Histone Acetyltransferase p300 Induces De Novo Super-Enhancers to Drive Cellular Senescence.

Accumulation of senescent cells during aging contributes to chronic inflammation and age-related diseases. While senescence is associated with profound alterations of the epigenome, a systematic view of epigenetic factors in regulating senescence is lacking. Here, we curated a library of short hairpin RNAs for targeted silencing of all known epigenetic proteins and performed a high-throughput screen to identify key candidates whose downregulation can delay replicative senescence of primary human cells. This screen identified multiple new players including the histone acetyltransferase p300 that was found to be a primary driver of the senescent phenotype. p300, but not the paralogous CBP, induces a dynamic hyper-acetylated chromatin state and promotes the formation of active enhancer elements in the non-coding genome, leading to a senescence-specific gene expression program. Our work illustrates a causal role of histone acetyltransferases and acetylation in senescence and suggests p300 as a potential therapeutic target for senescence and age-related diseases.

New Advances in Covalent Network Polymers via Dynamic Covalent Chemistry.

Covalent network polymers, as materials composed of atoms interconnected by covalent bonds in a continuous network, are known for their thermal and chemical stability. Over the past two decades, these materials have undergone significant transformations, gaining properties such as malleability, environmental responsiveness, recyclability, crystallinity, and customizable porosity, enabled by the development and integration of dynamic covalent chemistry (DCvC). In this review, we explore the innovative realm of covalent network polymers by focusing on the recent advances achieved through the application of DCvC. We start by examining the history and fundamental principles of DCvC, detailing its inception and core concepts and noting its key role in reversible covalent bond formation. Then the reprocessability of covalent network polymers enabled by DCvC is thoroughly discussed, starting from the significant milestones that marked the evolution of these polymers and progressing to their current trends and applications. The influence of DCvC on the crystallinity of covalent network polymers is then reviewed, covering their bond diversity, synthesis techniques, and functionalities. In the concluding section, we address the current challenges faced in the field of covalent network polymers and speculates on potential future directions.

Factors predicting long-term weight maintenance in anorexia nervosa: a systematic review.

PURPOSE: Eating disorder recovery is a poorly defined concept, with large variations among researchers' definitions. Weight maintenance is a key aspect of recovery that remains relatively underexplored in the literature. Understanding the role of weight maintenance may help guide the development of treatments. This paper aims to address this by (1) investigating the factors predicting long-term weight maintenance in anorexia nervosa (AN) patients; (2) exploring differences in predictive factors between adolescent and adult populations; and (3) exploring how weight maintenance is conceptualised in the literature. METHODS: We conducted a systematic review following PRISMA guidelines to address our research questions. Five databases were searched and filtered according to our exclusion criteria. RESULTS: From the search, 1059 studies were yielded, and 13 studies were included for review. A range of weight, biological and psychological factors were found to predict weight maintenance among these papers. BMI at admission and discharge from inpatient treatment was the most common predictor among the papers. Few studies investigated biological factors and mixed evidence was found for psychological factors. We found no observable differences between adult and adolescent populations. Finally, weight maintenance was defined and measured differently across studies. CONCLUSION: This review's findings can help contribute to a well-rounded understanding of weight maintenance, and ultimately, of recovery. This can help support clinicians in tailoring interventions to improve long-term outcomes in AN. Future research should aim to replicate studies to better understand the relationship between the factors identified and weight maintenance. LEVEL I: Systematic review.

The use and misuse of the SCOFF screening measure over two decades: a systematic literature review.

PURPOSE: The SCOFF questionnaire was designed as a simple, memorable screening tool to raise suspicion that a person might have an eating disorder. It is over 20 years since the creation of the SCOFF, during which time it has been widely used. Considering this, we wish to review the use of the SCOFF in peer-reviewed scientific journals, and to assess whether it is being used appropriately in the manner in which it was originally devised and tested. METHODS: The Preferred Reporting Items for a Systematic Review and Meta-analysis (PRISMA) guidelines were followed, and all search strategies and methods were determined before the onset of the study. PubMed and Wiley Online Library were searched using the terms SCOFF and eating. Two reviewers were involved in the reviewing process. Criteria for appropriate use of the SCOFF were formalised with the tool's original authors. RESULTS: 180 articles were included in the final review. 48 articles had used the SCOFF appropriately, 117 articles inappropriately and 15 articles had been mixed in the appropriateness of their use. CONCLUSION: This systematic review highlights the inappropriate use of the SCOFF in diverse languages and settings. When used correctly the SCOFF has made a significant contribution to the understanding of eating disorders and its simplicity has been applauded and led to widespread use. However in over two-thirds of studies, the use of the SCOFF was inappropriate and the paper highlights how and in what way it was misused, Guidelines for the appropriate use of the SCOFF are stated. Future validation and avenues of research are suggested. LEVEL OF EVIDENCE: Level I.

Dynamic Entwined Topology in Helical Covalent Polymers Dictated by Competing Supramolecular Interactions.

Naturally occurring polymeric structures often consist of 1D polymer chains intricately folded and entwined through non-covalent bonds, adopting precise topologies crucial for their functionality. The exploration of crystalline 1D polymers through dynamic covalent chemistry (DCvC) and supramolecular interactions represents a novel approach for developing crystalline polymers. This study shows that sub-angstrom differences in the counter-ion size can lead to various helical covalent polymer (HCP) topologies, including a novel metal-coordination HCP (m-HCP) motif. Single-crystal X-ray diffraction (SCXRD) analysis of HCP-Na revealed that double helical pairs are formed by sodium ions coordinating to spiroborate linkages to form rectangular pores. The double helices are interpenetrated by the unreacted diols coordinating sodium ions. The reticulation of the m-HCP structure was demonstrated by the successful synthesis of HCP-K. Finally, ion-exchange studies were conducted to show the interconversion between HCP structures. This research illustrates how seemingly simple modifications, such as changes in counter-ion size, can significantly influence the polymer topology and determine which supramolecular interactions dominate the crystal lattice.

Ionic Covalent Organic Frameworks Consisting of Tetraborate Nodes and Flexible Linkers.

Covalent organic frameworks (COFs) have emerged as versatile materials with many applications, such as carbon capture, molecular separation, catalysis, and energy storage. Traditionally, flexible building blocks have been avoided due to their potential to disrupt ordered structures. Recent studies have demonstrated intriguing properties and enhanced structural diversity achievable with flexible components by judicious selection of building blocks. This study presents a novel series of ionic COFs (ICOFs) consisting of tetraborate nodes and flexible linkers. These ICOFs use borohydrides to irreversibly deprotonate the alcohol monomers to achieve a high polymerization degree. Structural analysis confirms the dia topologies. Reticulation is explored using various monomers and metal counter-ions. Also, these frameworks exhibit excellent stability in alcohols and coordinating solvents. The materials are tested as single-ion conductive solid-state electrolytes. ICOF-203-Li displays one of the lowest activation energies reported for ion conduction. This tetraborate chemistry is anticipated to facilitate further structural diversity and functionality in crystalline polymers.

Single-Crystal Cage Framework with High Selectivity and Reversibility in Fullerene Binding.

Host-guest chemistry, a pivotal branch of supramolecular chemistry, plays an essential role in understanding and constructing complex structures through non-covalent interactions. Organic molecular cages, characterized by their intrinsic confined cavities, can selectively bind a variety of guest molecules. Their host-guest chemistry has been well studied in the solution phase, and several attempts have been made to encode well-defined molecular architectures into solid-state polymeric materials. However, only limited studies have explored their potential in the solid state, where their lack of robustness and less ordered networks significantly hinder practical applications. Herein, we report the synthesis of a single-crystal cage framework and a systematic study of its host-guest chemistry, spanning from the solution state to the solid state. Our studies reveal that the host-guest interactions inherent to the cage are successfully maintained in the solid-state polymeric material. Furthermore, the framework's robustness allows for the guest molecules (fullerene) to be released triggered by an organic acid (trifluoracetic acid), with subsequent regeneration of the framework through an organic base (triethylamine) treatment. Our findings represent the first synthesis of a robust, single-crystal cage framework exhibiting highly selective and reversible host-guest chemistry, thus showing great potential towards molecular separation application.

3D Covalent Organic Framework as a Metastable Intermediate in the Formation of a Double-Stranded Helical Covalent Polymer.

The design and development of intricate artificial architectures have been pursued for decades. Helical covalent polymer (HCP) was recently reported as an unexpected topology that consists of chiral 1D polymers assembled through weak hydrogen bonds from achiral building blocks. However, many questions remained about the formation, driving force, and the single-handedness observed in each crystal. In this work, we reveal a metastable, racemic, fully covalently cross-linked, 3D covalent organic framework (COF) as an intermediate in the early stage of polymerization, which slowly converts into single-handed HCP double helices through partial fragmentation and self-sorting with the aid of a series of hydrogen bonding. Our work provides an intriguing example where weak noncovalent bonds serve as the determining factor of the overall product structure and facilitate the formation of a sophisticated polymeric architecture.

Neural ensemble dynamics underlying a long-term associative memory.

The brain's ability to associate different stimuli is vital for long-term memory, but how neural ensembles encode associative memories is unknown. Here we studied how cell ensembles in the basal and lateral amygdala encode associations between conditioned and unconditioned stimuli (CS and US, respectively). Using a miniature fluorescence microscope, we tracked the Ca2+ dynamics of ensembles of amygdalar neurons during fear learning and extinction over 6 days in behaving mice. Fear conditioning induced both up- and down-regulation of individual cells' CS-evoked responses. This bi-directional plasticity mainly occurred after conditioning, and reshaped the neural ensemble representation of the CS to become more similar to the US representation. During extinction training with repetitive CS presentations, the CS representation became more distinctive without reverting to its original form. Throughout the experiments, the strength of the ensemble-encoded CS-US association predicted the level of behavioural conditioning in each mouse. These findings support a supervised learning model in which activation of the US representation guides the transformation of the CS representation.

Specific psychological therapies versus other therapies or no treatment for severe and enduring anorexia nervosa.

BACKGROUND: Anorexia nervosa is a psychological condition characterised by self-starvation and fear or wait gain or other body image disturbance. The first line of treatment is specific psychological therapy; however, there is no consensus on best practice for treating people who develop severe and enduring anorexia nervosa (SEAN). Notably, there is no universal definition of SEAN. OBJECTIVES: To evaluate the benefits and harms of specific psychological therapies for severe and enduring anorexia nervosa compared with other specific therapies, non-specific therapies, no treatment/waiting list, antidepressant medication, dietary counselling alone, or treatment as usual. SEARCH METHODS: We used standard, extensive Cochrane search methods. The last search date was 22 July 2022. SELECTION CRITERIA: We included parallel randomised controlled trials (RCTs) of people (any age) with anorexia nervosa of at least three years' duration. Eligible experimental interventions were any specific psychological therapy for improved physical and psychological health in anorexia nervosa, conducted in any treatment setting with no restrictions in terms of number of sessions, modality, or duration of therapy. Eligible comparator interventions included any other specific psychological therapy for anorexia nervosa, non-specific psychological therapy for mental health disorders, no treatment or waiting list, antipsychotic treatment (with or without psychological therapy), antidepressant treatment (with or without psychological therapy), dietary counselling, and treatment as usual as defined by the individual trials. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcomes were clinical improvement (weight restoration to within the normal weight range for participant sample) and treatment non-completion. Results were presented using the GRADE appraisal tool. MAIN RESULTS: We found two eligible studies, but only one study provided usable data. This was a parallel-group RCT of 63 adults with SEAN who had an illness duration of at least seven years. The trial compared outpatient cognitive behaviour therapy for SEAN (CBT-SEAN) with specialist supportive clinical management for SEAN (SSCM-SE) over eight months. It is unclear if there is any difference between the effect of CBT-SEAN versus SSCM-SE on clinical improvement at 12 months (risk ratio (RR) 1.42, 95% confidence interval (CI) 0.66 to 3.05) or treatment non-completion (RR 1.72, 95% CI 0.45 to 6.59). There were no reported data on adverse effects. The trial was at high risk of performance and detection bias. We rated the GRADE level of evidence as very low-certainty for both primary outcomes, downgrading for imprecision and risk of bias concerns. AUTHORS' CONCLUSIONS: This review reports evidence from one trial that evaluated CBT-SEAN versus SSCM-SE. There was very low-certainty evidence of little or no difference in clinical improvement and treatment non-completion between the two therapies. There is a need for larger high-quality trials to determine the benefits of specific psychological therapies for people with SEAN. These should take into account the duration of illness as well as participants' previous experience with evidence-based psychological therapy for anorexia nervosa.

Developments in Pb-210 methodologies to provide chronologies for environmental change.

Chronologies generated from core profiles to apply dates to environmental changes commonly use the measurement of the activity of radionuclides deposited and stratified with physical environmental material. The most commonly reported nuclide to define chronologies covering the last 150 years is Pb-210, for which accepted data processing methodologies in the literature have focussed on the constant rate of supply (CRS) model and the more recently published Bayesian Plum model. This short communication describes a validation approach using defined sediment layers referred to as 'varve' counting, which provide known points of reference to account for uncertainty between generated dates from each model using published Pb-210 measurements. A significant improvement in the chronologies was observed when applying reference date corrections to the models. This was shown to be essential in providing confidence in reported datasets and accuracy of predicted chronologies, which will better inform the interpretation of environmental change, e.g. sedimentation rates, climate change, pollution pathways and land degradation. Generated chronologies from both the CRS and Plum methods showed good agreement with the established varve dates (typically < 4-year difference).

Dynamic Covalent Self-sorting in Molecular and Polymeric Architectures Enabled by Spiroborate Bond Exchange.

Self-sorting is commonly observed in complex reaction systems, which has been utilized to guide the formation of single major by-design molecules. However, most studies have been focused on non-covalent systems, and using self-sorting to achieve covalently bonded architectures is still relatively less explored. Herein, we first demonstrated the dynamic nature of spiroborate linkage and systematically studied the self-sorting behavior observed in the transformation between spiroborate-linked well-defined polymeric and molecular architectures, which is enabled by spiroborate bond exchange. The scrambling between a macrocycle and a 1D helical covalent polymer led to the formation of a molecular cage, whose structures are all unambiguously elucidated by single-crystal X-ray diffraction. The results indicate that the molecular cage is the thermodynamically favored product in this multi-component reaction system. This work represents the first example of a 1D polymeric architecture transforming into a shape-persistent molecular cage, driven by dynamic covalent self-sorting. This study will further guide the design of spiroborate-based materials and open the possibilities for the development of novel complex yet responsive dynamic covalent molecular or polymeric systems.

Cyanurate-Linked Covalent Organic Frameworks Enabled by Dynamic Nucleophilic Aromatic Substitution.

We report, for the first time, highly crystalline cyanurate-linked covalent organic frameworks synthesized via dynamic nucleophilic aromatic substitution. The high crystallinity is enabled by the bond exchange reaction (self-correction) between 2,4,6-triphenoxy-1,3,5-triazine and diphenols via reversible SNAr catalyzed by triazabicyclodecene. The CN-COFs contain flexible backbones that exhibit a unique AA'-stacking due to interlayer hydrogen bonding interactions. The isoreticular expansion study demonstrates the general applicability of this synthetic method. The resulting CN-COFs exhibited good stability, as well as high CO2/N2 selectivity.

Cefazolin susceptibility of coagulase-negative staphylococci (CoNS) causing late-onset neonatal bacteraemia.

BACKGROUND: CoNS bacteraemia causes significant neonatal morbidity. Previous work has suggested that ß-lactam antibiotics vary in their binding affinity to PBP2a (produced by the mecA gene) present in most CoNS. OBJECTIVES: We evaluated cefazolin MICs for CoNS isolated in an Australian neonatal ICU (NICU) and correlated them with isolate genotype and phenotype. METHODS: Significant blood isolates from 2009 to 2017 were speciated and underwent broth microdilution testing for cefazolin, cefoxitin, oxacillin and flucloxacillin. Correlation with mecA presence and PBP2a expression was evaluated. A selection of Staphylococcus capitis isolates underwent WGS. RESULTS: The CoNS (n = 99) isolates were confirmed as S. capitis (n = 57), Staphylococcus epidermidis (n = 32), Staphylococcus haemolyticus (n = 2) and Staphylococcus warneri (n = 8). The MIC of cefazolin was ≤2 mg/L for 30% of isolates and 75% had an MIC of ≤8 mg/L (MIC90 = 16 mg/L). This contrasted with MIC90s of cefoxitin, oxacillin and flucloxacillin, which were all ≥32 mg/L. WGS found a number of S. capitis isolates closely related to the globally established NRCS-A clone. CONCLUSIONS: CoNS displayed distinctly lower MIC values of cefazolin than of other agents tested. MIC variation may be related to binding affinity of PBP2a or regulation of expression of mecA by mecR1-mecI functional genes. Further, NRCS-A S. capitis strains were present in this Australian NICU before and after the unit underwent physical relocation, which raised questions about a common environmental source. It is considered justified to conduct a randomized clinical trial that assesses cefazolin versus vancomycin for management of late-onset neonatal sepsis.

S184: preoperative sarcopenia is associated with worse short-term outcomes following transanal total mesorectal excision (TaTME) for rectal cancer.

INTRODUCTION: Malnutrition and deconditioning impact postoperative morbidity and mortality. Computed tomography (CT) body composition variables are used as markers of nutritional status and sarcopenia. The objective of this study is to evaluate the impact of sarcopenia, using CT variables, on postoperative outcomes following transanal total mesorectal excision (TaTME) for rectal cancer. METHODS: This was an institutional retrospective cohort analysis of consecutive rectal cancer patients who underwent TaTME between April 2014 and May 2020. Psoas muscle index (PMI) was calculated from diagnostic CT scans. Based on previous studies, patients in the lowest PMI tertile by gender were considered sarcopenic. Fisher's exact and Mann-Whitney U test were used to compare categorical and continuous variables, respectively. Readmission rates and postoperative complications were compared between groups. Backward stepwise logistic regression was used to determine the association between sarcopenia and 30-day postoperative complications. RESULTS: 85 patients were analyzed, of which 63% were male, with a median age of 59 (IQR: 51-65), and median BMI of 28 (IQR: 24-32). Of the entire cohort, 34% (n = 29) were sarcopenic (median PMI 5.39 IQR: 4.49-6.71). No significant difference in baseline characteristics between sarcopenic and nonsarcopenic patients were observed. 55% of sarcopenic patients experienced a complication within 30 days compared to 24% of nonsarcopenic patients (p = 0.01). 41% of sarcopenic patients required hospital readmission within 30 days compared to 17% of their nonsarcopenic counterparts (p = 0.014). Sarcopenic patients also experienced significantly higher rates of post-operative small bowel obstruction (10% vs. 0%, p = 0.04). Multivariable analyses identified that sarcopenic patients have a fourfold increase in odds of experiencing a 30-day postoperative complication (OR: 4.44, 95%CI: 1.6-12.4, p < 0.05) after adjusting for gender. CONCLUSION: Preoperative sarcopenia is associated with increased 30-day postoperative complications following TaTME for rectal cancer. Postoperative complications can have serious oncologic implications by delaying adjuvant chemotherapy. Therefore, preoperative recognition of sarcopenia prior to undergoing TaTME for rectal cancer may provide an opportunity for early intervention with prehabilitation programs.

Self-esteem as a catalyst for change in adolescent inpatients with anorexia nervosa: a pilot randomised controlled trial.

PURPOSE: To determine the potential effectiveness of a six-session manualised self-esteem group using CBT approaches when given as an adjuvant to adolescent inpatients with Anorexia Nervosa (AN). METHODS: Using a randomised controlled design, 50 girls aged 12-17 years with AN were assigned to either self-esteem group with treatment as usual (TAU) (n = 25) or TAU alone (n = 25). 50/78 (64%) consented to be randomised. Both groups completed self-report measures of self-esteem and eating disorder psychopathology at three time points to measure the potential effectiveness of the treatment. Qualitative feedback was collected to assess acceptability. RESULTS: 29 participants completed the study: 15 self-esteem group with TAU, 14 TAU alone. Self-esteem group participants had greater improvement in all outcomes than TAU participants at all time points, the difference in self-report self-esteem at T2 is 1.12 (95% CI - 1.44-3.69; effect size = 0.21). Similar small effect sizes were found for the eating disorder psychopathology measure following completion of the intervention but not at four-week follow-up. Favourable qualitative feedback was gained. CONCLUSION: These findings demonstrate that the self-esteem group supplements an intensive treatment package which also addresses elements of low self-esteem. The self-esteem group was beneficial for addressing self-esteem and acted as a catalyst for change in eating disorder psychopathology. Positive qualitative feedback indicated the intervention was acceptable to users. Self-esteem group is a potential new adjuvant treatment for AN. EMB RATING: Level 1.

Disturbed families or families disturbed: a reconsideration.

BACKGROUND: The relationship between anorexia nervosa (AN) and family disturbance has been a subject of debate since its first description. What began as a clear view of the pathologically disturbed family causing AN has become ever more complex over the decades. OBJECTIVE: The aim of this review is to explore the literature to examine the changes and evolution of clinical opinion around family dysfunction and AN over the last 20 years. METHODS: A narrative review of heterogeneous studies in peer-reviewed publications sourced from the major databases, including PubMed and ScienceDirect, to illuminate the topic of family distress and AN by highlighting the conflicting and complementary ways it has been studied. RESULTS: This review has highlighted the complexity of the relationship between anorectic sufferers and their families. It has explored the literature about parental burden, emotions and cognitive mechanisms together with parental attitudes about weight and shape. It is clear that there is no consistent psycho-social pathology in families which has been shown to be causative. However, over the last twenty years, research has highlighted the distress and family dysfunction caused by having to look after an anoretic child with poor mentalisation skills, insecure attachment and emotion dysregulation. CONCLUSION: The area has become clearer over the last 20 years; research suggests a bi-directional relationship between AN and family dysfunction, with difficult dynamics becoming entrenched within the family. This is best addressed, the consensus suggests, by specialist family therapy and carer skills interventions. Longitudinal research is needed to definitively answer the question with rigorous scientific certainty. EMB RATING: Level V. LEVEL OF EVIDENCE: Level I: Evidence obtained from: at least one properly designed randomized controlled trials; systematic reviews and meta-analyses; experimental studies. Level II: Evidence obtained from well-designed controlled trials without randomization. Level III: Evidence obtained from well-designed cohort or case-control analytic studies. Level IV: Evidence obtained from with multiple time series analysis such as case studies. Dramatic results in uncontrolled trials might also be regarded as this type of evidence. Level V: Opinions of respected authorities, based on descriptive studies, narrative reviews, clinical experience, or reports of expert committees.

sp-Carbon Incorporated Conductive Metal-Organic Framework as Photocathode for Photoelectrochemical Hydrogen Generation.

Metal-organic frameworks (MOFs) have attracted increasing interest for broad applications in catalysis and gas separation due to their high porosity. However, the insulating feature and the limited active sites hindered MOFs as photocathode active materials for application in photoelectrocatalytic hydrogen generation. Herein, we develop a layered conductive two-dimensional conjugated MOF (2D c-MOF) comprising sp-carbon active sites based on arylene-ethynylene macrocycle ligand via CuO4 linking, named as Cu3 HHAE2 . This sp-carbon 2D c-MOF displays apparent semiconducting behavior and broad light absorption till the near-infrared band (1600 nm). Due to the abundant acetylene units, the Cu3 HHAE2 could act as the first case of MOF photocathode for photoelectrochemical (PEC) hydrogen generation and presents a record hydrogen-evolution photocurrent density of ≈260 µA cm-2 at 0 V vs. reversible hydrogen electrode among the structurally-defined cocatalyst-free organic photocathodes.

CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study.

BACKGROUND: Standard chemotherapy remains inadequate in metastatic pancreatic adenocarcinoma. Combining an agonistic CD40 monoclonal antibody with chemotherapy induces T-cell-dependent tumour regression in mice and improves survival. In this study, we aimed to evaluate the safety of combining APX005M (sotigalimab) with gemcitabine plus nab-paclitaxel, with and without nivolumab, in patients with pancreatic adenocarcinoma to establish the recommended phase 2 dose. METHODS: This non-randomised, open-label, multicentre, four-cohort, phase 1b study was done at seven academic hospitals in the USA. Eligible patients were adults aged 18 years and older with untreated metastatic pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status score of 0-1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. All patients were treated with 1000 mg/m2 intravenous gemcitabine and 125 mg/m2 intravenous nab-paclitaxel. Patients received 0·1 mg/kg intravenous APX005M in cohorts B1 and C1 and 0·3 mg/kg in cohorts B2 and C2. In cohorts C1 and C2, patients also received 240 mg intravenous nivolumab. Primary endpoints comprised incidence of adverse events in all patients who received at least one dose of any study drug, incidence of dose-limiting toxicities (DLTs) in all patients who had a DLT or received at least two doses of gemcitabine plus nab-paclitaxel and one dose of APX005M during cycle 1, and establishing the recommended phase 2 dose of intravenous APX005M. Objective response rate in the DLT-evaluable population was a key secondary endpoint. This trial (PRINCE, PICI0002) is registered with ClinicalTrials.gov, NCT03214250 and is ongoing. FINDINGS: Between Aug 22, 2017, and July 10, 2018, of 42 patients screened, 30 patients were enrolled and received at least one dose of any study drug; 24 were DLT-evaluable with median follow-up 17·8 months (IQR 16·0-19·4; cohort B1 22·0 months [21·4-22·7], cohort B2 18·2 months [17·0-18·9], cohort C1 17·9 months [14·3-19·7], cohort C2 15·9 months [12·7-16·1]). Two DLTs, both febrile neutropenia, were observed, occurring in one patient each for cohorts B2 (grade 3) and C1 (grade 4). The most common grade 3-4 treatment-related adverse events were lymphocyte count decreased (20 [67%]; five in B1, seven in B2, four in C1, four in C2), anaemia (11 [37%]; two in B1, four in B2, four in C1, one in C2), and neutrophil count decreased (nine [30%]; three in B1, three in B2, one in C1, two in C2). 14 (47%) of 30 patients (four each in B1, B2, C1; two in C2) had a treatment-related serious adverse event. The most common serious adverse event was pyrexia (six [20%] of 30; one in B2, three in C1, two in C2). There were two chemotherapy-related deaths due to adverse events: one sepsis in B1 and one septic shock in C1. The recommended phase 2 dose of APX005M was 0·3 mg/kg. Responses were observed in 14 (58%) of 24 DLT-evaluable patients (four each in B1, C1, C2; two in B2). INTERPRETATION: APX005M and gemcitabine plus nab-paclitaxel, with or without nivolumab, is tolerable in metastatic pancreatic adenocarcinoma and shows clinical activity. If confirmed in later phase trials, this treatment regimen could replace chemotherapy-only standard of care in this population. FUNDING: Parker Institute for Cancer Immunotherapy, Cancer Research Institute, and Bristol Myers Squibb.

COVID-19 Vaccination-Related Uptake on FDG PET/CT: An Emerging Dilemma and Suggestions for Management.

As mass COVID-19 vaccination is underway, radiologists are encountering transient FDG uptake in normal or enlarged axillary, supraclavicular, and cervical lymph nodes after ipsilateral deltoid vaccination. This phenomenon may confound interpretation in patients with cancer undergoing FDG PET/CT. In this article, we present our institutional approach for management of COVID-19 vaccine-related lymphadenopathy on FDG PET/CT according to early experience. We suggest performing PET/CT at least 2 weeks after vaccination in patients with a cancer for which interpretation is anticipated to be potentially impacted by the vaccination but optimally 4-6 weeks after vaccination given increased immunogenicity of mRNA vaccines and potentially longer time for resolution than lymphadenopathy after other vaccines. PET/CT should not be delayed when clinically indicated to be performed sooner. Details regarding vaccination should be collected at the time of PET/CT to facilitate interpretation. Follow-up recommendations for postvaccination lymphadenopathy are provided, considering the lymph node's morphology and likely clinical relevance. Consideration should be given to administering the vaccine in the arm contralateral to a unilateral cancer to avoid confounding FDG uptake on the side of cancer. Our preliminary experience and suggested institutional approach should guide radiologists in management of patients with cancer undergoing PET/CT after COVID-19 vaccination.