bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diet or medication in primary care patients with IBS: the DOMINO study - a randomised trial supported by the Belgian Health Care Knowledge Centre (KCE Trials Programme) and the Rome Foundation Research Institute
Authors: Carbone Florencia , Van den Houte Karen , Besard Linde , Tack Céline , Arts Joris , Caenepeel Philip , Piessevaux Hubert , Vandenberghe Alain , Matthys Christophe , Biesiekierski Jessica , Capiau Luc , Ceulemans Steven , Gernay Olivier , Jones Lydia , Maes Sophie , Peetermans Christian , Raat Willem , Stubbe Jeroen , Van Boxstael Rudy , Vandeput Olivia , Van Steenbergen Sophie , Van Oudenhove Lukas , Vanuytsel Tim , Jones Michael , Tack Jan 
Published: May 2022

BackgroundIn Europe, IBS is commonly treated with musculotropic spasmolytics (eg, otilonium bromide, OB). In tertiary care, a low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet provides significant improvement. Yet, dietary treatment remains to be explored in primary care. We evaluated the effect of a smartphone FODMAP-lowering diet application versus OB on symptoms in primary care IBS.MethodsIBS patients, recruited by primary care physicians, were randomised to 8 weeks of OB (40 mg three times a day) or diet and followed for 24 weeks. We compared IBS Symptom Severity Score and the proportion of responders (improvement ≥50 points) in all patients and the subgroup fulfilling Rome IV criteria (Rome+). We also evaluated treatment efficacy, quality of life, anxiety, depression, somatic symptom severity (Patient Health Questionnaire (PHQ15, PHQ9)) and treatment adherence and analysed predictors of response.Results459 primary care IBS patients (41±15 years, 76% female, 70% Rome+) were randomised. The responder rate after 8 weeks was significantly higher with diet compared with OB (71% (155/218) vs 61% (133/217), p=0.03) and more pronounced in Rome+ (77% (118/153) vs 62% (98/158), p=0.004). Patients allocated to diet (199/212) were 94% adherent compared with 73% with OB (148/202) (p<0.001). The significantly higher response rate with diet was already observed after 4 weeks (62% (132/213) vs 51% (110/215), p=0.02) and a high symptom response persisted during follow-up. Predictors of response were female gender (OR=2.08, p=0.04) for diet and PHQ15 (OR=1.10, p=0.02) for OB.ConclusionIn primary care IBS patients, a FODMAP-lowering diet application was superior to a spasmolytic agent in improving IBS symptoms. A FODMAP-lowering diet should be considered the first-line treatment for IBS in primary care.Trial registration numberNCT04270487.
Using agent-based modelling to test hypotheses on the role of neighbourhood social mechanisms in the development of small-area health inequalities
Authors: Zolitschka Kim Alexandra , Razum Oliver , Sauzet Odile 
Published: May 2022

BackgroundSmall-area health inequalities may originate from differentials in the spatial distribution of environmental stressors on health. The role played by neighbourhood social mechanisms on small-area health inequalities is difficult to evaluate. We demonstrate that agent-based modelling (ABM) is a useful technique to overcome existing limitations. It allows testing hypotheses that social contagion has the potential to modify the effects of environmental stressors by reducing or increasing small-area health inequalities.MethodsParameters defining the strength of the effect of social contagion on health behaviour were used together with a stochastic model to obtain for every year the health outcome of every agent based on health the previous year, environmental stressors and health behaviour. Unequal spatial distribution of stressors was operationalised with spatial correlation structure. We measured changes in health inequalities using parameters of the spatial correlation structure of health after 10 years. In a further round of simulations, social contagion depended on the environmental stressors.ResultsA social contagion mechanism led to a reduction of small-area health inequalities together with an increase in the spatial reach of the effect of environmental stressors. An association between environmental stressor and social contagion mechanism led to a stronger localisation of the effect of environmental stressors.ConclusionsHypotheses about the role of neighbourhood social mechanisms can be tested using ABM. The respective models provide a better understanding of mechanisms in the causal chain between environmental stressors and health inequalities. This can pave the way to the development of a new type of neighbourhood-based intervention informed by social mechanisms.
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

BackgroundRetrospective 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.ResultsIn 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.ConclusionAltogether, 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

BackgroundAmino 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.MethodsWe 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.ResultsOn 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.ConclusionsThe 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

BackgroundCD19-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.MethodsIn 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.ResultsIn 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).ConclusionsThese 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

BackgroundActivin-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.MethodsWe 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.ResultsWe 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.ConclusionsOur 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

BackgroundLong-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.MethodsAn 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.ResultsTheHLA-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.ConclusionThe 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.
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

BackgroundOncolytic 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.MethodsTo 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.ResultsOur 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.ConclusionsThese 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 purposeInitiation 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).MethodsBased 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.ResultsA 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).ConclusionsAntiplatelet 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

BackgroundResearch 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.AimTo understand how healthcare leaders describe the acquisition and development of political skills with the aim of providing evidence for leadership development programme.MethodsA 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.ResultsThe 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.ConclusionsThe 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.