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Introduction Inadequate treatment of enlarged lateral lymph nodes (LLNs) in rectal cancer patients is associated with an increased lateral local recurrence (LLR) risk, despite neoadjuvant treatment and total mesorectal excision (TME) surgery. There is a promising role for LLN dissection (LLND) to lower this risk, but this challenging procedure requires appropriate training. This study protocol describes a prospective evaluation of oncological outcomes after standardised treatment based on multidisciplinary training, thereby aiming for a 50% reduction in LLR rate.Methods and analysis A prospective registration study will be opened in hospitals in which the involved multidisciplinary team members (radiologists, radiation oncologists, surgeons and pathologists) have received dedicated training to enhance knowledge and awareness of LLNs and in which standardised treatment including LLND has been implemented. Patients with rectal cancer and at least one enlarged LLN (short-axis ≥7.0 mm), or intermediate LLN (short-axis 5.0–6.9 mm) with at least one malignant feature on primary MRI, evaluated by a trained radiologist, are eligible. Patients will undergo neoadjuvant treatment by trained radiation oncologists, followed by TME surgery in combination with a minimally invasive, nerve-sparing LLND performed by trained surgeons. LLND specimens are evaluated by trained pathologists or grossing assistants. The primary outcome is LLR rate 3 years postoperatively. Secondary outcomes are morbidity, disease-free survival, overall survival and quality of life. To demonstrate a significant reduction in LLR rate from 13% (based on historical control data) to 6% after optimised treatment, 200 patients with enlarged LLNs are required.Ethics and dissemination The medical ethics board of the Vrije Universiteit Medical Centre (VUMC), the Netherlands, approved the study on 23 November 2022 (reference: 2021.0524). Participating centres must obtain local approval and participants are required to provide written informed consent. Results obtained from this study will be communicated via peer-reviewed medical journals and presentations at conferences.Trail registration number NCT04486131, 24 July 2020, https://clinicaltrials.gov/ct2/show/NCT04486131.

Abstract Living objects are able to consume chemical energy and process information independently from others. However, living objects can coordinate to form ordered groups such as schools of fish. This work considers these complex groups as living materials and presents imaging-based experiments of laboratory schools of fish to understand how activity, which is a non-equilibrium feature, affects the structure and dynamics of a group. We use spatial confinement to control the motion and structure of fish within quasi-2D shoals of fish and use image analysis techniques to make quantitative observations of the structures, their spatial heterogeneity, and their temporal fluctuations. Furthermore, we utilize Monte Carlo simulations to replicate the experimentally observed data which provides insight into the effective interactions between fish and confirms the presence of a confinement-based behavioral preference transition. In addition, unlike in short-range interacting systems, here structural heterogeneity and dynamic activities are positively correlated as a result of complex interplay between spatial arrangement and behavioral dynamics in fish collectives.

Infants born to mothers with type 2 diabetes (T2D) and gestational diabetes (GDM) are at an increased risk of being overweight/obese. Modifiable lifestyle factors play a role in prevention of overweight and obesity. In 2017, the Canadian 24 h Movement Guidelines for the Early Years (CMG) were released. Alongside physical activity recommendations, sweetened beverage consumption (SBC) recommendations were also released by the American Academy of Pediatrics in 2017. The objective of this study was to determine the knowledge pregnant women with T2D and GDM have on the CMG and SBC recommendations, and to determine what factors affect this. A survey with questions regarding demographics, socioeconomic variables and the CMG and SBC recommendations was administered to pregnant women at Diabetes in Pregnancy clinics in Calgary, Alberta from July 2019 to January 2020. Surveys were analyzed utilizing the non-parametric Kruskall-Wallis Rank-Sum test, chi-square test and linear regression. A total of 79 respondents with T2D and GDM were collected. Respondents had the highest knowledge of SBC recommendations and the lowest knowledge of CMG recommendations. A bachelor’s or higher degree was associated with significantly higher knowledge scores than a high-school education or less. In conclusion, pregnant women with T2D and GDM in this study had overall poor knowledge of the CMG and SBC recommendations, with less knowledge regarding the CMG. Level of education was found to be associated with knowledge regarding these recommendations. Future programs to improve education around infant and toddler physical activity and SBC recommendations may be beneficial for this patient population.

We interviewed families to explore their views on the role of family navigation (FN) to improve access to and use of health services for managing pediatric obesity. From March to December, 2020, we conducted individual, structured telephone interviews with adolescents with obesity (13-17 years old) and their caregivers from Edmonton and Calgary, Canada. Among our 37 participants (14 adolescents, 23 caregivers), most (n = 27; 73.0%) reported FN could improve their access to obesity management. Participants recommended several activities to support healthcare access and use, including appointment reminders, evening/weekend appointments, parking/transportation support, and in-clinic childcare, all of which help families to attend appointments over an extended period to support obesity management. Most participants preferred FN be offered by healthcare professional ‘navigators’ who were approachable, empathic, and compassionate since issues regarding health and obesity can be sensitive, emotional topics to discuss. Overall, families supported integrating FN into multidisciplinary pediatric obesity management to improve healthcare access and use by navigators who apply a range of practical strategies and relational skills to enhance long-term access and adherence to care.

IntroductionWe present here a strategy to identify immunogenic neoantigen candidates from unique amino acid sequences at the junctions of fusion proteins which can serve as targets in the development of tumor vaccines for the treatment of breastcancer.MethodWe mined the sequence reads of breast tumor tissue that are usually discarded as discordant paired-end reads and discovered cancer specific fusion transcripts using tissue from cancer free controls as reference. Binding affinity predictions of novel peptide sequences crossing the fusion junction were analyzed by the MHC Class I binding predictor, MHCnuggets. CD8+ T cell responses against the 15 peptides were assessed through in vitro Enzyme Linked Immunospot (ELISpot).ResultsWe uncovered 20 novel fusion transcripts from 75 breast tumors of 3 subtypes: TNBC, HER2+, and HR+. Of these, the NSFP1-LRRC37A2 fusion transcript was selected for further study. The 3833 bp chimeric RNA predicted by the consensus fusion junction sequence is consistent with a read-through transcription of the 5’-gene NSFP1-Pseudo gene NSFP1 (NSFtruncation at exon 12/13) followed by trans-splicing to connect withLRRC37A2 located immediately 3’ through exon 1/2. A total of 15 different 8-mer neoantigen peptides discovered from the NSFP1 and LRRC37A2 truncations were predicted to bind to a total of 35 unique MHC class I alleles with a binding affinity of IC50

In spring 2021, during the COVID-19 pandemic, research projects funded by the UK’s Global Challenges Research Fund (GCRF) were subjected to budget cuts. The cuts were the result of UK government’s decision to reduce its Official Development Assistance (ODA), which had devastating effects for humanitarian, development and research work. This article draws on focus group discussions with project teams working on three large GCRF-funded projects to explore the effects of these cuts. The article documents how the cuts curtailed project aspirations and impact, had a negative toll on the mental health of researchers, and imperilled the trusting relationships upon which international research collaborations are built. The article argues that the cuts expose the shallow commitments to research ethics and equitable partnerships of powerful actors in the UK research ecosystem, including research councils and government. In ‘doing harm’ via these cuts, the article explores the failure of research governance structures and the continued coloniality underpinning the UK’s approach to researching ‘global challenges’.

In this study, the authors present an analysis of 247 full-genome SARS-CoV-2 sequences obtained from two communities in Wisconsin, USA, and report distinct patterns of viral spread. Their results suggest that patterns of SARS-CoV-2 transmission and spread may vary substantially, even between neighbouring communities.

This paper tests short-term and mid-term VIX indexes as a hedge and safe haven asset against U.S. stock risk from January 2006 through July 2016. GARCH dynamic conditional correlation analysis indicates that VIX indexes are an effective hedge due to the consistent inverse relationship between the VIX indexes and stocks. VIX indexes are either a strong or weak safe haven in times of extreme stock market volatility. Additionally, VIX indexes provide a strong safe haven during recent periods of turmoil including the 2008 global financial crisis, the 2011 downgrade of the U.S. government triple-A credit rating, and the 2016 U.K. vote to leave the E.U. (Brexit).

This paper summarizes the problems caused for wastewater systems by changing wastewater composition, especially the increasing use of nonwoven wet wipes and their disposal via the toilet. The nonwoven wet wipes do not disintegrate in the sewer system as paper-based toilet does, but accumulate to large agglomerations that can block the system and clog pumps. This not only reduces the operational safety and stability of the wastewater system, but also costs the operator a lot of money. The paper introduces an approach to estimate the composition of wastewater and presents first results for the city of Berlin.

Several contagious diseases were nearly eradicated through childhood vaccination, but some parents have decided in recent years not to fully vaccinate their children, raising new public health concerns. The question of whether and how beliefs about vaccination are linked to political ideology has been hotly debated. This study investigates the effects of ideology on perceptions of harms and benefits related to vaccination as well as judgments of others' attitudes. A total of 367 U.S. adults (131 men, 236 women; Mage = 34.92 years, range = 18-72) completed an online survey through Mechanical Turk. Results revealed that liberals were significantly more likely to endorse pro-vaccination statements and to regard them as "facts" (rather than "beliefs"), in comparison with moderates and conservatives. Whereas conservatives overestimated the proportion of like-minded others who agreed with them, liberals underestimated the proportion of others who agreed with them. That is, conservatives exhibited the "truly false consensus effect," whereas liberals exhibited an "illusion of uniqueness" with respect to beliefs about vaccination. Conservative and moderate parents in this sample were less likely than liberals to report having fully vaccinated their children prior to the age of two. A clear limitation of this study is that the sample is not representative of the U.S.Nevertheless, a recognition of ideological sources of potential variability in health-related beliefs and perceptions is a prerequisite for the design of effective forms of public communication.

Curation and interpretation of copy number variants identified by genome-wide testing is challenged by the large number of events harbored in each personal genome. Conventional determination of phenotypic relevance relies on patterns of higher frequency in affected individuals versus controls; however, an increasing amount of ascertained variation is rare or private to clans. Consequently, frequency data have less utility to resolve pathogenic from benign. One solution is disease-specific algorithms that leverage gene knowledge together with variant frequency to aid prioritization. We used large-scale resources including Gene Ontology, protein-protein interactions and other annotation systems together with a broad set of 83 genes with known associations to epilepsy to construct a pathogenicity score for the phenotype. We evaluated the score for all annotated human genes and applied Bayesian methods to combine the derived pathogenicity score with frequency information from our diagnostic laboratory. Analysis determined Bayes factors and posterior distributions for each gene. We applied our method to subjects with abnormal chromosomal microarray results and confirmed epilepsy diagnoses gathered by electronic medical record review. Genes deleted in our subjects with epilepsy had significantly higher pathogenicity scores and Bayes factors compared to subjects referred for non-neurologic indications. We also applied our scores to identify a recently validated epilepsy gene in a complex genomic region and to reveal candidate genes for epilepsy. We propose a potential use in clinical decision support for our results in the context of genome-wide screening. Our approach demonstrates the utility of integrative data in medical genomics.

Historically, it was thought that healthy humans predominantly described their breathing as a sense of increased work or effort (W/E) during maximal exercise. However, emerging data shows that many healthy adults select unpleasant dyspnea descriptors such as "unsatisfied inspiration" (UI), with relatively more females selecting UI than males. We hypothesized that males and females who select UI would report higher dyspnea intensity ratings during exercise; select more distressing dyspnea qualities post-exercise; and have greater inspiratory constraints than those who do not. Sixty-four healthy, non-smokers (32M:32F; 23±5yr) completed questionnaires, pulmonary function tests, and maximal incremental cycling with detailed dyspnea evaluation. Males in UI and Non-UI subgroups reported similar Borg 0-10 dyspnea intensity ratings of W/E, UI, and unsatisfied expiration (UE) (all P >0.05). Females in the UI subgroup reported significantly higher UI and UE ratings than females in the Non-UI subgroup (both P <0.01). Both UI subgroups reported greater air hunger, chest tightness, and mental breathing effort than Non-UI participants (all P <0.05). In males only, masculine gender was negatively correlated (r=-0.402, P =0.02) and anxiety positively correlated (r=0.363, P =0.04) with submaximal UI ratings. Females with UI had smaller peak tidal volume (V T ) (1.74 (0.32) vs 2.06 (0.33) L, P =0.03) than Non-UI females; and V T was negatively correlated with submaximal (r=-0.496, P =0.004) and peak (r=-0.495, P =0.004) UI ratings in all females. There were no differences in V T or correlations between V T and dyspnea in male subgroups. Absolute lung volumes and psychosocial factors appear important in understanding sex differences in the perception of UI during exercise.

RTS,S/AS01 E , the first approved malaria vaccine, demonstrated moderate efficacy during the phase 3 pediatric trial. We previously investigated cell-mediated immune (CMI) responses following the primary 3-dose immunization and now report responses to the booster dose given 18 months later. Thirty CMI markers were measured by Luminex in supernatants of peripheral blood mononuclear cells from 709 children and infants after RTS,S/AS01 E antigen stimulation, and their associations with malaria risk and antibodies one month post-booster and one year later were assessed. IL-2, IFN-γ, IL-17, IL-5, and IL-13 were associated with RTS,S/AS01 E booster vaccination, and IL-2 responses to the circumsporozoite protein (CSP) remained higher after one year. IL-2 was associated with reduced malaria risk in one site, and IL-10 was associated with increased risk in infants. Anti-CSP IgG and IL-2 were moderately correlated one year after booster. This study highlights the moderate cell-mediated immunogenicity of the RTS,S/AS01 E booster dose that aligns with partial recovery of RTS,S/AS01 E vaccine efficacy., (© 2024. The Author(s).)

Introduction: Contrary to common belief, a growing body of evidence suggests that unsatisfied inspiration (UI), an inherently uncomfortable quality of dyspnea, is experienced by ostensibly healthy adults during high-intensity exercise. Based on our understanding of the mechanisms of UI among people with chronic respiratory conditions, this analysis tested the hypothesis that the experience of UI at peak exercise in young, healthy adults reflects the combination of high ventilatory demand and critical inspiratory constraints., Methods: In a retrospective analysis design, data included 321 healthy individuals (129 females) aged 25 ± 5 yr. Data were collected during one visit to the laboratory, which included anthropometrics, spirometry, and an incremental cardiopulmonary cycling test to exhaustion. Metabolic and cardiorespiratory variables were measured at peak exercise, and qualitative descriptors of dyspnea at peak exercise were assessed using a list of 15 descriptor phrases., Results: Thirty-four percent of participants ( n = 109) reported sensations of UI at peak exercise. Compared with the non-UI group, the UI group achieved a significantly higher peak work rate (243 ± 77 vs 235 ± 69 W, P = 0.016, d = 0.10), rate of O 2 consumption (3.32 ± 1.02 vs 3.27 ± 0.96 L·min -1 , P = 0.018, d = 0.05), minute ventilation (120 ± 38 vs 116 ± 35 L·min -1 , P = 0.047, d = 0.11), and breathing frequency (50 ± 9 vs 47 ± 9 breaths per minute, P = 0.014, d = 0.33), while having a lower exercise-induced change (peak-baseline) in inspiratory capacity (0.07 ± 0.41 vs 0.20 ± 0.49 L, P = 0.023, d = 0.29). The inspiratory reserve volume to minute ventilation ratio at peak exercise was also lower in the UI versus non-UI group. Dyspnea intensity and unpleasantness ratings were significantly higher in the UI versus non-UI group at peak exercise (both P < 0.001)., Conclusions: Healthy individuals reporting UI at peak exercise have relatively greater inspiratory constraints compared with those who do not select UI., (Copyright © 2024 by the American College of Sports Medicine.)

Scedosporium spp. is a fungal species documented as the cause of infections involving the lungs, brain, and other organ systems in both immunocompetent and immunocompromised individuals. Many cases of this type of fungal infection occurring in immunocompetent patients are subsequent to traumatic injury or drowning events in or near waters containing the fungi. Infection commonly involves the lungs. Rarely, it has been shown to cause disease in the endocardium, but there is even less documentation of the fungi invading the myocardium and causing myocarditis. In this report, we present a case of disseminated Scedosporium boydii infection in a 52-year-old male patient without any known risk factors. He presented with acute onset chest pain and dyspnea accompanied by bilateral lower extremity edema. He was found to have new onset heart failure with reduced ejection fraction, and his hospital course was complicated by pneumonia, disseminated intravascular coagulation (DIC), and brain abscess formation. Multiple blood cultures failed to reveal the source of the infection. At autopsy, septated branching hyphae were identified invading both the myocardium and the cortical brain tissue. DNA sequencing revealed the fungal organisms to be Scedosporium boydii. This case reinforces the importance of autopsies in the clinical setting. It not only established the definitive diagnosis of an unexpected fungal infection, but it also helped to recognize new clinical and pathologic features of this particular fungal organism., Competing Interests: Declarations of competing interest Sean X. Zhang declares having received grants or contracts, consulting fees, and support for attending meetings and/or travel. Charles Steenbergen declared having received grants or contracts, and serving in an unpaid leadership or fiduciary role in a board, society, committee or advocacy group. Both authors wish to disclose that these were not related to this study and did not interfere in any way with the study. The other authors did not have any conflicts of interest to disclose., (Copyright © 2024 National Medical Association. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Treatment planning for MR-guided stereotactic body radiotherapy (SBRT) for pancreatic tumors can be challenging, leading to a wide variation of protocols and practices. This study aimed to harmonize treatment planning by developing a consensus planning protocol for MR-guided pancreas SBRT on a 1.5 T MR-Linac., Materials and Methods: A consortium was founded of thirteen centers that treat pancreatic tumors on a 1.5 T MR-Linac. A phased planning exercise was conducted in which centers iteratively created treatment plans for two cases of pancreatic cancer. Each phase was followed by a meeting where the instructions for the next phase were determined. After three phases, a consensus protocol was reached., Results: In the benchmarking phase (phase I), substantial variation between the SBRT protocols became apparent (for example, the gross tumor volume (GTV) D 99% ranged between 36.8 - 53.7 Gy for case 1, 22.6 - 35.5 Gy for case 2). The next phase involved planning according to the same basic dosimetric objectives, constraints, and planning margins (phase II), which led to a large degree of harmonization (GTV D 99% range: 47.9-53.6 Gy for case 1, 33.9-36.6 Gy for case 2). In phase III, the final consensus protocol was formulated in a treatment planning system template and again used for treatment planning. This not only resulted in further dosimetric harmonization (GTV D 99% range: 48.2-50.9 Gy for case 1, 33.5-36.0 Gy for case 2) but also in less variation of estimated treatment delivery times., Conclusion: A global consensus protocol has been developed for treatment planning for MR-guided pancreatic SBRT on a 1.5 T MR-Linac. Aside from harmonizing the large variation in the current clinical practice, this protocol can provide a starting point for centers that are planning to treat pancreatic tumors on MR-Linac systems., (© 2024 The Author(s).)

Chronic immune activation from persistent malaria infections can induce immunophenotypic changes associated with T-cell exhaustion. However, associations between T and B cells during chronic exposure remain undefined. We analyzed peripheral blood mononuclear cells from malaria-exposed pregnant women from Papua New Guinea and Spanish malaria-naïve individuals using flow cytometry to profile T-cell exhaustion markers phenotypically. T-cell lineage (CD3, CD4, and CD8), inhibitory (PD1, TIM3, LAG3, CTLA4, and 2B4), and senescence (CD28-) markers were assessed. Dimensionality reduction methods revealed increased PD1, TIM3, and LAG3 expression in malaria-exposed individuals. Manual gating confirmed significantly higher frequencies of PD1+CD4+ and CD4+, CD8+, and double-negative (DN) T cells expressing TIM3 in malaria-exposed individuals. Increased frequencies of T cells co-expressing multiple markers were also found in malaria-exposed individuals. T-cell data were analyzed with B-cell populations from a previous study where we reported an alteration of B-cell subsets, including increased frequencies of atypical memory B cells (aMBC) and reduction in marginal zone (MZ-like) B cells during malaria exposure. Frequencies of aMBC subsets and MZ-like B cells expressing CD95+ had significant positive correlations with CD28+PD1+TIM3+CD4+ and DN T cells and CD28+TIM3+2B4+CD8+ T cells. Frequencies of aMBC, known to associate with malaria anemia, were inversely correlated with hemoglobin levels in malaria-exposed women. Similarly, inverse correlations with hemoglobin levels were found for TIM3+CD8+ and CD28+PD1+TIM3+CD4+ T cells. Our findings provide further insights into the effects of chronic malaria exposure on circulating B- and T-cell populations, which could impact immunity and responses to vaccination., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The malignant microenvironment plays a major role in the development of resistance to therapies and the occurrence of relapses in acute myeloid leukemia (AML). We previously showed that interactions of AML blasts with bone marrow macrophages (MΦ) shift their polarization towards a protumoral (M2-like) phenotype, promoting drug resistance; we demonstrated that inhibiting the colony-stimulating factor-1 receptor (CSF1R) repolarizes MΦ towards an antitumoral (M1-like) phenotype and that other factors may be involved. We investigated here macrophage migration inhibitory factor (MIF) as a target in AML blast survival and protumoral interactions with MΦ. We show that pharmacologically inhibiting MIF secreted by AML blasts results in their apoptosis. However, this effect is abrogated when blasts are co-cultured in close contact with M2-like MΦ. We next demonstrate that pharmacological inhibition of MIF secreted by MΦ, in the presence of granulocyte macrophage-colony stimulating factor (GM-CSF), efficiently reprograms MΦ to an M1-like phenotype that triggers apoptosis of interacting blasts. Furthermore, contact with reprogrammed MΦ relieves blast resistance to venetoclax and midostaurin acquired in contact with CD163 + protumoral MΦ. Using intravital imaging in mice, we also show that treatment with MIF inhibitor 4-IPP and GM-CSF profoundly affects the tumor microenvironment in vivo: it strikingly inhibits tumor vasculature, reduces protumoral MΦ, and slows down leukemia progression. Thus, our data demonstrate that MIF plays a crucial role in AML MΦ M2-like protumoral phenotype that can be reversed by inhibiting its activity and suggest the therapeutic targeting of MIF as an avenue towards improved AML treatment outcomes., (© 2024. The Author(s).)

Chronic obstructive pulmonary disease (COPD) is a heterogeneous respiratory condition characterized by symptoms of dyspnea, cough, and sputum production. We review sex-differences in disease mechanisms, structure-function-symptom relationships, responses to therapies, and clinical outcomes in COPD with a specific focus on dyspnea. Females with COPD experience greater dyspnea and higher morbidity compared to males. Imaging studies using chest computed tomography scans have demonstrated that females with COPD tend to have smaller airways than males as well as a lower burden of emphysema. Sex-differences in lung and airway structure lead to critical respiratory mechanical constraints during exercise at a lower absolute ventilation in females compared to males, which is largely explained by sex differences in maximum ventilatory capacity. Females experience similar benefit with respect to inhaled COPD therapies, pulmonary rehabilitation, and smoking cessation compared to males. Ongoing re-assessment of potential sex-differences in COPD may offer insights into the evolution of patterns of care and clinical outcomes in COPD patients over time., 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., (Copyright © 2024 Milne, Mitchell, Ferguson, Hind and Guenette.)

Importance: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or organ dysfunction after the acute phase of infection, termed Post-Acute Sequelae of SARS-CoV-2 (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are poorly understood. The objectives of the Researching COVID to Enhance Recovery (RECOVER) tissue pathology study (RECOVER-Pathology) are to: (1) characterize prevalence and types of organ injury/disease and pathology occurring with PASC; (2) characterize the association of pathologic findings with clinical and other characteristics; (3) define the pathophysiology and mechanisms of PASC, and possible mediation via viral persistence; and (4) establish a post-mortem tissue biobank and post-mortem brain imaging biorepository., Methods: RECOVER-Pathology is a cross-sectional study of decedents dying at least 15 days following initial SARS-CoV-2 infection. Eligible decedents must meet WHO criteria for suspected, probable, or confirmed infection and must be aged 18 years or more at the time of death. Enrollment occurs at 7 sites in four U.S. states and Washington, DC. Comprehensive autopsies are conducted according to a standardized protocol within 24 hours of death; tissue samples are sent to the PASC Biorepository for later analyses. Data on clinical history are collected from the medical records and/or next of kin. The primary study outcomes include an array of pathologic features organized by organ system. Causal inference methods will be employed to investigate associations between risk factors and pathologic outcomes., Discussion: RECOVER-Pathology is the largest autopsy study addressing PASC among US adults. Results of this study are intended to elucidate mechanisms of organ injury and disease and enhance our understanding of the pathophysiology of PASC., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Brendan Parent reports receiving a research gift from United Therapeutics. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Troxel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Immune checkpoint inhibitor (ICI) therapy is effective against many cancers for a subset of patients; a large percentage of patients remain unresponsive to this therapy. One contributing factor to ICI resistance is accumulation of monocytic myeloid-derived suppressor cells (M-MDSCs), a subset of innate immune cells with potent immunosuppressive activity against T lymphocytes. Here, using lung, melanoma, and breast cancer mouse models, we show that CD73-expressing M-MDSCs in the tumor microenvironment (TME) exhibit superior T cell suppressor function. Tumor-derived PGE 2 , a prostaglandin, directly induces CD73 expression in M-MDSCs via both Stat3 and CREB. The resulting CD73 overexpression induces elevated levels of adenosine, a nucleoside with T cell-suppressive activity, culminating in suppression of antitumor CD8 + T cell activity. Depletion of adenosine in the TME by the repurposed drug PEGylated adenosine deaminase (PEG-ADA) increases CD8 + T cell activity and enhances response to ICI therapy. Use of PEG-ADA can therefore be a therapeutic option to overcome resistance to ICIs in cancer patients.

Background: Pancreatic cancer (PC) is a challenging diagnosis that is yet to benefit from the advancements in immuno-oncologic treatments. Irreversible electroporation (IRE), a non-thermal method of tumor ablation, is used in treatment of select patients with locally-advanced unresectable PC and has potentiated the effect of certain immunotherapies. Yeast-derived particulate β-glucan induces trained innate immunity and successfully reduces murine PC tumor burden. This study tests the hypothesis that IRE may augment β-glucan induced trained immunity in the treatment of PC., Methods: β-Glucan-trained pancreatic myeloid cells were evaluated ex vivo for trained responses and antitumor function after exposure to ablated and unablated tumor-conditioned media. β-Glucan and IRE combination therapy was tested in an orthotopic murine PC model in wild-type and Rag -/- mice. Tumor immune phenotypes were assessed by flow cytometry. Effect of oral β-glucan in the murine pancreas was evaluated and used in combination with IRE to treat PC. The peripheral blood of patients with PC taking oral β-glucan after IRE was evaluated by mass cytometry., Results: IRE-ablated tumor cells elicited a potent trained response ex vivo and augmented antitumor functionality. In vivo, β-glucan in combination with IRE reduced local and distant tumor burden prolonging survival in a murine orthotopic PC model. This combination augmented immune cell infiltration to the PC tumor microenvironment and potentiated the trained response from tumor-infiltrating myeloid cells. The antitumor effect of this dual therapy occurred independent of the adaptive immune response. Further, orally administered β-glucan was identified as an alternative route to induce trained immunity in the murine pancreas and prolonged PC survival in combination with IRE. β-Glucan in vitro treatment also induced trained immunity in peripheral blood monocytes obtained from patients with treatment-naïve PC. Finally, orally administered β-glucan was found to significantly alter the innate cell landscape within the peripheral blood of five patients with stage III locally-advanced PC who had undergone IRE., Conclusions: These data highlight a relevant and novel application of trained immunity within the setting of surgical ablation that may stand to benefit patients with PC., Competing Interests: Competing interests: RCGM is an educational consultant for AngioDynamics., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

A rigorous determination of effector contributions of tumor-infiltrating immune cells is critical for identifying targetable molecular mechanisms for the development of novel cancer immunotherapies. A tumor/immune cell-admixture model is an advantageous strategy to study tumor immunology as the fundamental methodology is relatively straightforward, while also being adaptable to scale to address increasingly complex research queries. Ultimately, this method can provide robust experimental information to complement more traditional murine models of tumor immunology. Here, we describe a tumor/macrophage-admixture model using bone marrow-derived macrophages to investigate macrophage-dependent tumorigenesis. Additionally, we provide commentary on potential branch points for optimization with other immune cells, experimental techniques, and cancer types., Competing Interests: Competing interests The authors declare no competing interests., (Copyright © 2023 The Authors; This is an open access article under the CC BY-NC license ( https://creativecommons.org/licenses/by-nc/4.0/ ).)

Introduction: During the coronavirus disease 2019 pandemic, public health officials widely adopted the use of face masks (FM) to minimize infections. Despite consistent evidence that FMs increase dyspnea, no studies have examined the multidimensional components of dyspnea or their underlying physiological mechanisms., Methods: In a randomized crossover design, 16 healthy individuals ( n = 9 women, 25 ± 3 yr) completed incremental cycling tests over three visits, where visits 2 and 3 were randomized to either surgical FM or no mask control. Dyspnea intensity and unpleasantness were assessed throughout exercise (0-10 Borg scale), and the Multidimensional Dyspnea Profile was administered immediately after exercise. Crural diaphragmatic EMG and esophageal pressure were measured using a catheter to estimate neural respiratory drive and respiratory muscle effort, respectively., Results: Dyspnea unpleasantness was significantly greater with the FM at the highest equivalent submaximal work rate achieved by a given participant in both conditions (iso-work; 5.9 ± 1.7 vs 3.9 ± 2.9 Borg 0-10 units, P = 0.007) and at peak exercise (7.8 ± 2.1 vs 5.9 ± 3.4 Borg 0-10 units, P = 0.01) with no differences in dyspnea intensity ratings throughout exercise compared with control. There were significant increases in the sensory quality of "smothering/air hunger" ( P = 0.01) and the emotional response of "anxiousness" ( P = 0.04) in the FM condition. There were significant increases in diaphragmatic EMG and esophageal pressure at select submaximal work rates, but no differences in heart rate, pulse oximetry-derived arterial oxygen saturation, or breathing frequency throughout exercise with FMs compared with control. FMs significantly reduced peak work rate and exercise duration (both P = 0.02)., Conclusions: FMs negatively impact the affective domain of dyspnea and increase neural respiratory drive and respiratory muscle effort during exercise, although the impact on other cardiorespiratory responses are minimal., (Copyright © 2022 by the American College of Sports Medicine.)

After a bout of isolated inspiratory work, such as inspiratory pressure threshold loading (IPTL), the human diaphragm can exhibit a reversible loss in contractile function, as evidenced by a decrease in transdiaphragmatic twitch pressure (P DI,TW ). Whether or not diaphragm fatigability after IPTL is affected by neural mechanisms, measured through voluntary activation of the diaphragm (D-VA) in addition to contractile mechanisms, is unknown. It is also unknown if changes in D-VA are similar between sexes given observed differences in diaphragm fatigability between males and females. We sought to determine whether D-VA decreases after IPTL and whether this was different between sexes. Healthy females (n = 11) and males (n = 10) completed an IPTL task with an inspired duty cycle of 0.7 and targeting an intensity of 60% maximal transdiaphragmatic pressure until task failure. P DI,TW and D-VA were measured using cervical magnetic stimulation of the phrenic nerves in combination with maximal inspiratory pressure maneuvers. At task failure, P DI,TW decreased to a lesser degree in females vs. males (87 ± 15 vs. 73 ± 12% baseline, respectively, p = 0.016). D-VA decreased after IPTL but was not different between females and males (91 ± 8 vs. 88 ± 10% baseline, respectively, p = 0.432). When all participants were pooled together, the decrease in P DI,TW correlated with both the total cumulative diaphragm pressure generation (R 2  = 0.43; p = 0.021) and the time to task failure (TTF, R 2 = 0.40; p = 0.30) whereas the decrease in D-VA correlated only with TTF (R 2  = 0.24; p = 0.041). Our results suggest that neural mechanisms can contribute to diaphragm fatigability, and this contribution is similar between females and males following IPTL., (© 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

We evaluated the kinetics of antibody responses to Two years into the COVID-19 pandemic and 1 year after the start of vaccination rollout, the world faced a peak of cases associated with the highly contagious Omicron variant of concern (VoC) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) and nucleocapsid (N) antigens over five cross-sectional visits (January-November 2021), and the determinants of pre-booster immunoglobulin levels, in a prospective cohort of vaccinated primary health care workers in Catalonia, Spain. Antibodies against S antigens after a full primary vaccination course, mostly with BNT162b2, decreased steadily over time and were higher in pre-exposed (n = 247) than naïve (n = 200) individuals, but seropositivity was maintained at 100% (100% IgG, 95.5% IgA, 30.6% IgM) up to 319 days after the first dose. Antibody binding to variants of concern was highly maintained for IgG compared to wild type but significantly reduced for IgA and IgM, particularly for Beta and Gamma. Factors significantly associated with longer-term antibodies included age, sex, occupation, smoking, adverse reaction to vaccination, levels of pre-vaccination SARS-CoV-2 antibodies, interval between disease onset and vaccination, hospitalization, oxygen supply, post COVID and symptomatology. Earlier morning vaccination hours were associated with higher IgG responses in pre-exposed participants. Symptomatic breakthroughs occurred in 9/447 (2.01%) individuals, all among naïve (9/200, 4.5%) and generally boosted antibody responses. Additionally, an increase in IgA and/or IgM seropositivity to variants, and N seroconversion at later time points (6.54%), indicated asymptomatic breakthrough infections, even among pre-exposed. Seropositivity remained highly stable over almost a year after vaccination. However, gradually waning of anti-S IgGs that correlate with neutralizing activity, coupled to evidence of an increase in breakthrough infections during the Delta and Omicron predominance, provides a rationale for booster immunization., (© 2022 John Wiley & Sons Ltd.)

Background: Urochloa (syn. Brachiaria) is a genus of tropical grasses sown as forage feedstock, particularly in marginal soils. Here we aimed to clarify the genetic diversity and population structure in Urochloa species to understand better how population evolution relates to ploidy level and occurrence of apomictic reproduction., Methods: We explored the genetic diversity of 111 accessions from the five Urochloa species used to develop commercial cultivars. These accessions were conserved from wild materials collected at their centre of origin in Africa, and they tentatively represent the complete Urochloa gene pool used in breeding programmes. We used RNA-sequencing to generate 1.1 million single nucleotide polymorphism loci. We employed genetic admixture, principal component and phylogenetic analyses to define subpopulations., Results: We observed three highly differentiated subpopulations in U. brizantha, which were unrelated to ploidy: one intermixed with U. decumbens, and two diverged from the former and the other species in the complex. We also observed two subpopulations in U. humidicola, unrelated to ploidy; one subpopulation had fewer accessions but included the only characterized sexual accession in the species. Our results also supported a division of U. decumbens between diploids and polyploids, and no subpopulations within U. ruziziensis and U. maxima., Conclusions: Polyploid U. decumbens are more closely related to polyploid U. brizantha than to diploid U. decumbens, which supports the divergence of both polyploid groups from a common tetraploid ancestor and provides evidence for the hybridization barrier of ploidy. The three differentiated subpopulations of apomictic polyploid U. brizantha accessions constitute diverged ecotypes, which can probably be utilized in hybrid breeding. Subpopulations were not observed in non-apomictic U. ruziziensis. Sexual Urochloa polyploids were not found (U. brizantha, U. decumbens) or were limited to small subpopulations (U. humidicola). The subpopulation structure observed in the Urochloa sexual-apomictic multiploidy complexes supports geographical parthenogenesis, where the polyploid genotypes exploit the evolutionary advantage of apomixis, i.e. uniparental reproduction and clonality, to occupy extensive geographical areas., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Annals of Botany Company.)