality of life and cost-effectiveness of the intervention. DISCUSSION: This trial will provide evidence as to whether PGx-informed antidepressant prescribing is clinically efficacious and cost-effective. It will inform national and international policy and guidelines about the use of PGx to select antidepressants for people with moderate to severe depressive symptoms presenting in primary care. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry ACTRN12621000181808. Registered on 22 February 2021.

Endothelial cells are a key target of IFN-g during response to combined PD-1/CTLA-4 ICB treatment in a mouse model of bladder cancer.

To explore mechanisms of response to combined PD-1/CTLA-4 immune checkpoint blockade (ICB) treatment in individual cell types, we generated scRNA-seq using a mouse model of invasive urothelial carcinoma with three conditions: untreated tumor, treated tumor, and tumor treated after CD4+ T cell depletion. After classifying tumor cells based on detection of somatic variants and assigning non-tumor cell types using SingleR, we performed differential expression analysis, overrepresentation analysis, and gene set enrichment analysis (GSEA) within each cell type. GSEA revealed that endothelial cells were enriched for upregulated IFN-g response genes when comparing treated cells to both untreated cells and cells treated after CD4+ T cell depletion. Functional analysis showed that knocking out IFNgR1 in endothelial cells inhibited treatment response. Together, these results indicated that IFN-g signaling in endothelial cells is a key mediator of ICB induced anti-tumor activity.

Entospletinib with decitabine in acute myeloid leukemia with mutant TP53 or complex karyotype: A phase 2 substudy of the Beat AML Master Trial.

BACKGROUND: Patients with acute myeloid leukemia (AML) who have tumor protein p53 (TP53) mutations or a complex karyotype have a poor prognosis, and hypomethylating agents are often used. The authors evaluated the efficacy of entospletinib, an oral inhibitor of spleen tyrosine kinase, combined with decitabine in this patient population. METHODS: This was a multicenter, open-label, phase 2 substudy of the Beat AML Master Trial (ClinicalTrials.gov identifier NCT03013998) using a Simon two-stage design. Eligible patients aged 60 years or older who had newly diagnosed AML with mutations in TP53 with or without a complex karyotype (cohort A; n = 45) or had a complex karyotype without TP53 mutation (cohort B; n = 13) received entospletinib 400 mg twice daily with decitabine 20 mg/m2 on days 1-10 every 28 days for up to three induction cycles, followed by up to 11 consolidation cycles, in which decitabine was reduced to days 1-5. Entospletinib maintenance was given for up to 2 years. The primary end point was complete remission (CR) and CR with hematologic improvement by up to six cycles of therapy. RESULTS: The composite CR rates for cohorts A and B were 13.3% (95% confidence interval, 5.1%-26.8%) and 30.8% (95% confidence interval, 9.1%-61.4%), respectively. The median duration of response was 7.6 and 8.2 months, respectively, and the median overall survival was 6.5 and 11.5 months, respectively. The study was stopped because the futility boundary was crossed in both cohorts. CONCLUSIONS: The combination of entospletinib and decitabine demonstrated activity and was acceptably tolerated in this patient population; however, the CR rates were low, and overall survival was short. Novel treatment strategies for older patients with TP53 mutations and complex karyotype remain an urgent need.