bluuebunny/crossref_metadata_2025 huggingface dataset:
Local anesthetics elicit immune-dependent anticancer effects
Authors: Bezu Lucillia , Wu Chuang Alejandra , Sauvat Allan , Humeau Juliette , Xie Wei , Cerrato Giulia , Liu Peng , Zhao Liwei , Zhang Shuai , Le Naour Julie , Pol Jonathan , van Endert Peter , Kepp Oliver , Barlesi Fabrice , Kroemer Guido
Published: May 2022

Background

Retrospective clinical trials reported a reduced local relapse rate, as well as improved overall survival after injection of local anesthetics during cancer surgery. Here, we investigated the anticancer effects of six local anesthetics used in clinical practice.

Results

In vitro, local anesthetics induced signs of cancer cell stress including inhibition of oxidative phosphorylation, and induction of autophagy as well as endoplasmic reticulum (ER) stress characterized by the splicing of X-box binding protein 1 (XBP1s) mRNA, cleavage of activating transcription factor 6 (ATF6), phosphorylation of eIF2α and subsequent upregulation of activating transcription factor 4 (ATF4). Both eIF2α phosphorylation and autophagy required the ER stress-relevant eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, best known as PERK). Local anesthetics also activated two hallmarks of immunogenic cell death, namely, the release of ATP and high-mobility group box 1 protein (HMGB1), yet failed to cause the translocation of calreticulin (CALR) from the ER to the plasma membrane.In vivo, locally injected anesthetics decreased tumor growth and improved survival in several models of tumors established in immunocompetent mice. Systemic immunotherapy with PD-1 blockade or intratumoral injection of recombinant CALR protein, increased the antitumor effects of local anesthetics. Local anesthetics failed to induce antitumor effects in immunodeficient mice or against cancers unable to activate ER stress or autophagy due to the knockout of EIF2AK3/PERK or ATG5, respectively. Uncoupling agents that inhibit oxidative phosphorylation and induce autophagy and ER stress mimicked the immune-dependent antitumor effects of local anesthetics.

Conclusion

Altogether, these results indicate that local anesthetics induce a therapeutically relevant pattern of immunogenic stress responses in cancer cells.
Clinical significance of plasma-free amino acids and tryptophan metabolites in patients with non-small cell lung cancer receiving PD-1 inhibitor: a pilot cohort study for developing a prognostic multivariate model
Authors: Azuma Koichi , Xiang Huihui , Tagami Tomoyuki , Kasajima Rika , Kato Yumiko , Karakawa Sachise , Kikuchi Shinya , Imaizumi Akira , Matsuo Norikazu , Ishii Hidenobu , Tokito Takaaki , Kawahara Akihiko , Murotani Kenta , Sasada Tetsuro , Miyagi Yohei , Hoshino Tomoaki
Published: May 2022

Background

Amino acid metabolism is essential for tumor cell proliferation and regulation of immune cell function. However, the clinical significance of free amino acids (plasma-free amino acids (PFAAs)) and tryptophan-related metabolites in plasma has not been fully understood in patients with non-small cell lung cancer (NSCLC) who receive immune checkpoint inhibitors.

Methods

We conducted a single cohort observational study. Peripheral blood samples were collected from 53 patients with NSCLC before treatment with PD-1 (Programmed cell death-1) inhibitors. The plasma concentrations of 21 PFAAs, 14 metabolites, and neopterin were measured by liquid chromatography–mass spectrometry. Using Cox hazard analysis with these variables, a multivariate model was established to stratify patient overall survival (OS). Gene expression in peripheral blood mononuclear cells (PBMCs) was compared between the high-risk and low-risk patients by this multivariate model.

Results

On Cox proportional hazard analysis, higher concentrations of seven PFAAs (glycine, histidine, threonine, alanine, citrulline, arginine, and tryptophan) as well as lower concentrations of three metabolites (3h-kynurenine, anthranilic acid, and quinolinic acid) and neopterin in plasma were significantly correlated with better OS (p<0.05). In particular, the multivariate model, composed of a combination of serine, glycine, arginine, and quinolinic acid, could most efficiently stratify patient OS (concordance index=0.775, HR=3.23, 95% CI 2.04 to 5.26). From the transcriptome analysis in PBMCs, this multivariate model was significantly correlated with the gene signatures related to immune responses, such as CD8 T-cell activation/proliferation and proinflammatory immune responses, and 12 amino acid-related genes were differentially expressed between the high-risk and low-risk groups.

Conclusions

The multivariate model with PFAAs and metabolites in plasma might be useful for stratifying patients who will benefit from PD-1 inhibitors.
The CAR-HEMATOTOX risk-stratifies patients for severe infections and disease progression after CD19 CAR-T in R/R LBCL
Authors: Rejeski Kai , Perez Ariel , Iacoboni Gloria , Penack Olaf , Bücklein Veit , Jentzsch Liv , Mougiakakos Dimitrios , Johnson Grace , Arciola Brian , Carpio Cecilia , Blumenberg Viktoria , Hoster Eva , Bullinger Lars , Locke Frederick L , von Bergwelt-Baildon Michael , Mackensen Andreas , Bethge Wolfgang , Barba Pere , Jain Michael D , Subklewe Marion
Published: May 2022

Background

CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) represents a promising treatment modality for an increasing number of B-cell malignancies. However, prolonged cytopenias and infections substantially contribute to the toxicity burden of CAR-T. The recently developed CAR-HEMATOTOX (HT) score—composed of five pre-lymphodepletion variables (eg, absolute neutrophil count, platelet count, hemoglobin, C-reactive protein, ferritin)—enables risk stratification of hematological toxicity.

Methods

In this multicenter retrospective analysis, we characterized early infection events (days 0–90) and clinical outcomes in 248 patients receiving standard-of-care CD19 CAR-T for relapsed/refractory large B-cell lymphoma. This included a derivation cohort (cohort A, 179 patients) and a second independent validation cohort (cohort B, 69 patients). Cumulative incidence curves were calculated for all-grade, grade ≥3, and specific infection subtypes. Clinical outcomes were studied via Kaplan-Meier estimates.

Results

In a multivariate analysis adjusted for other baseline features, the HT score identified patients at high risk for severe infections (adjusted HR 6.4, 95% CI 3.1 to 13.1). HThighpatients more frequently developed severe infections (40% vs 8%, p<0.0001)—particularly severe bacterial infections (27% vs 0.9%, p<0.0001). Additionally, multivariate analysis of post-CAR-T factors revealed that infection risk was increased by prolonged neutropenia (≥14 days) and corticosteroid use (≥9 days), and decreased with fluoroquinolone prophylaxis. Antibacterial prophylaxis significantly reduced the likelihood of severe bacterial infections in HThigh(16% vs 46%, p<0.001), but not HTlowpatients (0% vs 2%, p=n.s.). Collectively, HThighpatients experienced worse median progression-free (3.4 vs 12.6 months) and overall survival (9.1 months vs not-reached), and were hospitalized longer (median 20 vs 16 days). Severe infections represented the most common cause of non-relapse mortality after CAR-T and were associated with poor survival outcomes. A trend toward increased non-relapse mortality in HThighpatients was observed (8.0% vs 3.7%, p=0.09).

Conclusions

These data demonstrate the utility of the HT score to risk-stratify patients for infectious complications and poor survival outcomespriorto CD19 CAR-T. High-risk patients likely benefit from anti-infective prophylaxis and should be closely monitored for potential infections and relapse.
Activin-A impairs CD8 T cell-mediated immunity and immune checkpoint therapy response in melanoma
Authors: Pinjusic Katarina , Dubey Olivier Andreas , Egorova Olga , Nassiri Sina , Meylan Etienne , Faget Julien , Constam Daniel Beat
Published: May 2022

Background

Activin-A, a transforming growth factor β family member, is secreted by many cancer types and is often associated with poor disease prognosis. Previous studies have shown that Activin-A expression can promote cancer progression and reduce the intratumoral frequency of cytotoxic T cells. However, the underlying mechanisms and the significance of Activin-A expression for cancer therapies are unclear.

Methods

We analyzed the expression of the Activin-A encoding geneINHBAin melanoma patients and the influence of its gain- or loss-of-function on the immune infiltration and growth ofBRAF-driven YUMM3.3 and iBIP2 mouse melanoma grafts and in B16 models. Using antibody depletion strategies, we investigated the dependence of Activin-A tumor-promoting effect on different immune cells. Immune-regulatory effects of Activin-A were further characterized in vitro and by an adoptive transfer of T cells. Finally, we assessedINHBAexpression in melanoma patients who received immune checkpoint therapy and tested whether it impairs the response in preclinical models.

Results

We show that Activin-A secretion by melanoma cells inhibits adaptive antitumor immunity irrespective ofBRAFstatus by inhibiting CD8+T cell infiltration indirectly and even independently of CD4 T cells, at least in part by attenuating the production of CXCL9/10 by myeloid cells. In addition, we show that Activin-A/INHBAexpression correlates with anti-PD1 therapy resistance in melanoma patients and impairs the response to dual anti-cytotoxic T-Lymphocyte associated protein 4/anti-PD1 treatment in preclinical models.

Conclusions

Our findings suggest that strategies interfering with Activin-A induced immune-regulation offer new therapeutic opportunities to overcome CD8 T cell exclusion and immunotherapy resistance.
Inhibition of D-2HG leads to upregulation of a proinflammatory gene signature in a novel HLA-A2/HLA-DR1 transgenic mouse model of IDH1R132H-expressing glioma
Authors: Chuntova Pavlina , Yamamichi Akane , Chen Tiffany , Narayanaswamy Rohini , Ronseaux Sebastien , Hudson Christine , Tron Adriana E , Hyer Marc L , Montoya Megan , Mende Abigail L , Nejo Takahide , Downey Kira M , Diebold David , Lu Min , Nicolay Brandon , Okada Hideho
Published: May 2022

Background

Long-term prognosis of WHO grade II, isocitrate dehydrogenase (IDH)-mutated low-grade glioma (LGG) is poor due to high risks of recurrence and malignant transformation into high-grade glioma. Immunotherapy strategies are attractive given the relatively intact immune system of patients with LGG and the slow tumor growth rate. However, accumulation of the oncometabolite D-2-hydroxyglutarate (D-2HG) in IDH-mutated gliomas leads to suppression of inflammatory pathways in the tumor microenvironment, thereby contributing to the ‘cold’ tumor phenotype. Inhibiting D-2HG production presents an opportunity to generate a robust antitumor response following tumor antigen vaccination and immune checkpoint blockade.

Methods

An IDH1R132Hglioma model was created in syngeneicHLA-A2/HLA-DR1-transgenic mice, allowing us to evaluate the vaccination with the human leukocyte antigens (HLA)-DR1-restricted, IDH1R132Hmutation-derived neoepitope. The effects of an orally available inhibitor of mutant IDH1 and IDH2, AG-881, were evaluated as monotherapy and in combination with the IDH1R132Hpeptide vaccination or anti-PD-1 immune checkpoint blockade.

Results

TheHLA-A2/HLA-DR1-syngeneic IDH1R132Hcell line expressed the IDH1 mutant protein and formed D-2HG producing orthotopic gliomas in vivo. Treatment of tumor-bearing mice with AG-881 resulted in a reduction of D-2HG levels in IDH1R132Hglioma cells (10 fold) and tumor-associated myeloid cells, which demonstrated high levels of intracellular D-2HG in the IDH1R132Hgliomas. AG-881 monotherapy suppressed the progression of IDH1R132Hgliomas in a CD4+and CD8+cell-dependent manner, enhanced proinflammatory IFNγ-related gene expression, and increased the number of CD4+tumor-infiltrating T-cells. Prophylactic vaccination with the HLA-DR1-restricted IDH1R132Hpeptide or tumor-associated HLA-A2-restricted peptides did not enhance survival of tumor-bearing animals; however, vaccination with both HLA-A2-IDH1R132Hand DR1-IDH1R132Hpeptides in combination with the IDH inhibitor significantly prolonged survival. Finally, tumor-bearing mice treated with both AG-881 and a PD-1 blocking antibody demonstrated improved survival when compared with either treatment alone.

Conclusion

The development of effective IDH1R132H-targeting vaccine may be enhanced by integration with HLA class I-restricted cytotoxic T cell epitopes and AG-881. OurHLA-A2/HLA-DR1-syngeneic IDH1R132Hglioma model should allow us to evaluate key translational questions related to the development of novel strategies for patients with IDH-mutant glioma.
Emerging NK cell therapies for cancer and the promise of next generation engineering of iPSC-derived NK cells
Authors: Maddineni Sainiteesh , Silberstein John L , Sunwoo John B
Published: May 2022

Adoptive cell therapy is a rapidly advancing approach to cancer immunotherapy that seeks to facilitate antitumor responses by introducing potent effector cells into the tumor microenvironment. Expanded autologous T cells, particularly T cells with engineered T cell receptors (TCR) and chimeric antigen receptor-T cells have had success in various hematologic malignancies but have faced challenges when applied to solid tumors. As a result, other immune subpopulations may provide valuable and orthogonal options for treatment. Natural killer (NK) cells offer the possibility of significant tumor clearance and recruitment of additional immune subpopulations without the need for prior antigen presentation like in T or B cells that could require removal of endogenous antigen specificity mediated via the T cell receptor (TCR and/or the B ecll receptor (BCR). In recent years, NK cells have been demonstrated to be increasingly important players in the immune response against cancer. Here, we review multiple avenues for allogeneic NK cell therapy, including derivation of NK cells from peripheral blood or umbilical cord blood, the NK-92 immortalized cell line, and induced pluripotent stem cells (iPSCs). We also describe the potential of engineering iPSC-derived NK cells and the utility of this platform. Finally, we consider the benefits and drawbacks of each approach and discuss recent developments in the manufacturing and genetic or metabolic engineering of NK cells to have robust and prolonged antitumor responses in preclinical and clinical settings.
TNF blockade enhances the efficacy of myxoma virus-based oncolytic virotherapy
Authors: Valenzuela-Cardenas Miriam , Gowan Cody , Dryja Parker , Bartee Mee Y , Bartee Eric
Published: May 2022

Background

Oncolytic virotherapy (OV) represents a method to treat a variety of solid tumors by inducing antitumor immune responses. While this therapy has been extremely efficacious in preclinical models, translating these successes into human patients has proven challenging. One of the major reasons for these failures is the existence of immune-regulatory mechanisms, which dampen the efficacy of virally induced antitumor immunity. Unfortunately, the full extent of these immune-regulatory pathways remains unclear.

Methods

To address this issue, we generated a doubly recombinant, oncolytic myxoma virus which expresses both a soluble fragment of programmed cell death protein 1 (PD1) and an interleukin 12 (IL-12) fusion protein (vPD1/IL-12 (virus-expressing PD1 and IL-12)). We then tested the molecular impact and therapeutic efficacy of this construct in multiple models of disseminated disease to identify novel pathways, which are associated with poor therapeutic outcomes.

Results

Our results demonstrate that vPD1/IL-12 causes robust inflammation during therapy including inducing high levels of tumor necrosis factor (TNF). Surprisingly, although expression of TNF has generally been assumed to be beneficial to OV, the presence of this TNF appears to inhibit therapeutic efficacy by reducing intratumoral T-cell viability. Likely because of this, disruption of the TNF pathway, either through genetic knockout or antibody-based blockade, significantly enhances the overall outcomes of vPD1/IL-12-based therapy that allows for the generation of complete cures in normally non-responsive models.

Conclusions

These data suggest that some aspects of OV-induced inflammation might represent a double-edged sword during therapy and that specific blockade of TNF might enhance the efficacy of these treatments.
Stroke outcome of early antiplatelet in post-thrombolysis haemorrhagic infarction
Authors: Zhong Wansi , Yan Shenqiang , Chen Zhicai , Luo Zhongyu , Chen Yi , Zhang Xuting , Wu Chenglong , Tang Weiguo , Zhang Xiaoling , Wang Yaxian , Gu Qun , Xu Dongjuan , Chen Hongfang , Lou Min
Published: May 2022

Background and purpose

Initiation of early antiplatelet (EA) therapy after acute ischaemic stroke (AIS) is essential. We aimed to investigate the safety and effectiveness of EA therapy in patients who had an AIS with haemorrhagic infarction (HI) after intravenous thrombolysis (IVT).

Methods

Based on a multicentre stroke registry database, patients who had an AIS with post-thrombolysis HI at 24 hours were identified. EA users and non-EA users were defined as patients with HI who received or did not receive antiplatelet therapy between 24 and 48 hours after IVT. Primary outcome was favourable outcome defined as modified Rankin Scale scores 0–2 at 3 months. Secondary outcomes were early neurological deterioration (END) and haemorrhagic transformation expansion.

Results

A total of 842 patients with HI were identified from 24 061 thrombolytic patients within 4.5 hours, and 341 (40.5%) received EA therapy. EA users were more likely to have a favourable outcome (55.7% vs 39.5%, OR 1.565; 95% CI 1.122 to 2.182; p=0.008) and lower rate of END (12.6% vs 21.4%, OR 0.585; 95% CI 0.391 to 0.875; p=0.009) compared with non-EA users. EA therapy was not associated with haemorrhagic transformation expansion (p=0.125). After propensity score matching, EA therapy was still independently associated with favourable outcome (54.3% vs 46.3%, OR 1.495; 95% CI 1.031 to 2.167; p=0.038) and lower risk of END (13.5% vs 21.2%, OR 0.544; 95% CI 0.350 to 0.845; p=0.007).

Conclusions

Antiplatelet therapy can be safely used between 24 and 48 hours when HI occurs after IVT, and such therapy is associated with reduced risk of END and improved neurological outcome in patients who had an AIS.
Acquiring and developing healthcare leaders’ political skills: an interview study with healthcare leaders
Authors: Waring Justin , Bishop Simon , Clarke Jenelle , Exworthy Mark , Fulop Naomi J , Hartley Jean , Ramsay Angus I G , Black Georgia , Roe Bridget
Published: May 2022

Background

Research suggests health and care leaders need to develop a distinct set of political skills in order to understand and manage the competing interests and agenda that characterise health and care services.

Aim

To understand how healthcare leaders describe the acquisition and development of political skills with the aim of providing evidence for leadership development programme.

Methods

A qualitative interview study was carried out between 2018 and 2019 with 66 health and care leaders located within the English National Health Service. Qualitative data were subject to interpretative analysis and coding, with themes related to pre-existing literature on the methods of leadership skill development.

Results

The primary method of acquiring and developing political skill is through direct experience in leading and changing services. This is unstructured and incremental in nature with skill development increased through the accumulation of experience. Many participants described mentoring as an important source of political skill development, especially for reflecting on first-hand experiences, understanding the local environment and fine-tuning strategies. A number of participants describe formal learning opportunities as giving them permission to discuss political issues, and providing frameworks for conceptual understanding of organisational politics. Overall, no one approach appears to reflect the changing developmental needs of leaders.

Conclusions

The study suggests that healthcare leaders’ development of political skills and behaviours might be supported through an integrative approach that takes into account the evolving learning needs and opportunities at different career stages in the form of a maturation framework.
Directed and conditional uterus donation
Authors: Romanis Elizabeth Chloe , Parsons Jordan A
Published: May 2022

Uterus transplantation (UTx) is highly anticipated for the benefits that it might bring to individuals wanting to carry a pregnancy in order to reproduce who do not have a functioning uterus. The surgery—now having been performed successfully in several countries around the world—remains experimental. However, UTx is at some point expected to become a routine treatment for people without a uterus and considering themselves in need of one: women with absolute uterine factor infertility; transgender women; and even cisgender men who wish to gestate. Given the unique benefits UTx offers, uteri are likely to be ‘in demand’, and such demand, we suggest, will feasibly outstrip supply. Therefore, allocation of those uteri available for transplant may become a pressing issue. In this paper, we consider one aspect of organ allocation—the preferences of donors in making a directed or conditional donation of their uterus. To what extent, in the context of uterus donation, would such donations be ethically permissible?
Equipoise, standard of care and consent: responding to the authorisation of new COVID-19 treatments in randomised controlled trials
Authors: Holm Soren , Lewis Jonathan , Dal-Ré Rafael
Published: May 2022

In response to the COVID-19 pandemic, large-scale research and pharmaceutical regulatory processes have proceeded at a dramatically increased pace with new and effective, evidence-based COVID-19 interventions rapidly making their way into the clinic. However, the swift generation of high-quality evidence and the efficient processing of regulatory authorisation have given rise to more specific and complex versions of well-known research ethics issues. In this paper, we identify three such issues by focusing on the authorisation of molnupiravir, a novel antiviral medicine aimed at reducing the ability of SARS-CoV-2 to multiply in the body, for clinical use by the National Health Service in England and the concomitant testing of molnupiravir through the large-scale Platform Adaptive trial of Novel antiviRals for eArly treatMent of COVID-19 In the Community randomised control trial. By analysing the ways in which the authorisation and clinical use of molnupiravir complicate standard approaches to clinical equipoise, standard of care and participant consent in the PANORAMIC randomised control trial, we will explain some of ethical implications for clinical trials that aim to study the efficacy and safety of new COVID-19 and other therapeutics when conditional authorisation has already been granted and when such treatments have already been made available to patients by national health providers.
Bioethics to the rescue! A response to Emmerich
Authors: Hardman Douglas , Hutchinson Phil
Published: May 2022

In our article,Where the ethical action is,we argue that medical and ethical modes of thought are not different in kind but merely different aspects of a clinical situation. In response, Emmerich argues that in so doing, we neglect several important features of healthcare and medical education. Although we applaud the spirit of Emmerich’s response, we argue that his critique is an attempt at a general defence of the value of bioethical expertise in clinical practice, rather than a specific critique of our account.
(De)troubling transparency: artificial intelligence (AI) for clinical applications
Authors: Winter Peter David , Carusi Annamaria
Published: May 2022

Artificial intelligence (AI) and machine learning (ML) techniques occupy a prominent role in medical research in terms of the innovation and development of new technologies. However, while many perceive AI as a technology of promise and hope—one that is allowing for more early and accurate diagnosis—the acceptance of AI and ML technologies in hospitals remains low. A major reason for this is the lack of transparency associated with these technologies, in particular epistemic transparency, which results in AI disturbing or troubling established knowledge practices in clinical contexts. In this article, we describe the development process of one AI application for a clinical setting. We show how epistemic transparency is negotiated and co-produced in close collaboration between AI developers and clinicians and biomedical scientists, forming the context in which AI is accepted as an epistemic operator. Drawing on qualitative research with collaborative researchers developing an AI technology for the early diagnosis of a rare respiratory disease (pulmonary hypertension/PH), this paper examines how including clinicians and clinical scientists in the collaborative practices of AI developers de-troubles transparency. Our research shows how de-troubling transparency occurs in three dimensions of AI development relating to PH:querying of data sets,building softwareandtraining the model. The close collaboration results in an AI application that is at once social and technological: it integrates and inscribes into the technology the knowledge processes of the different participants in its development. We suggest that it is a misnomer to call these applications ‘artificial’ intelligence, and that they would be better developed and implemented if they were reframed as forms of sociotechnical intelligence.
Peak troponin T in STEMI: a predictor of all-cause mortality and left ventricular function
Authors: Khullar Natasha , Buckley Anthony James , O’Connor Cormac , Ibrahim Abdalla , Ibrahim Alsamawal , Ahern Catriona , Cahill Ciara , Arnous Samer , Kiernan Thomas John
Published: May 2022

Background

The clinical significance of peak troponin levels following ST-elevation myocardial infarction (STEMI) has not been definitively established. The purpose of this study was to examine the relationship between peak high-sensitivity cardiac troponin T (hs-cTnT) and all-cause mortality at 30 days and 1 year, and left ventricular ejection fraction (LVEF) in STEMI.

Methods

A single-centre retrospective observational study was conducted of all patients with STEMI between January 2015 and December 2017. Demographics and clinical data were obtained through electronic patient records. Standard Bayesian statistics were employed for analysis.

Results

During the study period, 568 patients presented with STEMI. The mean age was 63.6±12 years and 76.4% were men. Of these, 535 (94.2%) underwent primary percutaneous coronary intervention, 12 (2.1%) underwent urgent coronary artery bypass and 21 (3.7%) were treated medically. Mean peak hs-cTnT levels were significantly higher in those who died within 30 days compared with those who survived (12 238 ng/L vs 4657 ng/L, respectively; p=0.004). Peak hs-cTnT levels were also significantly higher in those who died within 1 year compared with those who survived (10 319 ng/L vs 4622 ng/L, respectively; p=0.003). The left anterior descending artery was associated with the highest hs-cTnT and was the most common culprit in those who died at 1 year. An inverse relationship was demonstrated between peak hs-cTnT and LVEF (Pearson’s R=0.379; p<0.00001).

Conclusions

In STEMI, those who died at 30 days and 1 year had significantly higher peak troponin levels than those who survived. Peak troponin is also inversely proportional to LVEF with higher troponins associated with lower LVEF.
Discovery of insulin 100 years on
Authors: Russell-Jones David , Bawlchhim Zosanglura
Published: May 2022

The discovery of insulin 100 years ago ranks among the greatest medical achievements ever. This sparked a revolution of scientific discovery and therapeutic intervention to treat people suffering with diabetes. A light was shone for other areas of medicine to illuminate what was possible with detailed scientific endeavour. There followed a range of firsts leading to the current time in which we now know more about this peptide hormone than almost any other protein in existence. This has allowed therapeutic advancement from a positon of knowledge leading to stunning innovation. This innovation is likely to lead to more physiological insulin replacement reducing the disease burden to individuals and society as whole.
COVID-19 infection among patients with autoinflammatory diseases: a study on 117 French patients compared with 1545 from the French RMD COVID-19 cohort: COVIMAI – the French cohort study of SARS-CoV-2 infection in patient with systemic autoinflammatory diseases
Authors: Bourguiba Rim , Kyheng Maeva , Koné-Paut Isabelle , Rouzaud Diane , Avouac Jerome , Devaux Mathilde , Abdallah Nassim Ait , Fautrel Bruno , Ferreira-Maldent Nicole , Langlois Vincent , Ledoult Emmanuel , Nielly Hubert , Queyrel Viviane , Sellam Jérémie , Tieulie Nathalie , Chazerain Pascal , Evon Philippe , Labreuche Julien , Savey Léa , Hentgen Veronique , Grateau Gilles , Georgin-lavialle Sophie
Published: May 2022

Objective

There is little known about SARS-CoV-2 infection in patients with systemic autoinflammatory disease (SAID). This study aimed to describe epidemiological features associated with severe disease form and death. Mortality between patients with and without SAID hospitalised for SARS-CoV-2 infection was compared.

Methods

A national multicentric prospective cohort study was conducted from the French Rheumatic and Musculoskeletal Diseases (RMD) COVID-19 cohort. Patients with SAID were matched with patients with non-SAID on age±7 years, gender and number of comorbidities to consider important confounding factors. Impact of SAID on severity of SARS-CoV-2 infection was analysed using multinomial logistic regression for severity in three classes (mild, moderate and severe with mild status as reference). Fine-Gray regression model for length of hospital stay and binomial logistic regression model for risk of death at 30 days.

Results

We identified 117 patients with SAID (sex ratio 0.84, 17 children) and compared them with 1545 patients with non-autoinflammatory immune-mediated inflammatory disorders (non-SAID). 67 patients had a monogenic SAID (64 with familial Mediterranean fever). Other SAIDs were Behçet’ disease (n=21), undifferentiated SAID (n=16), adult-onset Still disease (n=9) and systemic-onset juvenile idiopathic arthritis (n=5). Ten adults developed severe form (8.6%). Six patients died. All children had a benign disease. After matching on age±7 years, sex and number of comorbidities, no significant difference between the two groups in length of stay and the severity of infection was noted.

Conclusion

As identified in the whole French RMD COVID-19 cohort, patients with SAID on corticosteroids and with multiple comorbidities are prone to develop more severe COVID-19 forms.
Recent changes in the reporting of STIs in Japan during the COVID-19 pandemic
Authors: Ghaznavi Cyrus , Tanoue Yuta , Kawashima Takayuki , Eguchi Akifumi , Yoneoka Daisuke , Sakamoto Haruka , Ueda Peter , Ishikane Masahiro , Ando Naokatsu , Miyazato Yusuke , Nomura Shuhei
Published: May 2022

Objectives

The COVID-19 pandemic has had variable effects on the rates of STIs reported across the globe. This study sought to assess how the number of STI reports changed during the pandemic in Japan.

Methods

We used national infectious disease surveillance data from the National Institute of Infectious Diseases (Tokyo, Japan) for the period between January 2013 and December 2021. We compared reported rates of chlamydia, gonorrhoea, condyloma acuminata and genital herpes, as well as total notifications for HIV/AIDS and syphilis during the pandemic versus previous years in Japan. We used a quasi-Poisson regression to determine whether any given week or month between January 2018 and December 2021 had a significant excess or deficit of STIs. Notification values above or below the 95% upper and lower prediction thresholds were considered as statistically significant. The start of the pandemic was defined as January 2020.

Results

Chlamydia generally remained within predicted range during the pandemic period. Reporting of gonorrhoea was significantly higher than expected throughout early-to-mid 2021 but otherwise generally remained within predicted range prior to 2021. Condyloma, herpes and HIV/AIDS reporting were transiently significantly lower than expected throughout the pandemic period, but no significant periods of higher-than-expected reporting were detected. Syphilis showed widespread evidence of significantly lower-than-predicted reporting throughout 2020 but eventually reversed, showing significantly higher-than-predicted reporting in mid-to-late 2021.

Conclusions

The COVID-19 pandemic was associated with variable changes in the reporting of STIs in Japan. Higher-than-predicted reporting was more likely to be observed in the later phases of the pandemic. These changes may have been attributable to pandemic-related changes in sexual behaviour and decreased STI clinic attendance and testing, but further research on the long-term impact of the pandemic on STIs is necessary.
Person-centred language and HIV research: a cross-sectional examination of stigmatising terminology in medical literature
Authors: McPherson Kristen A , Reddy Arjun K , Sajjadi Nicholas B , Deboy Kyle , Gajjar Swapnil , Lad Madhuri , Hartwell Micah
Published: May 2022

Objective

We sought to quantify the use of person-centred language (PCL) in research journals that publish high volumes of HIV-related manuscripts.

Design

In this cross-sectional study, we searched PubMed for HIV-related articles published between 1 January 2017 and 7 March 2021. After journal reduction and article randomisation, title and abstract screening was conducted among 500 studies in a masked, duplicate fashion.

Methods

Studies that were included were systematically searched for prespecified, stigmatising terms, partial terms and phrases. Prevalence rates of non-person-centred terminology were totalled, and the total number of articles adherent to PCL guidelines were reported. Fisher’s exact tests were used to determine associations between PCL adherence and article funding source, type of article, continent of origin and research, among others.

Results

Among 237 studies included, 21.52% (51) of HIV-related publications in this cross-sectional analysis were found to be PCL adherent. Stigmatising labels such as ‘HIV- or AIDS-infected’ and ‘HIV- or AIDS-person or patient’ were used most frequently, with the former appearing in 57.38% of articles and the latter appearing in 30.80% of articles.

Conclusion

Despite numerous guidelines and requirements for the use of PCL in research, our findings suggest that an alarming number of HIV-related articles are not following these guidelines. This is concerning because this labelling likely contributes to the persistence of stigma in HIV-centred care. The intentional use of person-centred language in medical research has the potential to minimise the use of stigmatising language among medical professionals, in medical education, in medical records and patient encounters, and thus reduce stigma.
COVID-19-related changes in outpatient CPAP setup pathways for OSA are linked with decreased 30-day CPAP usage
Authors: Turnbull Chris D , Allen Martin , Appleby Jennifer , Brown Richard , Bryan Nathalie , Cooper Ann , Cooper Brendan G , Gillooly Cathie , Davidson James , Farley Hannah , Gaspar Ana , Gibbons Gillian , Gray Beverley , Hill Graham , Kendrick Adrian , Marsh Blake , McMillan Alison , Page Joseph , Pepperell Justin Charles Thane , Quinnell Tim , Rogers Chris , Sexton Jane , Sheperd Naomi , Steier Joerg , Stockley James , Stradling John , Woroszyl Asia , West Sophie , Wright Susan , Nickol Annabel
Published: May 2022

The COVID-19 pandemic changed continuous positive airway pressure (CPAP) setup pathways. We evaluated patients commenced on CPAP in 2019 (prepandemic) and 2020 (post-first UK wave). Face-to-face (F2F) setup numbers, with CPAP turned on, decreased from 613 patients (98.9%) in 2019, to 6 (1.1%) in 2020. In 2020, setups were F2F without CPAP turned on (403 (71.1%)), or remote (158 (27.9%)). Prepandemic median CPAP usage at first follow-up was 5.4 (2.7–6.9) hours/night and fell by 0.9 hours/night (95% CI 0.5 to 1.2, p<0.0001) in 2020. We found clinically relevant reductions in CPAP usage with pathway changes post-COVID-19.
Establishing normal ranges for fetal and neonatal small and large intestinal lengths: results from a prospective postmortem study
Authors: Bardwell Cameron , El Demellawy Dina , Oltean Irina , Murphy Michelle , Agarwal Amisha , Hamid Jemila S , Reddy Deepti , Barrowman Nick , de Nanassy Joseph , Nasr Ahmed
Published: May 2022

Objective

To establish reference intervals (RIs) for fetal and neonatal small and large intestinal lengths.

Methods

Linear measurements on small and large intestines were made upon postmortem examination of 131 preterm and term infants with gestational ages between 13 and 41 weeks. All cases were referred from the Eastern Ontario and Western Québec regions to a tertiary care hospital. Age and sex partitions were considered and RI limits were estimated.

Results

Data consisted of 72 male (54.96%) and 59 female (45.04%) fetuses and neonates with mean gestational age of 25.6 weeks. Results showed that small and large intestinal lengths increased linearly with gestational age. RIs for small intestinal length (cm) of fetuses and neonates aged 13–20 weeks were (21.1, 122.4); of those aged 21–28 weeks were (57.7, 203.8); of those aged 29–36 weeks were (83.6, 337.1); and of those aged 37–41 weeks were (132.8, 406.4). RIs for large intestinal length (cm) of fetuses and neonates from the same four age groups were (5.1, 21.4), (12.7, 39.7), (32.4, 62.4), and (29.1, 82.2).

Conclusions

Establishing accurate RIs for premature and term infants has clinical relevance for pathologists performing postmortem analysis and for surgeons planning postoperative management of patients. The results of this study reaffirm that fetal small and large intestinal lengths increase linearly with gestational age irrespective of sex. Future studies should aim to further investigate the role of possible confounders on growth of fetal intestinal length, including maternal factors such as age and substance use during pregnancy.
$${\mathcal {N}}=(2,2)$$ extended $${\mathfrak {sl}}(3|2)$$ Chern–Simons $$AdS_3$$ supergravity with new boundaries
Authors: Özer H. T. , Filiz Aytül
Published: May 2022

We present the first example of $${\mathcal {N}}=(2,2)$$

N
=
(
2
,
2
)

formulation for the extended higher-spin $$AdS_3$$

A
d

S
3

supergravity with the most general boundary conditions as an extension of the $${\mathcal {N}}=(1,1)$$

N
=
(
1
,
1
)

work, discovered recently by us (Özer and Filiz in Eur Phys J C 80(11):1072, 2020). Using the method proposed by Grumiller and Riegler, we restrict a consistent class of the most general boundary conditions to extend it. An important consequence of our method is that, for the loosest set of boundary conditions it ensures that their asymptotic symmetry algebras consist of two copies of the $${\mathfrak {sl}}(3|2)_k$$

sl

(
3
|
2
)

k

. Moreover, we impose some restrictions on the gauge fields for the most general boundary conditions, leading to the supersymmetric extensions of the Brown and Henneaux boundary conditions. Based on these results, we finally find out that the asymptotic symmetry algebras are two copies of the super $${\mathcal {W}}_3$$

W
3

algebra for $${\mathcal {N}}=(2,2)$$

N
=
(
2
,
2
)

extended higher-spin supergravity theory in $$AdS_3$$

A
d

S
3

.
From Continental Shelf to Slope: Mapping the Oceanic Realm: Introduction
Authors: Asch Kristine , Kitazato Hiroshi , Vallius Henry
Published: May 2022

This volume covers multidisciplinary Research and Development contributions on geology, geophysics, bathymetric and biologic aspects, towards data sampling and acquisition, data analysis and its results, and innovative ways of data access. It also presents the development of processes to map, harmonize and integrate marine data across EEZ boundaries, an impressive example of which is the European EMODnet (European Marine Observation and Data network) initiative. EMODnet assembles scattered and partially hidden marine data into continentally harmonized geospatial data products for public benefit and increasingly within overseas collaboration. The volume also aims to shed light on an evaluation of biological and mineral resources and environmental assessments at continental shelf to slope depths. Western Pacific examples provide excellent case studies for this topic.
Correlating Automated and Human Evaluation of Code Documentation Generation Quality
Authors: Hu Xing , Chen Qiuyuan , Wang Haoye , Xia Xin , Lo David , Zimmermann Thomas
Published: May 2022

Automatic code documentation generation has been a crucial task in the field of software engineering. It not only relieves developers from writing code documentation but also helps them to understand programs better. Specifically, deep-learning-based techniques that leverage large-scale source code corpora have been widely used in code documentation generation. These works tend to use automatic metrics (such as BLEU, METEOR, ROUGE, CIDEr, and SPICE) to evaluate different models. These metrics compare generated documentation to reference texts by measuring the overlapping words. Unfortunately, there is no evidence demonstrating the correlation between these metrics and human judgment. We conduct experiments on two popular code documentation generation tasks, code comment generation and commit message generation, to investigate the presence or absence of correlations between these metrics and human judgments. For each task, we replicate three state-of-the-art approaches and the generated documentation is evaluated automatically in terms of BLEU, METEOR, ROUGE-L, CIDEr, and SPICE. We also ask 24 participants to rate the generated documentation considering three aspects (i.e., language, content, and effectiveness). Each participant is given Java methods or commit diffs along with the target documentation to be rated. The results show that the ranking of generated documentation from automatic metrics is different from that evaluated by human annotators. Thus, these automatic metrics are not reliable enough to replace human evaluation for code documentation generation tasks. In addition, METEOR shows the strongest correlation (with moderate Pearson correlation
r
about 0.7) to human evaluation metrics. However, it is still much lower than the correlation observed between different annotators (with a high Pearson correlation
r
about 0.8) and correlations that are reported in the literature for other tasks (e.g., Neural Machine Translation  [
39
]). Our study points to the need to develop specialized automated evaluation metrics that can correlate more closely to human evaluation metrics for code generation tasks.
Co-opted Marginality in a Controlled Media Environment: The Influence of Social Media Affordances on the Immigration Discourse
Authors: Emes Claire Stravato , Chib Arul
Published: May 2022

An emerging narrative on social media challenges the premise that the repertoire against immigrants is caused by xenophobia. We identify and propose the phenomenon of co-opted marginality or the claims of being victimized by dominant groups that are not conventionally at the margin. We examine how a controlled media environment in Singapore influences citizens (
n
= 36) who claim co-opted marginality when expressing anti-immigrant sentiments online. We further investigate the role of the social media techno-structure in encouraging interactions with this discourse. Contrary to prior literature, we find that social media affordances, such as curation and identification, can discourage citizens from actively engaging with prejudicial and discriminatory language while facilitating the emergence and maintenance of discursive strategies such as co-opted marginality, which conform to contextual normative constraints.
Digital Music Recommendation Technology for Music Teaching Based on Deep Learning
Authors: Lu Meng , Pengcheng Du , Yanfeng Song
Published: May 2022

With the rapid development of music streaming media service industry, users can easily hear any song on mobile devices. Internet has become a huge music storage platform. With the development of network and large-scale digital music industry, the acquisition and listening of music are presented to users in a more convenient way. How to find the music loved by users from the massive Internet digital music data has become the key problem and main goal to be solved in the field of music information retrieval. Personalized music recommendation system can accurately find and push songs that users may be interested in from tens of millions of huge music libraries according to users’ information under the condition that users only have vague demand for listening to songs. Relying on the traditional search method to find the music that you are interested in can no longer meet the needs of users, so the current music recommendation system needs to dig out the music that has no clear needs in the long tail to help people find their favorite songs.
FTX Regulated miR-153-3p/FOXR2 to Promote Cisplatin Resistance in Ovarian Cancer
Authors: Liu Ming , Peng Jingwei
Published: May 2022

Purpose. The present study was aimed at exploring the role of FTX in cisplatin (DDP) resistance in ovarian cancer (OC). Methods. QPCR was applied to evaluate mRNA expression in OC tissue and cells. CCK-8 assay was conducted to evaluate cell proliferation. Transwell chamber assay was performed to evaluate invasion of SKOV3/DDP cells. The protein expression was evaluated via western blot assay. Flow cytometry was performed to evaluate the apoptosis of SKOV3/DDP cells. Results. The expression of FTX in DDP-resistant cells was observably higher in contrast to DDP-sensitive cells and normal ovarian cells. FTX was higher expressed in DDP-resistant tissues by comparison with DDP-sensitive tissues. Knockdown of FTX obviously suppressed the proliferation ability invasion ability of SKOV3/DDP cells. Knockdown of FTX obviously enhanced apoptosis of SKOV3/DDP cells. miR-153-3p was proved to be directly regulated by FTX via the luciferase reporter assays. By comparison with normal cells, miR-153-3p was lower expressed in OC cells. miR-153-3p was lower expressed in SKOV3/DDP cells in contrast to SKOV3 cells. More interestingly, FTX reversed the inhibiting influence of miR-153-3p on cisplatin resistance of OC cells. Moreover, miR-153-3p was proved to directly regulate FOXR2. Knockdown of miR-153-3p attenuated the inhibitory influence of knockdown FOXR2 on cisplatin resistance of OC cells. Conclusion. FTX regulated miR-153-3p/FOXR2 to promote cisplatin resistance via inhibiting the apoptosis and promoting the viability and invasion in OC.