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Liquid biopsy with sequencing of circulating tumor DNA (ctDNA) is a minimally invasive method for sampling body fluids and offers a promising alternative to tissue biopsies that involve greater risks, costs, and time. ctDNA not only identifies actionable targets by revealing unique molecular signatures in cancer, but also may assess treatment response, treatment resistance and progression, and recurrence. Imaging correlates of these applications are already being identified and utilized for various solid tumors. Radiologists have new challenges in interpreting oncologic imaging. Given their integral role in cancer surveillance, they must become familiar with the importance of ctDNA in detecting recurrence and minimal residual disease, measuring treatment response, predicting survival and metastatic patterns, and identifying new molecular therapeutic targets. In this review, we provide an overview of ctDNA testing, and a snapshot of current clinical guidelines from the National Comprehensive Cancer Network and the European Society of Molecular Oncology on the use of ctDNA in lung, breast, colorectal, pancreatic, and hepatobiliary cancers. For each cancer type, we also highlight current research applications of ctDNA that are relevant to the field of diagnostic radiology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Background: Live fuel comprises a significant portion of the fuel consumed in forest and scrub crown fires. However, its flammability remains poorly understood. Although live fuel differs from dead fuel in moisture content, chemical composition, cellular structure and physiological characteristics, its higher moisture content masks the effect of other characteristics on its flammability. Aims: The aim of the study was to delineate and assess the effects of live/dead condition, moisture content and particle size on flammability of gorse (Ulex europaeus L.). Methods: Live and dead gorse material of three size classes (0–3, 3–6, and 6–10 mm in diameter) at six moisture contents (0, 10, 25, 50, 75 and 100%) was tested in a cone calorimeter to evaluate its flammability using new sample preparation and moisture conditioning techniques. Key results: On average, live fuel ignited 21% slower, reached 11% higher peak heat release rate, and had a 12% shorter burn duration than dead fuel of the same moisture content. These differences were most pronounced in coarser material. Conclusions: For gorse, fine dead fuels increase the likelihood of ignition, fine live fuels contribute to high burning intensities, and coarser live and dead fuels prolong combustion. Implications: These findings highlight the need to account for flammability differences between live and dead fuels in fire behaviour models beyond those driven by variations in moisture content. This study compares the flammability of live and dead vegetation at a range of moisture contents and particle sizes. Live fuel took longer to ignite but burned faster and more intensely than dead fuel of the same moisture content, emphasising the importance of live fuel flammability in fire prediction models. [ABSTRACT FROM AUTHOR]

Abstract: Graft-versus-host disease (GVHD) remains a major challenge after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and further understanding of its immunopathology is crucial for developing new treatments. CD70 interacts with CD27 and is upregulated transiently on T cells after recent T-cell receptor (TCR) engagement. Here, we investigated the functional and clinical significance of CD70 expression on T cells during the early posttransplantation period. CD70 was expressed on a subset of highly activated memory T cells within the first 2 weeks after transplant, which then gradually declined in most patients. CD70+ T cells exhibited an open chromatin landscape and a transcriptional profile indicative of intense Myelocytomatosis oncogene (MYC)-driven glycolysis and proliferation. CD4+ and CD8+CD70+ T-cell numbers increased by ninefold and fourfold, respectively, during acute GVHD (aGVHD) and displayed an oligoclonal TCR repertoire. These cells expressed CCR4 and CCR6 chemokine receptors and were markedly increased in aGVHD tissue samples. Furthermore, CD70+ T cells demonstrated alloreactive specificity in vitro, and proliferative and inflammatory cytokine responses were markedly attenuated by CD70 blockade. These findings identify CD70 as a marker of highly activated alloreactive T cells and reveal the potential therapeutic importance of inhibiting CD27-CD70 costimulation in both the prophylaxis and treatment of aGVHD., (© 2024 by The American Society of Hematology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Objective: To examine the association between missed CMS Star Ratings quality measures for medication adherence over 3 years for diabetes, hypertension, and hyperlipidemia medications (9 measures) and health care utilization and relative costs., Study Design: Retrospective cohort study., Methods: The study examined eligible patients who qualified for the diabetes, statin, and renin-angiotensin system antagonist medication adherence measures in 2018, 2019, and 2020 and were continuously enrolled in a Medicare Advantage prescription drug plan from 2017 through 2021. A total of 103,900 patients were divided into 4 groups based on the number of adherence measures missed (3 medication classes over 3 years): (1) missed 0 measures, (2) missed 1 measure, (3) missed 2 or 3 measures, and (4) missed 4 or more measures. To achieve a quality measure, patients had to meet the Pharmacy Quality Alliance 80% threshold of proportion of days covered during the calendar year., Results: The mean age of the cohort was 71.1 years, and 49.9% were female. Compared with patients who missed 0 of 9 adherence measures, those who missed 1 measure, 2 or 3 measures, and 4 or more measures experienced 12% to 26%, 22% to 42%, and 24% to 50% increased risks, respectively, of all-cause and diabetes-related inpatient stays and all-cause and diabetes-related emergency department visits (all  P  values < .01). Additionally, patients who missed 1, 2 or 3, and 4 or more adherence measures experienced 14%, 19%, and 20% higher monthly medical costs, respectively., Conclusions: Missing Star Ratings quality measures for medication adherence was associated with an increased likelihood of health care resource utilization and increased costs for patients taking medications to treat diabetes, hypertension, and hyperlipidemia.

Background. Wildfire spread is influenced significantly by the weather variability. Wind speed and direction changes, resulting from synoptic weather systems and small-scale meteorological processes in complex terrain, can drastically alter fire intensity and spread. Aims. To investigate the use of vector wind change (VWC) integrated with the Fire Weather Index (FWI) as a new metric in fire danger. Methods. A 20-year FWI and modified FWI was calculated from weather station and gridded numerical weather simulation data. Key results. High VWC is found primarily on the South Island, inland and in areas of complex terrain. After incorporating VWC into the FWI, data from the modified FWI show spatiotemporal patterns that highlight the impact of wind variability in the fire danger. Conclusions. High VWC station data mapped with synoptic type suggest the primary factor in determining high VWC is meso- and micro-scale terrain-driven meteorology, not larger synoptic regimes. Implications. The current fire danger metric, the Fire Weather Index (FWI), does not include wind direction changes for high wind speeds. Therefore, the inclusion of VWC as an additional metric in fire danger calculations in a modified FWI could increase operational understanding of high-danger locations and terrain impacts on extreme and unpredictable fire behaviour. [ABSTRACT FROM AUTHOR]

Background: Galectins (Gal's) are a family of carbohydrate-binding proteins that are known to support the tumour microenvironment through their immunosuppressive activity and ability to promote metastasis. As such they are attractive therapeutic targets, but little is known about the cellular expression pattern of galectins within the tumour and its neighbouring stromal microenvironment. Here we investigated the cellular expression pattern of Gals within pancreatic ductal adenocarcinoma (PDAC)., Methods: Galectin gene and protein expression were analysed by scRNAseq (n=4) and immunofluorescence imaging (n=19) in fibroblasts and epithelial cells of pancreatic biopsies from PDAC patients. Galectin surface expression was also assessed on tumour adjacent normal fibroblasts and cancer associated primary fibroblasts from PDAC biopsies using flow cytometry., Results: scRNAseq revealed higher Gal-1 expression in fibroblasts and higher Gal-3 and -4 expression in epithelial cells. Both podoplanin (PDPN + , stromal/fibroblast) cells and EpCAM + epithelial cells expressed Gal-1 protein, with highest expression seen in the stromal compartment. By contrast, significantly more Gal-3 and -4 protein was expressed in ductal cells expressing either EpCAM or PDPN, when compared to the stroma. Ductal Gal-4 cellular expression negatively correlated with ductal Gal-1, but not Gal-3 expression. Higher ductal cellular expression of Gal-1 correlated with smaller tumour size and better patient survival., Conclusions: In summary, the intricate interplay and cell-specific expression patterns of galectins within the PDAC tissue, particularly the inverse correlation between Gal-1 and Gal-4 in ducts and its significant association with patient survival, highlights the complex molecular landscape underlying PDAC and provides valuable insights for future therapeutic interventions., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AJI and HMM have received funding from Roche. All authors have no conflict of interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The systemic and local immunosuppression exhibited by pancreatic ductal adenocarcinoma (PDAC) contributes significantly to its aggressive nature. There is a need for a greater understanding of the mechanisms behind this profound immune evasion, which makes it one of the most challenging malignancies to treat and thus one of the leading causes of cancer death worldwide. The gut microbiome is now thought to be the largest immune organ in the body and has been shown to play an important role in multiple immune-mediated diseases. By summarizing the current literature, this review examines the mechanisms by which the gut microbiome may modulate the immune response to PDAC. Evidence suggests that the gut microbiome can alter immune cell populations both in the peripheral blood and within the tumour itself in PDAC patients. In addition, evidence suggests that the gut microbiome influences the composition of the PDAC tumour microbiome, which exerts a local effect on PDAC tumour immune infiltration. Put together, this promotes the gut microbiome as a promising route for future therapies to improve immune responses in PDAC patients.

Tracheostomies are indicated in children to facilitate long-term ventilatory support, aid in the management of secretions, or manage upper airway obstruction. Children with tracheostomies often experience ongoing airway complications, of which respiratory tract infections are common. They subsequently receive frequent courses of broad-spectrum antimicrobials for the prevention or treatment of respiratory tract infections. However, there is little consensus in practice with regard to the indication for treatment/prophylactic antimicrobial use, choice of antimicrobial, route of administration, or duration of treatment between different centers. Routine antibiotic use is associated with adverse effects and an increased risk of antimicrobial resistance. Tracheal cultures are commonly obtained from pediatric tracheostomy patients, with the aim of helping guide antimicrobial therapy choice. However, a positive culture alone is not diagnostic of infection and the role of routine surveillance cultures remains contentious. Inhaled antimicrobial use is also widespread in the management of tracheostomy-associated infections; this is largely based on the theoretical benefits of higher airway antibiotic concentrations. The role of prophylactic inhaled antimicrobial use for tracheostomy-associated infections remains largely unproven. This systematic review summarizes the current evidence base for antimicrobial selection, duration, and administration route in pediatric tracheostomy-associated infections. It also highlights significant variation in practice between centers and the urgent need for further prospective evidence to guide the management of these vulnerable patients., (© 2023 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The classification and quantification of fuel is traditionally a labour-intensive, costly and often subjective operation, especially in hazardous vegetation types, such as gorse (Ulex europaeus L.) scrub. In this study, unmanned aerial vehicle (UAV) technologies were assessed as an alternative to traditional field methodologies for fuel characterisation. UAV laser scanning (ULS) point clouds were captured, and a variety of spatial and intensity metrics were extracted from these data. These data were used as predictor variables in models describing destructively and non-destructively sampled field measurements of total above ground biomass (TAGB) and above ground available fuel (AGAF). Multiple regression of the structural predictor variables yielded correlations of R2 = 0.89 and 0.87 for destructively sampled measurements of TAGB and AGAF, respectively, with relative root mean square error (RMSE) values of 18.6% and 11.3%, respectively. The best metrics for non-destructive field-measurements yielded correlations of R2 = 0.50 and 0.49, with RMSE values of 40% and 30.8%, for predicting TAGB and AGAF, respectively, indicating that ULS-derived structural metrics offer higher levels of precision. UAV-derived versions of the field metrics (overstory height and cover) predicted TAGB and AGAF with R2 = 0.44 and 0.41, respectively, and RMSE values of 34.5% and 21.7%, demonstrating that even simple metrics from a UAV can still generate moderate correlations. In further analyses, UAV photogrammetric data were captured and automatically processed using deep learning in order to classify vegetation into different fuel categories. The results yielded overall high levels of precision, recall and F1 score (0.83 for each), with minimum and maximum levels per class of F1 = 0.70 and 0.91. In conclusion, these ULS-derived metrics can be used to precisely estimate fuel type components and fuel load at fine spatial resolutions over moderate-sized areas, which will be useful for research, wildfire risk assessment and fuel management operations. [ABSTRACT FROM AUTHOR]

Background. Complex interactions between fuel structure and fire substantially affect fire spread and spatial variability in fire behaviour. Heterogeneous arrangement of the fuel coupled with variability in fuel characteristics can impact heat transfer efficiency, preheating of unburned fuel and consequent ignition and spread. Aim. Study the influence of pre-burn fuel structure (canopy height, spatial arrangement) on fire behaviour (rate of spread, flame residence time) derived from high-resolution video of a prescribed gorse fire. Method. Rate of spread and flame residence time are calculated and mapped from high-resolution overhead visible-spectrum video, and compared with the Canopy Height Model derived from pre-burn Light Detection and Ranging (Lidar) scans. Results. Geospatial analytics can provide precision observations of fire behaviour metrics. Rates of spread under high wind conditions are influenced by local changes in canopy height and may be more dependent on other fuel characteristics, while flame residence time is better correlated with canopy height. Conclusions. These observational technology and spatio-temporal analytical techniques highlight how detailed fire behaviour characteristics can be derived from these data. Implications. The results have implications for wildfire modelling and Wildland--Urban Interface (WUI) building design engineers, as the reported dataset is suitable for model validation and the analysis contributes to further understanding of gorse fire hazard. [ABSTRACT FROM AUTHOR]

Wildfire is a highly variable natural phenomenon, yet despite this, climate change is already making wildfire conditions measurably worse around the world; however, detailed knowledge about Aotearoa New Zealand's wildfire climate is currently limited. This study blends weather observations with regional climate model projections to assess Aotearoa New Zealand's 21st‐century wildfire climate. We find that in the 21st‐century, the emergence of a new—more severe wildfire climate will occur. Detailed analysis of observed and simulated wildfire weather finds that "very‐extreme" wildfire weather conditions matching the levels observed in Australia's 2019/2020 "Black Summer" bushfires are possible in regions formerly unaffected. While the extent of emergence is dependent on future emissions, the frequency of very‐extreme conditions for the areas affected can occur at any time and is independent of projected 21st‐century climate changes. Our findings have significant implications for many rural fire authorities, forest managers and investors, and climate mitigation and afforestation programs. Plain Language Summary: Combining highly detailed climate simulations with daily observations of weather and wildfire conditions, we simulate Aotearoa New Zealand's current and future wildfire weather conditions. We find that wildfire weather conditions will increase on average, both in wildfire season length and in the intensity of fires that may take hold, with the most severe wildfire dangers in the central‐south inland areas of the South Island. We find that the wildfire weather conditions will become noticeably worse for many regions than current conditions. For the first time, we find that very‐extreme conditions that led to the devastating 2019–2020 "Black‐Summer" fires in Australia can occur in Aotearoa every 3–20 year for areas of the South Island (Mackenzie Country, Upper Otago, and Marlborough). Our findings have important implications for communities near pine forests, the Government's tree planting plan to tackle climate change, and financial investment stored in plantation forests. Key Points: In the 21st‐century, the emergence of a new—more severe wildfire climate will occurWe discover that "very‐extreme" wildfire weather conditions are possible in regions formerly unaffectedWhile the extent of emergence is dependent on future emissions, the frequency of very‐extreme conditions is independent [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma has a poor clinical outcome and responses to immunotherapy are suboptimal. Stromal fibroblasts are a dominant but heterogenous population within the tumor microenvironment and therapeutic targeting of stromal subsets may have therapeutic utility. Here, we combine spatial transcriptomics and scRNA-Seq datasets to define the transcriptome of tumor-proximal and tumor-distal cancer-associated fibroblasts (CAFs) and link this to clinical outcome. Tumor-proximal fibroblasts comprise large populations of myofibroblasts, strongly expressed podoplanin, and were enriched for Wnt ligand signaling. In contrast, inflammatory CAFs were dominant within tumor-distal subsets and expressed complement components and the Wnt-inhibitor SFRP2. Poor clinical outcome was correlated with elevated HIF-1α and podoplanin expression whilst expression of inflammatory and complement genes was predictive of extended survival. These findings demonstrate the extreme transcriptional heterogeneity of CAFs and its determination by apposition to tumor. Selective targeting of tumor-proximal subsets, potentially combined with HIF-1α inhibition and immune stimulation, may offer a multi-modal therapeutic approach for this disease., Competing Interests: WC, HP, SM, LL, SN, FZ, DB, FM, SP, BM, RM, JZ, GM, KR, RB, PM No competing interests declared, (© 2023, Croft, Pearce et al.)

Pancreatic ductal adenocarcinoma (PDAC) has a poor clinical outlook. Responses to immune checkpoint blockade are suboptimal and a much more detailed understanding of the tumor immune microenvironment is needed if this situation is to be improved. Here, we characterized tumor-infiltrating T-cell populations in patients with PDAC using cytometry by time of flight (CyTOF) and single-cell RNA sequencing. T cells were the predominant immune cell subset observed within tumors. Over 30% of CD4+ T cells expressed a CCR6+CD161+ Th17 phenotype and 17% displayed an activated regulatory T-cell profile. Large populations of CD8+ tissue-resident memory (TRM) T cells were also present and expressed high levels of programmed cell death protein 1 (PD-1) and TIGIT. A population of putative tumor-reactive CD103+CD39+ T cells was also observed within the CD8+ tumor-infiltrating lymphocytes population. The expression of PD-1 ligands was limited largely to hemopoietic cells whilst TIGIT ligands were expressed widely within the tumor microenvironment. Programmed death-ligand 1 and CD155 were expressed within the T-cell area of ectopic lymphoid structures and colocalized with PD-1+TIGIT+ CD8+ T cells. Combinatorial anti-PD-1 and TIGIT blockade enhanced IFNγ secretion and proliferation of T cells in the presence of PD-1 and TIGIT ligands. As such, we showed that the PDAC microenvironment is characterized by the presence of substantial populations of TRM cells with an exhausted PD-1+TIGIT+ phenotype where dual checkpoint receptor blockade represents a promising avenue for future immunotherapy., (©2023 The Authors; Published by the American Association for Cancer Research.)

This study presents two new remote sensing approaches that can be used to derive rate of spread and flaming zone velocities of a wildfire at very high spatiotemporal resolution. Time sequential image tracking from thermal or visible video collected on uncrewed aerial vehicles is used to estimate instantaneous spatial rate of spread of a surface fire. The techniques were developed using experimental wheat‐stubble burns carried out near Darfield, New Zealand, in March 2019. The thermal tracking technique is based on Thermal Image Velocimetry, which tracks evolving temperature patterns within an infrared video. The visible tracking technique uses colour thresholding, and tracks fire perimeter progression through time at pixel resolution. Results show that the visible perimeter tracking creates a higher mean rate of spread compared to thermal image velocimetry. The visible perimeter tracking provides rate of spread measurements for fire front progression whereas the thermal tracking techniqueis computationally more expensive, but can resolve velocities of thermal structures within the flaming zone and provides spatiotemporal rate of spread measurements. Both techniques are available as open‐source code and providevital scientific data for new studies concerning e.g. fire–atmospheric interactions or model validation. They may be adapted for operational purposes providing rate of spread at high spatiotemporal resolution. We present two new algorithms that can retrieve rate of spread and flaming velocities of fires from uncrewed aerial vehicles. The thermal tracking is well suited for studying fire–atmospheric interactions whereas the visible image tracking estimates the fire perimeter. Both techniques are available open‐source and may be adapted for operational purposes. [ABSTRACT FROM AUTHOR]

Allogeneic stem cell transplantation is used widely in the treatment of hematopoietic malignancy. However, relapse of malignant disease is the primary cause of treatment failure and reflects loss of immunological graft-versus-leukemia effect. We studied the transcriptional and phenotypic profile of CD8+ T cells in the first month following transplantation and related this to risk of subsequent relapse. Single cell transcriptional profiling identified five discrete CD8+ T-cell clusters. High levels of T-cell activation and acquisition of a regulatory transcriptome were apparent in patients who went on to suffer disease relapse. A relapse-associated gene signature of 47 genes was then assessed in a confirmation cohort of 34 patients. High expression of the inhibitory receptor CD94/NKG2A on CD8+ T cells within the first month was associated with 4.8 fold increased risk of relapse and 2.7 fold reduction in survival. Furthermore, reduced expression of the activatory molecule CD96 was associated with 2.2 fold increased risk of relapse and 1.9 fold reduction in survival. This work identifies CD94 and CD96 as potential targets for CD8-directed immunotherapy in the very early phase following allogeneic transplantation with the potential to reduce long term relapse rates and improve patient survival.

Consumer concern about farmed animal welfare is growing but does not always translate into real-world purchasing behaviour of welfare-friendly animal products for human consumption. Possible reasons for this include unfamiliarity with farming practices and economic sensitivity. In contrast, the number and role of pets in the United States have grown measurably, and spending on pets is strong. The pet food market has many opportunity niches as pet owners navigate strong marketing trends and nutrition philosophies. We hypothesised that pet owners in the US would be willing to pay a premium for pet food containing welfare-friendly animal ingredients. Eight hundred and thirty-eight pet owners completed an online survey asking questions that measured their knowledge of and interest in farm animal welfare, and their willingness-to-pay for pet food labelled as farm animal welfare-friendly. Respondents overall displayed relatively low knowledge about farm animal welfare, but poor self-assessment of their own knowledge. They displayed interest in farm animal welfare and an overall positive mean willingness-to-pay (WTP) for welfare-friendly pet food. Younger respondents, women and cat owners displayed a higher WTP than older respondents, men and dog owners. Income level was not correlated to WTP. Creating pet food products that contain animal ingredients produced using welfare-friendly practices may enhance farm animal welfare via two primary avenues: by providing a sustainable and value-added outlet for the by-products of welfare-friendly human food products, and by providing an educational opportunity about farm animal production via pet food packaging and other advertising., Competing Interests: HP was an employee of Hill’s Pet Nutrition during the preparation and writing of this manuscript, but all work was carried out independently using non-company time and resources. Hill’s Pet Nutrition was not involved in any part of the preparation of this manuscript and this work does not reflect their views or opinions. No other authors have any conflicts of interest to declare. There was no external funding source for this work., (© The Author(s) 2023.)

Alport syndrome is a rare genetic disease that results in disordered basement membrane type IV collagen resulting in haematuria, proteinuria and often development of renal fibrosis leading to progressive kidney disease. The therapeutic blockage of the renin-angiotensin-aldosterone system, which slows the progression to kidney failure, is supported by strong evidence. Recent clinical trials using sodium-glucose co-transporter-2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists (MRA) in patients with chronic kidney disease have changed the therapeutic landscape. Patients with Alport syndrome and progressive kidney disease may benefit from treatment with MRAs because research has shown that these drugs are nephroprotective through a variety of mechanisms, including by preventing fibrosis. Ongoing clinical trials show great promise in order to help establish the long-term safety and efficacy of Finerenone, a MRA. This review discusses the evidence for the use of MRAs as a potential treatment in Alport syndrome that may slow the progression of chronic kidney disease and prevent patients reaching kidney failure., Competing Interests: Competing interestNo conflicts of interest., (© The Author(s) 2023, corrected publication 2024.)

Although the COVID-19 pandemic has been shown to be detrimental to mental health, it may hold a parallel potential for positive change. Little is known about posttraumatic growth (PTG) as a potential outcome for individuals with lived experience of psychiatric disorders following trauma exposure, especially in the context of the COVID-19 pandemic. Participants were 1,424 adults with lived experience of a psychiatric disorder who took part in a longitudinal study of mental health during the COVID-19 pandemic conducted by the National Centre for Mental Health. PTG was measured using the Posttraumatic Growth Inventory-Short Form (PTGI-SF). Factors hypothesized to be associated with PTG were investigated using linear regression. The mean participant PTGI score was 12.64 (SD = 11.01). On average, participants reported the highest scores on items related to appreciation of life and lowest on those related to spiritual change subscale. We found the strongest evidence of associations between higher levels of PTG and higher scores on assessment items related to perceived social support, B = 2.86; perceptions of the pandemic as traumatic, B = 4.89; and higher psychological well-being, B = 0.40. Taken together, we did not observe evidence of widespread PTG related to the COVID-19 pandemic among individuals with lived experiences of psychiatric disorders., (© 2022 The Authors. Journal of Traumatic Stress published by Wiley Periodicals LLC on behalf of International Society for Traumatic Stress Studies.)

Immune checkpoint blockade has recently proven effective in subsets of patients with esophageal adenocarcinoma (EAC) but little is known regarding the EAC immune microenvironment. We determined the single cell transcriptional profile of EAC in 8 patients who were treatment-naive (n = 4) or had received neoadjuvant chemotherapy (n = 4). Analysis of 52,387 cells revealed 10 major cell subsets of tumor, immune and stromal cells. Prior to chemotherapy tumors were heavy infiltrated by T regulatory cells and exhausted effector T cells whilst plasmacytoid dendritic cells were markedly expanded. Two dominant cancer-associated fibroblast populations were also observed whilst endothelial populations were suppressed. Pathological remission following chemotherapy associated with broad reversal of immune abnormalities together with fibroblast transition and an increase in endothelial cells whilst a chemoresistant epithelial stem cell population correlated with poor response. These findings reveal features that underlie and limit the response to current immunotherapy and identify a range of novel opportunities for targeted therapy., (© 2022. The Author(s).)

Objective: To establish factors associated with ICD-11 post-traumatic stress disorder (PTSD) and complex PTSD (CPTSD) in a large sample of adults with lived experience of psychiatric disorder and examine the psychiatric burden associated with the two disorders., Methods: One thousand three hundred and five adults were recruited from the National Centre for Mental Health (NCMH) cohort. ICD-11 PTSD/CPTSD were assessed with the International Trauma Questionnaire (ITQ). Binary logistic regression was used to determine factors associated with both PTSD and CPTSD. One-way between-groups analysis of variance was conducted to examine the burden associated with the two disorders in terms of symptoms of anxiety, depression, and psychological wellbeing. For post-hoc pairwise comparisons, the Tukey HSD test was used, and the magnitude of between-group differences assessed using Cohen's d., Results: Probable ICD-11 CPTSD was more common than PTSD within the sample (PTSD 2.68%; CPTSD 12.72%). We found evidence that PTSD was associated with interpersonal trauma and household income under £20,000 a year. CPTSD was also associated with interpersonal trauma, higher rates of personality disorder, and lower rates of bipolar disorder. Those with probable-CPTSD had higher levels of current anxiety and depressive symptoms and lower psychological wellbeing in comparison to those with probable-PTSD and those with neither disorder., Conclusions: CPTSD was more prevalent than PTSD in our sample of people with lived experience of psychiatric disorder. Our findings indicate a need for routine screening for trauma histories and PTSD/CPTSD in clinical settings and a greater focus on the need for interventions to treat CPTSD., (© 2022 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Background: Prevalence estimates of COVID-19-related posttraumatic stress disorder (PTSD) have ranged from 1% to over 60% in the general population. Individuals with lived experience of a psychiatric disorder may be particularly vulnerable to COVID-19-related PTSD but this has received inadequate attention., Methods: Participants were 1571 adults with lived experience of psychiatric disorder who took part in a longitudinal study of mental health during the COVID-19 pandemic. PTSD was assessed by the International Trauma Questionnaire (ITQ) anchored to the participant's most troubling COVID-19-related experiencevent. Factors hypothesised to be associated with traumatic stress symptoms were investigated by linear regression., Results: 40.10% of participants perceived some aspect of the pandemic as traumatic. 5.28% reported an ICD-11 PTSD qualifying COVID-19 related traumatic exposure and 0.83% met criteria for probable ICD-11 COVID-19-related PTSD. Traumatic stress symptoms were associated with younger age, lower income, lower social support, and financial worries, and lived experience of PTSD/complex PTSD. Depression and anxiety measured in June 2020 predicted traumatic stress symptoms at follow-up approximately 20 weeks later in November 2020., Conclusions: We did not find evidence of widespread COVID-19-related PTSD among individuals with lived experience of a psychiatric disorder. There is a need for future research to derive valid prevalence estimates of COVID-19-related PTSD., (© The Authors. Depression and Anxiety published by Wiley Periodicals LLC.)

Oesophageal cancer is a disease that causes significant morbidity and mortality worldwide, and the prognosis of this condition has hardly improved in the past few years. Standard treatment includes a combination of chemotherapy, radiotherapy and surgery; however, only a proportion of patients go on to treatment intended to cure the disease due to the late presentation of this disease. New treatment options are of utmost importance, and immunotherapy is a new option that has the potential to transform the landscape of this disease. This treatment is developed to act on the changes within the immune system caused by cancer, including checkpoint inhibitors, which have recently shown great promise in the treatment of this disease and have recently been included in the adjuvant treatment of oesophageal cancer in many countries worldwide. This review will outline the mechanisms by which cancer evades the immune system in those diagnosed with oesophageal cancer and will summarize current and ongoing trials that focus on the use of our own immune system to combat disease.

We studied humoral and cellular immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 152 long-term care facility staff and 124 residents over a prospective 4-month period shortly after the first wave of infection in England. We show that residents of long-term care facilities developed high and stable levels of antibodies against spike protein and receptor-binding domain. Nucleocapsid-specific responses were also elevated but waned over time. Antibodies showed stable and equivalent levels of functional inhibition against spike-angiotensin-converting enzyme 2 binding in all age groups with comparable activity against viral variants of concern. SARS-CoV-2 seropositive donors showed high levels of antibodies to other beta-coronaviruses but serostatus did not impact humoral immunity to influenza or other respiratory syncytial viruses. SARS-CoV-2-specific cellular responses were similar across all ages but virus-specific populations showed elevated levels of activation in older donors. Thus, survivors of SARS-CoV-2 infection show a robust and stable immunity against the virus that does not negatively impact responses to other seasonal viruses., (© 2022. The Author(s).)

SARS-CoV-2 infection is generally mild or asymptomatic in children but a biological basis for this outcome is unclear. Here we compare antibody and cellular immunity in children (aged 3-11 years) and adults. Antibody responses against spike protein were high in children and seroconversion boosted responses against seasonal Beta-coronaviruses through cross-recognition of the S2 domain. Neutralization of viral variants was comparable between children and adults. Spike-specific T cell responses were more than twice as high in children and were also detected in many seronegative children, indicating pre-existing cross-reactive responses to seasonal coronaviruses. Importantly, children retained antibody and cellular responses 6 months after infection, whereas relative waning occurred in adults. Spike-specific responses were also broadly stable beyond 12 months. Therefore, children generate robust, cross-reactive and sustained immune responses to SARS-CoV-2 with focused specificity for the spike protein. These findings provide insight into the relative clinical protection that occurs in most children and might help to guide the design of pediatric vaccination regimens., (© 2021. The Author(s).)

Non-surgical treatment options for low-grade endometrial cancer and precancerous lesions are a critical unmet need for women who wish to preserve fertility or are unable to undergo hysterectomy. The PI3K/AKT/mTOR pathway is frequently activated in endometrial cancers and has been associated with resistance to endocrine therapy, making it a compelling target for early stage disease. Oral everolimus, an inhibitor against mTORC1, has shown clinical benefit in advanced or recurrent disease but has severe adverse effects that may lead to treatment interruption or dose reduction. To overcome this, we developed a polymer-based intrauterine delivery system to achieve persistent, local delivery of everolimus without systemic exposure. In vivo studies, using a rat model, showed that a poly(propylene fumarate)-based rod loaded with everolimus achieved everolimus delivery to the endometrium with levels similar to oral administration, but with limited systemic exposure and up to 84 days of release. Biological activity of everolimus delivered with this system was confirmed, measured by reduced lumen epithelial cell height and PI3K pathway biomarkers. This study shows a promising new delivery approach for anti-cancer drugs for non-surgical treatment of low-grade endometrial cancer., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Allogeneic immune responses underlie the graft-versus-leukaemia effect of stem cell transplantation, but disease relapse occurs in many patients. Minor histocompatibility antigen (mHAg) peptides mediate alloreactive T cell responses and induce graft-versus-leukaemia responses when expressed on patient haematopoietic tissue. We vaccinated nine HA-1-negative donors against HA-1 with a 'prime-boost' protocol of either two or three DNA 'priming' vaccinations prior to 'boost' with modified vaccinia Ankara (MVA). HA-1-specific CD8 + T cell responses were observed in seven donors with magnitude up to 1·5% of total CD8 + T cell repertoire. HA-1-specific responses peaked two weeks post-MVA challenge and were measurable in most donors after 12 months. HA-1-specific T cells demonstrated strong cytotoxic activity and lysed target cells with endogenous HA-1 protein expression. The pattern of T cell receptor (TCR) usage by HA-1-specific T cells revealed strong conservation of T cell receptor beta variable 7-9 (TRBV7-9) usage between donors. These findings describe one of the strongest primary peptide-specific CD8 + T cell responses yet recorded to a DNA-MVA prime-boost regimen and this may reflect the strong immunogenicity of mHAg peptides. Prime-boost vaccination in donors or patients may prove of substantial benefit in boosting graft-versus-leukaemia responses., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)