bluuebunny/crossref_metadata_2025 huggingface dataset:
Parental legacy versus regulatory innovation in salt stress responsiveness of allopolyploid cotton (Gossypium) species
Authors: Dong Yating , Hu Guanjing , Grover Corrinne E. , Miller Emma R. , Zhu Shuijin , Wendel Jonathan F.
Published: June 2022

Polyploidy provides an opportunity for evolutionary innovation and species diversification, especially under stressful conditions. In allopolyploids, the conditional dynamics of homoeologous gene expression can be either inherited from ancestral states pre‐existing in the parental diploids or novel upon polyploidization, the latter potentially permitting a wider range of phenotypic responses to stresses. To gain insight into regulatory mechanisms underlying the diversity of salt resistance in Gossypium species, we compared global transcriptomic responses to modest salinity stress in two allotetraploid (AD‐genome) cotton species, Gossypium hirsutum and G. mustelinum, relative to their model diploid progenitors (A‐genome and D‐genome). Multivariate and pairwise analyses of salt‐responsive changes revealed a profound alteration of gene expression for about one third of the transcriptome. Transcriptional responses and associated functional implications of salt acclimation varied across species, as did species‐specific coexpression modules among species and ploidy levels. Salt responsiveness in both allopolyploids was strongly biased toward the D‐genome progenitor. A much lower level of transgressive downregulation was observed in the more salt‐tolerant G. mustelinum than in the less tolerant G. hirsutum. By disentangling inherited effects from evolved responses, we show that expression biases that are not conditional upon salt stress approximately equally reflect parental legacy and regulatory novelty upon allopolyploidization, whereas stress‐responsive biases are predominantly novel, or evolved, in allopolyploids. Overall, our work suggests that allopolyploid cottons acquired a wide range of stress response flexibility relative to their diploid ancestors, most likely mediated by complex suites of duplicated genes and regulatory factors.
Multi‐national survey of transfusion experiences and preferences of patients with myelodysplastic syndrome
Authors: Vijenthira Abi , Starkman Rebecca , Lin Yulia , Stanworth Simon J. , Bowen David , Harrison Lea , Wintrich Sophie , Callum Jeannie , Buckstein Rena
Published: June 2022

Background

Transfusion dependence on red blood cells (RBCs) is common for patients with myelodysplastic syndromes (MDS) but transfusion practice and experience for outpatients with MDS are largely unknown.

Methods

We conducted a web‐based cross‐sectional multi‐national survey to audit real‐world transfusion practices and understand the experiences and preferences of patients with MDS requiring RBC transfusion. The survey comprised 57 questions and was distributed to patients in the United States of America, Canada, and the United Kingdom.

Results

447 respondents (45% female) with a median age of 72 years (IQR 66–77) were eligible on the basis of receiving an RBC transfusion in the last 8 weeks. There was wide variability in the hemoglobin thresholds for transfusion with the most common being <80 g/L. 40% of patients were transfused at a lower threshold (<70–75 g/L), with the largest proportion of these patients from the United States. Patients experienced significant symptoms prior to receiving a transfusion with fatigue and dyspnea having the most negative impacts on quality of life. Finally, patients endorsed two potential alterations to transfusion care that could improve their quality of life, including self‐administered point of care testing of hemoglobin and higher hemoglobin transfusion thresholds. Of these patients, 62% preferred a threshold of at least 85 g/L, and 20% preferred a threshold of at least 100 g/L.

Discussion

In summary, this multi‐national survey of patients with MDS requiring RBC transfusions demonstrated substantial variation in patients' experiences and preferences that differed also by country, supporting the need for further comparative clinical trials of transfusion practice interventions.
Developing experimental skills: A hands-on course in acoustical measurement techniques at the Norwegian University of Science and Technology
Authors: Dong Hefeng , Svensson U. Peter , Dutilleux Guillaume , Martin Sara R. , Netland Tim Cato , Rørstadbotnen Robin André , Talberg Andreas Sørbrøden
Published: June 2022

The course “Acoustical Measurement Techniques TTT4250,” offered by the Acoustics Group at the Department of Electronic Systems, Norwegian University of Science and Technology, is a fourth-year course in the specialization of acoustics in the five-year master program “Electronics Systems Design and Innovation” or MTELSYS, and the two-year international master program “Electronic Systems Design” or MSELSYS. It is one of the four required courses for MTELSYS and one of the two required courses for MSELSYS. It offers a hands-on approach to acoustics. This paper outlines the topics covered in this course and the involvement of several academic staff members, as well as invited industry and research institute guest speakers, as teachers. The assessment of laboratory reports is described, and general lecture topics, including measurement uncertainty and statistics, the introduction of standards, and programming, are also described. All aspects of the course aim to maximize students' experience with a broad range of acoustic measurements and their interest in acoustics.
ATR-mediated CD47 and PD-L1 up-regulation restricts radiotherapy-induced immune priming and abscopal responses in colorectal cancer
Authors: Hsieh Rodney Cheng-En , Krishnan Sunil , Wu Ren-Chin , Boda Akash R. , Liu Arthur , Winkler Michelle , Hsu Wen-Hao , Lin Steven Hsesheng , Hung Mien-Chie , Chan Li-Chuan , Bhanu Krithikaa Rajkumar , Srinivasamani Anupallavi , De Azevedo Ricardo Alexandre , Chou Yung-Chih , DePinho Ronald A. , Gubin Matthew , Vilar Eduardo , Chen Chao Hsien , Slay Ravaen , Jayaprakash Priyamvada , Hegde Shweta Mahendra , Hartley Genevieve , Lea Spencer T. , Prasad Rishika , Morrow Brittany , Couillault Coline Agnes , Steiner Madeline , Wang Chun-Chieh , Venkatesulu Bhanu Prasad , Taniguchi Cullen , Kim Yon Son Betty , Chen Junjie , Rudqvist Nils-Petter , Curran Michael A.
Published: June 2022

Radiotherapy (RT) of colorectal cancer (CRC) can prime adaptive immunity against tumor-associated antigen (TAA)–expressing CRC cells systemically. However, abscopal tumor remissions are extremely rare, and the postirradiation immune escape mechanisms in CRC remain elusive. Here, we found that irradiated CRC cells used ATR-mediated DNA repair signaling pathway to up-regulate both CD47 and PD-L1, which through engagement of SIRPα and PD-1, respectively, prevented phagocytosis by antigen-presenting cells and thereby limited TAA cross-presentation and innate immune activation. This postirradiation CD47 and PD-L1 up-regulation was observed across various human solid tumor cells. Concordantly, rectal cancer patients with poor responses to neoadjuvant RT exhibited significantly elevated postirradiation CD47 levels. The combination of RT, anti-SIRPα, and anti–PD-1 reversed adaptive immune resistance and drove efficient TAA cross-presentation, resulting in robust TAA-specific CD8 T cell priming, functional activation of T effectors, and increased T cell clonality and clonal diversity. We observed significantly higher complete response rates to RT/anti-SIRPα/anti–PD-1 in both irradiated and abscopal tumors and prolonged survival in three distinct murine CRC models, including a cecal orthotopic model. The efficacy of triple combination therapy was STING dependent as knockout animals lost most benefit of adding anti-SIRPα and anti–PD-1 to RT. Despite activation across the myeloid stroma, the enhanced dendritic cell function accounts for most improvements in CD8 T cell priming. These data suggest ATR-mediated CD47 and PD-L1 up-regulation as a key mechanism restraining radiation-induced immune priming. RT combined with SIRPα and PD-1 blockade promotes robust antitumor immune priming, leading to systemic tumor regressions.
Clonal evolution and TCR specificity of the human T
FH
cell response to
Plasmodium falciparum
CSP
Authors: Wahl Ilka , Obraztsova Anna S. , Puchan Julia , Hundsdorfer Rebecca , Chakravarty Sumana , Sim B. Kim Lee , Hoffman Stephen L. , Kremsner Peter G. , Mordmüller Benjamin , Wardemann Hedda
Published: June 2022

T follicular helper (T
FH
) cells play a crucial role in the development of long-lived, high-quality B cell responses after infection and vaccination. However, little is known about how antigen-specific T
FH
cells clonally evolve in response to complex pathogens and what guides the targeting of different epitopes. Here, we assessed the cell phenotype, clonal dynamics, and T cell receptor (TCR) specificity of human circulating T
FH
(cT
FH
) cells during successive malaria immunizations with radiation-attenuated
Plasmodium falciparum
(
Pf
) sporozoites. Repeated parasite exposures induced a dynamic, polyclonal cT
FH
response with high frequency of cells specific to a small number of epitopes in
Pf
circumsporozoite protein (PfCSP), the primary sporozoite surface protein and well-defined vaccine target. Human leukocyte antigen (HLA) restrictions and differences in TCR generation probability were associated with differences in the epitope targeting frequency and indicated the potential of amino acids 311 to 333 in the Th2R/T* region as a T cell supertope. But most of vaccine-induced anti–amino acid 311 to 333 TCRs, including convergent TCRs with high sequence similarity, failed to tolerate natural polymorphisms in their target peptide sequence, thus demonstrating that the T
FH
cell response was limited to the vaccine strain. These data suggest that the high parasite diversity in endemic areas will limit boosting of the vaccine-induced T
FH
cell response by natural infections. Our findings may guide the further design of PfCSP-based malaria vaccines able to induce potent T helper cell responses for broad, long-lasting antibody responses.
Teaching evidence-based medicine in Mexico: a systematic review of medical doctor curriculums at a national level
Authors: Rodriguez David , Martinez-Alvarado Jhon Diego , Garcia-Toto Rebeca , Genel-Rey Tania Itzel
Published: June 2022

Objectives

To assess the teaching of evidence-based medicine (EBM) in medical curriculums. As a secondary objective, we assessed the representativeness of science courses related to EBM.

Design and setting

Systematic review. Accredited curriculums by the Mexican Council for the Accreditation of Medical Education.

Main outcome measures

We provided a descriptive analysis of the required or elective EBM courses and EBM-related courses, academic credits and teaching period. EBM-related courses included research methodology, epidemiology, biostatistics, clinical research, public health, clinical epidemiology, scientific dissemination and health informatics to explore scientific education and training offered by medical schools. Additionally, we examined the curriculum’s structure, location, type of institution, total programme duration and academic credits. Data collection occurred from December 2020 to February 2021.

Results

We identified 171 registered curriculums, of which we assessed 60 unique programmes (50% public) in our analysis. We identified 16 EBM single courses on the fifth and sixth semesters, of which 12 (20%) were mandatory and 4 were electives (6.7%). The allocated academic credits for EBM courses are minimal, without difference between public or private institutions, representing 0.08% of the total curriculum. Public health, epidemiology, research methodology and biostatistics courses are offered with greater frequency (55% or less) and curricular value (0.6% or less). In some cases, they are taught as combined courses. Clinical research, health informatics and clinical epidemiology are taught less than EBM, while scientific dissemination is nil.

Conclusion

In Mexico, EBM teaching is limited to only one of five curriculums with minimal curricular value. A comprehensive curricular review is necessary across programmes to incorporate EBM as a first step to improve medical education and, consequently, public health. We call to action through an online, collaborative platform with several applications to optimise teaching of EBM.

Review protocol registration

The systematic review protocol is excluded from the International Prospective Register of Systematic Reviews since this platform only accepts systematic reviews with health-related outcomes. Review protocol registration:https://osf.io/3xm2q/
Examining infant and child death clustering among families in the cross-sectional and nationally representative Bangladesh Demographic and Health Survey 2017–2018
Authors: Paul Ronak , Srivastava Shobhit , Rashmi Rashmi
Published: June 2022

Objectives

We aim to examine the phenomenon of infant and child death clustering while considering the unobserved heterogeneity (frailty) at the family level.

Design, setting, and participants

We analysed Bangladesh Demographic and Health Survey 2017–2018 data, including the birth history information for 47 828 children born to 18 134 women. We used Gompertz shared frailty model to control the correlation between event times at the mother level and capture the unobserved risks in infant and child deaths.

Outcome measures

We estimated two sets of survival regression models where the failure event is the survival status of the index child during the infancy period, that is, from birth to 11 months, and childhood period, that is, between 12 and 59 months, respectively. All children who died during infancy and childhood were coded as ‘yes’; otherwise, they were coded as ‘no’.

Results

About 2% of mothers experienced two or more infant deaths, and cumulatively these mothers account for 20% of all infant deaths in the sample. Children whose previous sibling was not alive at the time of their conception had 1.86 times (95% CI 1.59 to 2.17) more risk of dying as an infant. However, we did not find a statistically significant effect of death scarring on the risk of child mortality among siblings. Statistically significant frailty effect with a variance of 0.33 (95% CI CI 0.17 to 0.65) and 0.54 (95% CI 0.14 to 2.03)] in infancy and childhood, respectively, indicates the clustering of survival risks within families due to unobserved family-level characteristics shared by the siblings.

Conclusion

This study suggests that preceding birth interval, mother’s age at first birth and mother’s education are the most critical factors which can help in reducing scaring effect on infant mortality. Additionally, women from poor socioeconomic strata should be focused on as still an infant, and child mortality is concentrated among poor households.
Impact of biological sex and gender-related factors on public engagement in protective health behaviours during the COVID-19 pandemic: cross-sectional analyses from a global survey
Authors: Dev Rubee , Raparelli Valeria , Bacon Simon L , Lavoie Kim L , Pilote Louise , Norris Colleen M
Published: June 2022

Objective

Given the role of sociocultural gender in shaping human behaviours, the main objective of this study was to examine whether sex and gender-related factors were associated with the public’s adherence to COVID-19-recommended protective health behaviours.

Design

This was a retrospective analysis of the survey that captured data on people’s awareness, attitudes and behaviours as they relate to the COVID-19 policies.

Setting

Data from the International COVID-19 Awareness and Responses Evaluation survey collected between March 2020 and February 2021 from 175 countries.

Participants

Convenience sample around the world.

Main outcome measures

We examined the role of sex and gender-related factors in relation to non-adherence of protective health behaviours including: (1) hand washing; (2) mask wearing; and (3) physical distancing. Multivariable logistic regression was conducted to determine the factors associated with non-adherence to behaviours.

Results

Among 48 668 respondents (mean age: 43 years; 71% female), 98.3% adopted hand washing, 68.5% mask wearing and 76.9% physical distancing. Compared with males, females were more likely to adopt hand washing (OR=1.97, 95% CI: 1.71 to 2.28) and maintain physical distancing (OR=1.28, 95% CI: 1.22 to 1.34). However, in multivariable sex-stratified models, females in countries with higher Gender Inequality Indexes (GII) were less likely to report hand washing (adjusted OR (aOR)=0.47, 95% CI: 0.21 to 1.05). Females who reported being employed (aOR=0.22, 95% CI: 0.10 to 0.48) and in countries with low/medium GIIs (aOR=0.18, 95% CI 0.06 to 0.51) were less likely to report mask wearing. Females who reported being employed were less likely to report physical distancing (aOR=0.39, 95% CI: 0.32 to 0.49).

Conclusion

While females showed greater adherence to COVID-19 protective health behaviours, gender-related factors, including employment status and high country-wide gender inequality, were independently associated with non-adherence. These findings may inform public health and vaccination policies in current as well as future pandemics.
Heterogeneous adverse childhood experiences and cognitive function in an elderly Chinese population: a cohort study
Authors: Yuan Manqiong , Qin Fengzhi , Xu Chuanhai , Fang Ya
Published: June 2022

Objective

To identify the heterogeneity of adverse childhood experiences (ACEs) as well as their association with cognitive function in an elderly Chinese population.

Design

A retrospective cohort study.

Participants

The data were from the latest wave of the China Health and Retirement Longitudinal Study and a total of 7222 participants aged ≥60 were included.

Primary and secondary outcome measures

Latent class analysis was used to identify the classes characterised by 11 types of ACEs. Cognitive function was measured by the Mini-Mental State Examination (MMSE) and cognitive impairment was defined by education-specific threshold MMSE scores. Logistic models were constructed to examine the relationship between ACE classes and cognitive impairment. Several childhood and adulthood confounding factors were considered.

Results

Three ACE latent classes were identified. Of them, 76.09% were in the ‘Low ACEs’ class, 15.43% were in the ‘Household dysfunction’ class and 8.49% were in the ‘Child maltreatment’ class. The people in the ‘Low ACEs’ class seemed to have better childhood family financial situations and higher education levels. The population in the ‘Household dysfunction’ class tended to live in rural areas and have a higher proportion of men, whereas people in the ‘Child maltreatment’ class showed a significantly higher proportion of women and higher levels of chronic diseases. ‘Child maltreatment’ was related to a higher risk of cognitive impairment (OR=1.37, 95% CI: 1.12 to 1.68), while the risk of ‘Household dysfunction’ was not significantly different from that of the ‘Low ACEs’ participants (OR=1.06, 95% CI: 0.90 to 1.26).

Conclusions

The findings supported differences in cognitive function in elderly Chinese people exposed to different types of ACEs.
Patient experience of residents with restricted primary care access during the COVID-19 pandemic
Authors: Aoki Takuya , Fujinuma Yasuki , Matsushima Masato
Published: June 2022

Objectives

To evaluate primary care access for COVID-19 consultation among residents who have a usual source of care (USC) and to examine their associations with patient experience during the pandemic in Japan.

Design

Nationwide cross-sectional study.

Setting

Japanese general adult population.

Participants

1004 adult residents who have a USC.

Main outcome measures

Patient experience assessed by the Japanese version of Primary Care Assessment Tool Short Form (JPCAT-SF).

Results

A total of 198 (19.7%) reported restricted primary care access for COVID-19 consultation despite having a USC. After adjustment for possible confounders, restricted primary care access for COVID-19 consultation was negatively associated with the JPCAT-SF total score (adjusted mean difference = −8.61, 95% CI −11.11 to −6.10). In addition, restricted primary care access was significantly associated with a decrease in all JPCAT-SF domain scores.

Conclusions

Approximately one-fifth of adult residents who had a USC reported restricted primary care access for COVID-19 consultation during the pandemic in Japan. Our study also found that restricted primary care access for COVID-19 consultation was negatively associated with a wide range of patient experience including first contact. Material, financial and educational support to primary care facilities, the spread of telemedicine and the application of a patient registration system might be necessary to improve access to primary care during a pandemic.
Single-cell RNA-seq analysis reveals BHLHE40-driven pro-tumour neutrophils with hyperactivated glycolysis in pancreatic tumour microenvironment
Authors: Wang Liwen , Liu Yihao , Dai Yuting , Tang Xiaomei , Yin Tong , Wang Chaofu , Wang Ting , Dong Lei , Shi Minmin , Qin Jiejie , Xue Meilin , Cao Yizhi , Liu Jia , Liu Pengyi , Huang Jinyan , Wen Chenlei , Zhang Jun , Xu Zhiwei , Bai Fan , Deng Xiaxing , Peng Chenghong , Chen Hao , Jiang Lingxi , Chen Saijuan , Shen Baiyong
Published: June 2022

Objective

Innate immunity plays important roles in pancreatic ductal adenocarcinoma (PDAC), as non-T-cell-enriched tumour. Neutrophils are major players in innate immune system. Here, we aimed to explore the heterogeneity and pro-tumour mechanisms of neutrophils in PDAC.

Design

We analysed single-cell transcriptomes of peripheral blood polymorphonuclear leucocytes (PMNs) and tumour-infiltrating immune cells from five patients with PDAC, and performed immunofluorescence/immunohistochemistry staining, multi-omics analysis andin vitroexperiments to validate the discoveries of bioinformatics analysis.

Results

Exploration of the heterogeneity of tumour-associated neutrophils (TANs) revealed a terminally differentiated pro-tumour subpopulation (TAN-1) associated with poor prognosis, an inflammatory subpopulation (TAN-2), a population of transitional stage that have just migrated to tumour microenvironment (TAN-3) and a subpopulation preferentially expressing interferon-stimulated genes (TAN-4). Glycolysis signature was upregulated along neutrophil transition trajectory, and TAN-1 was featured with hyperactivated glycolytic activity. The glycolytic switch of TANs was validated by integrative multi-omics approach of transcriptomics, proteomics and metabolomics analysis. Activation of glycolytic activity by LDHA overexpression induced immunosuppression and pro-tumour functions in neutrophil-like differentiated HL-60 (dHL-60) cells. Mechanistic studies revealed BHLHE40, downstream to hypoxia and endoplasmic reticulum stress, was a key regulator in polarisation of neutrophils towards TAN-1 phenotype, and direct transcriptional regulation of BHLHE40 on TAN-1 marker genes was demonstrated by chromatin immunoprecipitation assay. Pro-tumour and immunosuppression functions were observed in dHL-60 cells overexpressing BHLHE40. Importantly, immunohistochemistry analysis of PDAC tissues revealed the unfavourable prognostic value of BHLHE40+neutrophils.

Conclusion

The dynamic properties of TANs revealed by this study will be helpful in advancing PDAC therapy targeting innate immunity.
Artificial intelligence in gastroenterology and hepatology: how to advance clinical practice while ensuring health equity
Authors: Uche-Anya Eugenia , Anyane-Yeboa Adjoa , Berzin Tyler M , Ghassemi Marzyeh , May Folasade P
Published: June 2022

Artificial intelligence (AI) and machine learning (ML) systems are increasingly used in medicine to improve clinical decision-making and healthcare delivery. In gastroenterology and hepatology, studies have explored a myriad of opportunities for AI/ML applications which are already making the transition to bedside. Despite these advances, there is a risk that biases and health inequities can be introduced or exacerbated by these technologies. If unrecognised, these technologies could generate or worsen systematic racial, ethnic and sex disparities when deployed on a large scale. There are several mechanisms through which AI/ML could contribute to health inequities in gastroenterology and hepatology, including diagnosis of oesophageal cancer, management of inflammatory bowel disease (IBD), liver transplantation, colorectal cancer screening and many others. This review adapts a framework for ethical AI/ML development and application to gastroenterology and hepatology such that clinical practice is advanced while minimising bias and optimising health equity.
DuoBody-CD40x4-1BB induces dendritic-cell maturation and enhances T-cell activation through conditional CD40 and 4-1BB agonist activity
Authors: Muik Alexander , Adams Homer C , Gieseke Friederike , Altintas Isil , Schoedel Kristina B , Blum Jordan M , Sänger Bianca , Burm Saskia M , Stanganello Eliana , Verzijl Dennis , Spires Vanessa M , Vascotto Fulvia , Toker Aras , Quinkhardt Juliane , Fereshteh Mark , Diken Mustafa , Satijn David P E , Kreiter Sebastian , Ahmadi Tahamtan , Breij Esther C W , Türeci Özlem , Sasser Kate , Sahin Ugur , Jure-Kunkel Maria
Published: June 2022

Background

Despite the preclinical promise of CD40 and 4-1BB as immuno-oncology targets, clinical efforts evaluating CD40 and 4-1BB agonists as monotherapy have found limited success. DuoBody-CD40×4-1BB (GEN1042/BNT312) is a novel investigational Fc-inert bispecific antibody for dual targeting and conditional stimulation of CD40 and 4-1BB to enhance priming and reactivation of tumor-specific immunity in patients with cancer.

Methods

Characterization of DuoBody-CD40×4-1BB in vitro was performed in a broad range of functional immune cell assays, including cell-based reporter assays, T-cell proliferation assays, mixed-lymphocyte reactions and tumor-infiltrating lymphocyte assays, as well as live-cell imaging. The in vivo activity of DuoBody-CD40×4-1BB was assessed in blood samples from patients with advanced solid tumors that were treated with DuoBody-CD40×4-1BB in the dose-escalation phase of the first-in-human clinical trial (NCT04083599).

Results

DuoBody-CD40×4-1BB exhibited conditional CD40 and 4-1BB agonist activity that was strictly dependent on crosslinking of both targets. Thereby, DuoBody-CD40×4-1BB strengthened the dendritic cell (DC)/T-cell immunological synapse, induced DC maturation, enhanced T-cell proliferation and effector functions in vitro and enhanced expansion of patient-derived tumor-infiltrating lymphocytes ex vivo. The addition of PD-1 blocking antibodies resulted in potentiation of T-cell activation and effector functions in vitro compared with either monotherapy, providing combination rationale. Furthermore, in a first-in-human clinical trial, DuoBody-CD40×4-1BB mediated clear immune modulation of peripheral antigen presenting cells and T cells in patients with advanced solid tumors.

Conclusion

DuoBody-CD40×4-1BB is capable of enhancing antitumor immunity by modulating DC and T-cell functions and shows biological activity in patients with advanced solid tumors. These findings demonstrate that targeting of these two pathways with an Fc-inert bispecific antibody may be an efficacious approach to (re)activate tumor-specific immunity and support the clinical investigation of DuoBody-CD40×4-1BB for the treatment of cancer.
Peripheral blood immune cell dynamics reflect antitumor immune responses and predict clinical response to immunotherapy
Authors: Hwang Michael , Canzoniero Jenna Vanliere , Rosner Samuel , Zhang Guangfan , White James R , Belcaid Zineb , Cherry Christopher , Balan Archana , Pereira Gavin , Curry Alexandria , Niknafs Noushin , Zhang Jiajia , Smith Kellie N , Sivapalan Lavanya , Chaft Jamie E , Reuss Joshua E , Marrone Kristen , Murray Joseph C , Li Qing Kay , Lam Vincent , Levy Benjamin P , Hann Christine , Velculescu Victor E , Brahmer Julie R , Forde Patrick M , Seiwert Tanguy , Anagnostou Valsamo
Published: June 2022

Background

Despite treatment advancements with immunotherapy, our understanding of response relies on tissue-based, static tumor features such as tumor mutation burden (TMB) and programmed death-ligand 1 (PD-L1) expression. These approaches are limited in capturing the plasticity of tumor–immune system interactions under selective pressure of immune checkpoint blockade and predicting therapeutic response and long-term outcomes. Here, we investigate the relationship between serial assessment of peripheral blood cell counts and tumor burden dynamics in the context of an evolving tumor ecosystem during immune checkpoint blockade.

Methods

Using machine learning, we integrated dynamics in peripheral blood immune cell subsets, including neutrophil-lymphocyte ratio (NLR), from 239 patients with metastatic non-small cell lung cancer (NSCLC) and predicted clinical outcome with immune checkpoint blockade. We then sought to interpret NLR dynamics in the context of transcriptomic and T cell repertoire trajectories for 26 patients with early stage NSCLC who received neoadjuvant immune checkpoint blockade. We further determined the relationship between NLR dynamics, pathologic response and circulating tumor DNA (ctDNA) clearance.

Results

Integrated dynamics of peripheral blood cell counts, predominantly NLR dynamics and changes in eosinophil levels, predicted clinical outcome, outperforming both TMB and PD-L1 expression. As early changes in NLR were a key predictor of response, we linked NLR dynamics with serial RNA sequencing deconvolution and T cell receptor sequencing to investigate differential tumor microenvironment reshaping during therapy for patients with reduction in peripheral NLR. Reductions in NLR were associated with induction of interferon-γ responses driving the expression of antigen presentation and proinflammatory gene sets coupled with reshaping of the intratumoral T cell repertoire. In addition, NLR dynamics reflected tumor regression assessed by pathological responses and complemented ctDNA kinetics in predicting long-term outcome. Elevated peripheral eosinophil levels during immune checkpoint blockade were correlated with therapeutic response in both metastatic and early stage cohorts.

Conclusions

Our findings suggest that early dynamics in peripheral blood immune cell subsets reflect changes in the tumor microenvironment and capture antitumor immune responses, ultimately reflecting clinical outcomes with immune checkpoint blockade.
Oncolytic virus expressing PD-1 inhibitors activates a collaborative intratumoral immune response to control tumor and synergizes with CTLA-4 or TIM-3 blockade
Authors: Ju Fei , Luo Yong , Lin Chaolong , Jia Xian , Xu Zilong , Tian Rui , Lin Yanhua , Zhao Min , Chang Yating , Huang Xiaoxuan , Li Shaopeng , Ren Wenfeng , Qin Yaning , Yu Mengqin , Jia Jizong , Han Jinle , Luo Wenxin , Zhang Jun , Fu Guo , Ye Xiangzhong , Huang Chenghao , Xia Ningshao
Published: June 2022

Background

Oncolytic viruses (OVs) are capable to inflame the tumor microenvironment (TME) and elicit infiltrating tumor-specific T cell responses. However, OV treatment negatively alters the cancer-immune set point in tumors to attenuate the antitumor immune response, which suggests the necessity of dissecting the immune landscape of the virus-treated tumors and developing novel strategies to maximize the potential of OVs. The aim of this study is to investigate the effect of the single-chain variable fragment (scFv)-armed OVs targeting PD-1 on the TME, and ultimately overcome localized immunosuppression to sensitize tumors to immunotherapies.

Methods

A tumor-selective oncolytic herpes simplex virus vector was engineered to encode a humanized scFv against human PD-1 (hPD-1scFv) (YST-OVH). The antitumor efficacy of YST-OVH was explored in multiple therapeutic mouse models. The neurotoxicity and safety of YST-OVH were evaluated in nonhuman primates. The precise dynamics in the TME involved in YST-OVH treatment were dissected using cytometry by time-of-flight (CyTOF).

Results

The identified hPD-1scFv showed superior T-cell activating activity. Localized delivery of hPD-1scFv by YST-OVH promotes systemic antitumor immunity in humanized PD-1 mouse models of established cancer. Immune profiling of tumors using CyTOF revealed the enhanced antitumor effect of YST-OVH, which largely relied on CD8+T cell activity by augmenting the tumor infiltration of effector CD8+T cells and establishment of memory CD8+T cells and reducing associated CD8+T cell exhaustion. Furthermore, YST-OVH treatment modified the cancer-immune set point of tumors coupled to coexpression of CTLA-4 and TIM-3 on exhausted CD8+T cells and high levels of CTLA-4+Treg cells. A combination approach incorporating anti-CTLA-4 or anti-TIM-3 further improved efficacy by increasing tumor immunogenicity and activating antitumor adaptive immune responses. Moreover, this therapeutic strategy showed no neurotoxicity and was well tolerated in nonhuman primates. The benefit of intratumoral hPD-1scFv expression was also observed in humanized mice bearing human cancer cells.

Conclusion

Localized delivery of PD-1 inhibitors by engineered YST-OVH was a highly effective and safe strategy for cancer immunotherapy. YST-OVH also synergized with CTLA-4 or TIM-3 blockade to enhance the immune response to cancer. These data provide a strong rationale for further clinical evaluation of this novel therapeutic approach.
Time to first treatment and risk of disability pension in relapsing-remitting multiple sclerosis
Authors: Wandall-Holm Malthe Faurschou , Buron Mathias Due , Kopp Tine Iskov , Thielen Karsten , Sellebjerg Finn , Magyari Melinda
Published: June 2022

BackgroundInitiation of disease-modifying therapy early in the disease course of relapsing-remitting multiple sclerosis (RRMS) has demonstrated beneficial effects on clinical outcomes, but socioeconomic outcomes remain largely unexplored.

ObjectiveTo investigate the association between the delay from disease onset to first treatment and the hazard of disability pension.

MethodsWe performed a population-based cohort study with data from the nationwide Danish Multiple Sclerosis Registry and Danish nationwide registries. Patients with a disease onset between 1 January 1996 to 5 April 2016 were followed until disability pension or a competing risk/censoring event. 7859 patients were assessed for eligibility of which 5208 were included in the final cohort. Key inclusion criteria were: a diagnosis of multiple sclerosis, relapsing-remitting phenotype, treatment in history, age 18–65 years and an Expanded Disability Status Scale≤4. Patients were categorised according to time from onset to first treatment: within 1 year (early), between 1 and 4 years (intermediate) and from 4 to 8 years (late).

ResultsOf the 5208 patients, 1922 were early, 2126 were intermediate and 1160 were late. Baseline clinical and socioeconomic variables were well balanced. The hazard of receiving disability pension increased with increasing delay of treatment initiation compared with the early group. Cox regression estimates adjusted for clinical and socioeconomic confounders: intermediate (HR, 1.37; 95% CI, 1.12 to 1.68) and late (HR, 1.97; 95% CI, 1.55 to 2.51).

ConclusionEarly treatment initiation is associated with a reduced risk of disability pension in patients with RRMS. This finding underlines the importance of early diagnosis and treatment on a patient-centred, socioeconomic disability milestone.
Predictors and outcome of early neurological deterioration after endovascular thrombectomy: a secondary analysis of the DIRECT-MT trial
Authors: Zhang Miaoyi , Xing Pengfei , Tang Jie , Shi Langfeng , Yang Pengfei , Zhang Yongwei , Zhang Lei , Peng Ya , Liu Sheng , Zhang Liyong , Fu Jianhui , Liu Jianmin
Published: June 2022

Background

There is uncertainty regarding the predictors of early neurological deterioration (END) after endovascular thrombectomy in patients with acute ischemic stroke (AIS). Limited studies have focused on the effect of END on functional outcome. Our aim was to determine the predictors of END after endovascular thrombectomy in AIS and its effect on functional outcome at 90 days.

Methods

This is a secondary analysis of the DIRECT-MT trial. Patients who failed to complete endovascular thrombectomy were additionally excluded. END was defined as ≥4-point increase in National Institutes of Health Stroke Scale score between admission and 24 hours after endovascular thrombectomy. Multivariable logistic regression was used to identify predictors for END and its effect on the modified Rankin Scale (mRS) score at 90 days.

Results

Of 591 patients enrolled, 111 (18.8%) had postoperative END, which was associated with higher ordinal mRS score at 90 days (adjusted common OR (aOR) 6.968, 95% CI 4.444 to 10.926). Non-modifiable factors included baseline Alberta Stroke Program Early CT Score (aOR 0.883, 95% CI 0.790 to 0.987), systolic blood pressure (aOR 1.017, 95% CI 1.006 to 1.028), glucose level (aOR 1.178, 95% CI 1.090 to 1.273), collateral status (aOR 0.238, 95% CI 0.093 to 0.608), occlusion site (aOR 0.496, 95% CI 0.290 to 0.851) and the presence of an anterior communicating artery (aOR 0.323, 95% CI 0.148 to 0.707). Admission-to-groin puncture time (aOR 1.010, 95% CI 1.003 to 1.017), general anesthesia (aOR 2.299, 95% CI 1.193 to 4.444), number of passes (aOR 1.561, 95% CI 1.243 to 1.961) and contrast extravasation (aOR 6.096, 95% CI 1.543 to 24.088) were modifiable predictors for END.

Conclusions

Postoperative END is associated with adverse functional outcome. Several non-modifiable and modifiable factors can predict END and support future treatment decision-making to improve the potential utility of endovascular thrombectomy.

Trial registration number

DIRECT-MT ClinicalTrials.govNCT03469206.
Comparison of lateral quadratus lumborum and lumbar plexus blocks for postoperative analgesia following total hip arthroplasty: a randomized clinical trial
Authors: Kelly Tara , Wolla Christopher D , Wolf Bethany J , Hay Ellen , Babb Sarah , Wilson Sylvia H
Published: June 2022

Introduction

Effective analgesia after total hip arthroplasty must minimize pain and optimize early ambulation. Lumbar plexus blocks (LPBs) provide analgesia but may cause motor weakness. Quadratus lumborum blocks (QLBs) may provide analgesia with preserved motor strength.

Methods

This trial randomized subjects scheduled for elective hip arthroplasty to receive an LPB or lateral QLB for postoperative analgesia. The primary outcome was opioid consumption at 12-hour postoperative. Non-inferiority of lateral QLBs compared with LPBs was conducted using a one-sided two-sample t-test. Secondary outcomes included pain scores, cumulative opioid consumption, quadriceps strength, time to ambulation, and distance ambulated. Differences in pain scores and opioid consumption over time between groups were evaluated using a linear mixed model.

Results

The trial consented and randomized 111 subjects and 103 completed the study: LPB (n=50) and lateral QLB (n=53). Mean (95% CI) cumulative opioid consumption (mg) at 12-hour postoperative was not found to be non-inferior in the lateral QLB (15.9 (12.7 to 19.2)) vs the LPB (12.7 (10.2 to 15.1)) group (p=0.625). Pain scores in postoperative anesthetic care unit (PACU) and 24-hour postoperative did not differ. The maximum distance ambulated did not differ, but lateral QLB patients were 2.4 times more likely to ambulate in the first 12 hours (p=0.024) and had significantly greater quadriceps strength in PACU (p<0.001).

Discussion

Although we were unable to demonstrate non-inferiority for opioid consumption at 12-hour postoperative, strength and mobilization were improved in lateral QLB subjects.

Trial registration number

NCT04402437.
Measurement of pile uplift forces due to soil heave in expansive clays
Authors: Burke T.S. da Silva , Jacobsz S.W. , Elshafie M.Z.E.B. , Osman A.S.
Published: June 2022

Piled foundations are widely used to limit the movement of foundations in expansive clays. These piles are subjected to large uplift forces as the clay swells (and downdrag forces when it shrinks). The appropriate method to estimate these forces is not well understood, and estimates from various methods presented in literature result in large variations. The uplift force generated in piles by soil heave was derived from strain measurements in full-scale field tests where a pile was installed in a highly expansive soil profile and flooded for several months. The results were compared to available theoretical estimates to comment on the most appropriate procedure to estimate the generated tension in the pile. The results showed that the use of an elastic solution related to the expected soil heave combined with a limiting shaft friction estimated from total stress capacity methods provided the most appropriate match to the measured results both in terms of the magnitude of the developed tension in the pile and shape of the tension profile along the depth of the pile.
Re-liquefaction resistance of lightly cemented sands
Authors: Rasouli Habib , Fatahi Behzad , Nimbalkar Sanjay
Published: June 2022

The re-liquefaction resistance of cemented sands under multiple liquefaction events such as pre-shock, main-shock, and after-shock earthquakes is a complex phenomenon because the response may alter due to bond breakage. A series of multistage liquefaction–re-consolidation soil element tests under undrained stress-controlled cyclic loading condition using cyclic triaxial were carried out to assess the liquefaction and re-liquefaction resistance of cemented sands with varying degrees of cementation. Lightly cemented specimens were reconstituted using Sydney sand and high early strength Portland cement with cement content ranging from 0.25% to 1% and unconfined compression strength from 15 to 80 kPa. The results showed that the re-liquefaction resistance of cemented sands with different amounts of cement decreased after the first liquefaction event and then increased for succeeding liquefaction events. While the trend of residual excess pore water pressure ratio and cyclic stiffness degradation index of untreated sand under successive liquefaction events remained consistent, the corresponding responses for cemented sands altered for the second to the fifth liquefaction events. In fact, the residual excess pore water pressure ratio and cyclic stiffness of cemented sand increased and degraded faster during the early cycles of loading for the second to fifth liquefaction events.
D(s) to light tensor meson form factors and semileptonic decays via LCSR in HQEFT
Authors: Zuo Yabing , Pan Tingting , Gong Hanyu , Kou Yinghui , Jin Hongyao , Tian Jingying
Published: June 2022

In this paper, the form factors of D(s) to light tensor mesons a2(1320), [Formula: see text], [Formula: see text], [Formula: see text] and corresponding semileptonic decays are investigated through the method of light cone sum rules (LCSR) in the framework of heavy quark effective field theory (HQEFT). Considering the light cone distribution amplitudes (DAs) of tensor mesons to twist-3, we give numerical results of form factors systematically, which are necessary inputs for the analysis of relevant D(s) decays. Based on the form factor results, the relevant semileptonic decays induced by charged current (CC) as well as flavor changing neutral current (FCNC) are studied. Our predictions for the branching ratios, longitudinal polarization fractions and forward–backward asymmetries can be tested by more precise experiments such as LHCb, BESIII and BelleII in the future.
Optimization of an electron injector for operating high-intensity polarized electron beam
Authors: Liu Wei , Wang Erdong
Published: June 2022

The simulation and optimization of an electron injector that operates a high-intensity polarized electron beam are presented. The electron injector would provide a single-bunch electron beam at a repetition rate of 1 Hz with a bunch charge of 10 nC, kinetic energy of 400 MeV and an electron spin polarization of 85[Formula: see text]. A direct current (DC) high-voltage photogun was employed to produce the 10 nC polarized electron beam with a kinetic energy of 350 keV, beam diameter of 1.44 cm (Gaussian distribution with [Formula: see text] of 0.36 cm) and full bunch length of 1.3 ns (Gaussian distribution with [Formula: see text] of 0.325 ns). The beam was compressed to 6 ps of RMS bunch length using one 114.24 MHz standing-wave sub-harmonic buncher, two 571.2 MHz standing-wave sub-harmonic bunchers and one 2.856 GHz traveling-wave buncher. The beam was accelerated finally to 400 MeV via eight 2.856 GHz traveling-wave Linacs. We performed the beam simulation, and the simulated results showed that the optimized RMS bunch length was 4.65 ps, RMS relative energy spread was 0.48[Formula: see text] and normalized RMS transverse emittance was [Formula: see text] at a beam energy of 400 MeV.
How does geometry affect quantum gases?
Authors: Araújo Filho A. A. , Reis J. A. A. S.
Published: June 2022

In this work, we study the thermodynamic functions of quantum gases confined to spaces of various shapes, namely, a sphere, a cylinder and an ellipsoid. We start with the simplest situation, namely, a spinless gas treated within the canonical ensemble framework. As a next step, we consider noninteracting gases (fermions and bosons) with the usage of the grand canonical ensemble description. For this case, the calculations are performed numerically. We also observe that our results may possibly be applied to Bose–Einstein condensate and to helium dimer. Moreover, the bosonic sector, independently of the geometry, acquires entropy and internal energy greater than for the fermionic case. Finally, we also devise a model allowing us to perform analytically the calculations in the case of interacting quantum gases, and, afterwards, we apply it to a cubical box.
Transition to magma-driven rifting in the South Turkana Basin, Kenya: Part 1
Authors: Muirhead James D. , Scholz Christopher A. , O. Rooney Tyrone
Published: June 2022

Characterization of the role of magma in driving rift basin evolution is fundamental to our understanding of how extensional plate boundaries develop. Here, we examine patterns of normal faulting, volcanism and magmatism in the South Turkana Basin, Kenya, to test how magmatism has impacted the Quaternary evolution of this system. Utilizing high-resolution, single-channel reflection seismic data and radiocarbon-dated cores, we estimate that shallow Holocene normal faulting accounts for 3.5–5.8 mm a
−1
of extension, consistent with estimates farther south in the Suguta Basin. Spatial fault patterns show that extension in the Holocene is concentrated along a
c.
20 km wide intra-rift fault network, aligning with the axial volcano, South Island. We suggest that up to 85% of Late Quaternary regional extension is accommodated within an axial magmatic segment rather than on the border fault system responsible for the original basin architecture. Axial extension increases towards South Island, highlighting magmatism as crucial in driving recent shallow upper crustal faulting in the South Turkana Basin. Below this zone of extensional faulting, geochemical evidence supports a developed magma plumbing system that broadly parallels equivalent axial magmatic systems within the Main Ethiopian Rift. Overall, our data support a recent (Mid- to Late Pleistocene) transition to magma-driven axial extension in the Lake Turkana rift.

Supplementary material:
Supplementary text and the fault, volcanic cone and radiocarbon age data utilized in this study are available at
https://doi.org/10.6084/m9.figshare.c.6026624