bluuebunny/crossref_metadata_2025_split huggingface dataset:
Progression patterns and therapeutic sequencing following immune checkpoint inhibition for hepatocellular carcinoma: An international observational study
Authors: Talbot Thomas , D'Alessio Antonio , Pinter Matthias , Balcar Lorenz , Scheiner Bernhard , Marron Thomas U. , Jun Tomi , Dharmapuri Sirish , Ang Celina , Saeed Anwaar , Hildebrand Hannah , Muzaffar Mahvish , Fulgenzi Claudia A. M. , Amara Suneetha , Naqash Abdul Rafeh , Gampa Anuhya , Pillai Anjana , Wang Yinghong , Khan Uqba , Lee Pei‐Chang , Huang Yi‐Hsiang , Bengsch Bertram , Bettinger Dominik , Mohamed Yehia I. , Kaseb Ahmed , Pressiani Tiziana , Personeni Nicola , Rimassa Lorenza , Nishida Naoshi , Kudo Masatoshi , Weinmann Arndt , Galle Peter R. , Muhammed Ambreen , Cortellini Alessio , Vogel Arndt , Pinato David J. 
Published: December 2022

AbstractBackground and AimsDifferent approaches are available after the progression of disease (PD) to immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC), including the continuation of ICI, treatment switching to tyrosine kinase inhibitors (TKIs) and cessation of anticancer therapy. We sought to characterise the relationship between radiological patterns of progression and survival post‐ICI, also appraising treatment strategies.MethodsWe screened 604 HCC patients treated with ICIs, including only those who experienced PD by data cut‐off. We evaluated post‐progression survival (PPS) according to the treatment strategy at PD and verified its relationship with radiological patterns of progression: intrahepatic growth (IHG), new intrahepatic lesion (NIH), extrahepatic growth (EHG), new extrahepatic lesion (NEH) and new vascular invasion (nVI).ResultsOf 604 patients, 364 (60.3%) experienced PD during observation. Median PPS was 5.3 months (95% CI: 4.4–6.9; 271 events). At the data cut‐off, 165 patients (45%) received no post‐progression anticancer therapy; 64 patients (17.6%) continued ICI beyond PD. IHG (HR 1.64 [95% CI: 1.21–2.22]; p = .0013) and nVI (HR 2.15 [95% CI: 1.38–3.35]; p = .0007) were associated with shorter PPS. Multivariate models adjusted for progression patterns, treatment line and albumin‐bilirubin grade and Eastern Cooperative Oncology Group performance status at PD confirmed receipt of ICI beyond PD with (HR 0.17, 95% CI: 0.09–0.32; p < .0001) or without subsequent TKI (HR 0.39, 95% CI: 0.26–0.58; p < .0001) as predictors of prolonged PPS versus no anticancer therapy.ConclusionsICI‐TKI sequencing is a consolidated option in advanced HCC. nVI and IHG predict a poorer prognosis. Despite lack of recommendation, the continuation of ICI beyond progression in HCC is adopted clinically: future efforts should appraise which patients benefit from this approach.
From whom Bells tolls: Reclassifying Bells among CR chondrites and implications for the formation conditions of CR parent bodies
Authors: Marrocchi Yves , Jacquet Emmanuel , Neukampf Julia , Villeneuve Johan , Zolensky Michael E. 
Published: December 2022

AbstractThe ungrouped carbonaceous chondrite (CC) Bells has long been considered petrographically similar to CM chondrites based on its matrix abundance and degree of aqueous alteration, but also shows significant isotopic affinities to CR chondrites. Its taxonomic status is thus important for clarifying the relationship of the CRHB (formerly “CR”) clan with other CCs. In this study, we measured the oxygen isotopic compositions of olivines in type I chondrules and isolated olivine grains in Bells. Bells olivines mostly have ∆17O > −4‰, similar to CR chondrites but unlike other CCs that are rich in refractory inclusions, in which chondrules are generally richer in 16O. Therefore, Bells is a CR chondrite (albeit an anomalous one), most similar to the rare, matrix‐rich CRs like Al Rais. These chondrites (i) may not necessarily derive from the same primary parent body as mainstream CRs, (ii) bear witness to significant variations of the matrix/chondrule ratio within the CRHB clan, and (iii) may be a good analog for samples retrieved by the space mission OSIRIS‐REx.
Lack of evidence that Pseudomonas aeruginosaAmpDh3‐PA0808 constitute a type VI secretion system effector–immunity pair
Authors: Colautti Jake , Bullen Nathan P. , Whitney John C. 
Published: December 2022

AbstractType VI secretion systems (T6SSs) are cell envelope‐spanning protein complexes that Gram‐negative bacteria use to inject a diverse arsenal of antibacterial toxins into competitor cells. Recently, Wang et al. reported that the H2‐T6SS of Pseudomonas aeruginosa delivers the peptidoglycan recycling amidase, AmpDh3, into the periplasm of recipient cells where it is proposed to act as a peptidoglycan degrading toxin. They further reported that PA0808, the open reading frame downstream of AmpDh3, encodes an immunity protein that localizes to the periplasm where it binds to and inactivates intercellularly delivered AmpDh3, thus protecting against its toxic activity. Given that AmpDh3 has an established role in cell wall homeostasis and that no precedent exists for cytosolic enzymes moonlighting as T6SS effectors, we attempted to replicate these findings. We found that cells lacking PA0808 are not susceptible to bacterial killing by AmpDh3 and that PA0808 and AmpDh3 do not physically interact in vitro or in vivo. Additionally, we found no evidence that AmpDh3 is exported from cells, including by strains with a constitutively active H2‐T6SS. Finally, subcellular fractionation experiments and a 1.97 Å crystal structure reveal that PA0808 does not contain a canonical signal peptide or localize to the correct cellular compartment to confer protection against a cell wall targeting toxin. Taken together, these results cast doubt on the assertion that AmpDh3‐PA0808 constitutes an H2‐T6SS effector–immunity pair.
Implications of plant N/P stoichiometry influenced by arbuscular mycorrhizal fungi for stability of plant species and community in response to nutrient limitation
Authors: Liu Hongfei , Pausch Johanna , Wu Yang , Xu Hongwei , Liu Guobin , Ma LiHui , Xue Sha 
Published: December 2022

Arbuscular mycorrhizal fungi (AMF) influence plant nitrogen/phosphorus (N/P) by modifying plant N and P uptake, which further affects plant stoichiometric N/P homeostasis. Plant species and community stoichiometric N/P homeostasis can impact plant species and community stability, respectively, in response to variations of soil N and P availabilities. We investigated interspecific plant interactions via AMF in regard to plant and soil microbial N/P stoichiometry across different soil N and P availabilities induced by N and P addition (0 mg N kg−1, 25 mg N kg−1, 50 mg N kg−1, 30 mg P kg−1 and 100 mg P kg−1). We selected one dominant (Bothriochloa ischaemum; C4 grass) and one subordinate (Lespedeza davurica; legume) species in a natural grassland climax community. We examined how AMF influences stoichiometric N/P homeostasis in monoculture and mixed culture systems, and the resulting consequences for temporal stability of plant species and community in response to variations in soil N and P availability.The AMF mitigated the P limitation of soil microbial communities and decreased the degree of stoichiometric N/P homeostasis of host plants in monoculture. Through their resource‐scavenging and soil organic matter mineralisation functions, AMF enhances plant ‘luxury consumption', promoting species stability in monoculture in response to soil N and P availability variations. Compared with plants in monoculture, the interaction between B. ischaemum and L. davurica via AMF increased shoot N/P under soil N‐poor conditions, leading to an enhanced degree of stoichiometric N/P homeostasis in both plant species, especially the legume.Our results suggest that interspecific plant interaction between C4 grass and legume mediated by AMF confers an advantage in complementarity in plant N acquisition under N‐poor conditions, leading to increased stability of plant communities and better maintenance of subordinate species (legume) in response to soil N deficiency.
Horizontally transferred genes as RNA interference targets for aphid and whitefly control
Authors: Feng Honglin , Chen Wenbo , Hussain Sonia , Shakir Sara , Tzin Vered , Adegbayi Femi , Ugine Todd , Fei Zhangjun , Jander Georg 
Published: December 2022

SummaryRNA interference (RNAi)‐based technologies are starting to be commercialized as a new approach for agricultural pest control. Horizontally transferred genes (HTGs), which have been transferred into insect genomes from viruses, bacteria, fungi or plants, are attractive targets for RNAi‐mediated pest control. HTGs are often unique to a specific insect family or even genus, making it unlikely that RNAi constructs targeting such genes will have negative effects on ladybugs, lacewings and other beneficial predatory insect species. In this study, we sequenced the genome of a red, tobacco‐adapted isolate of Myzus persicae (green peach aphid) and bioinformatically identified 30 HTGs. We then used plant‐mediated virus‐induced gene silencing (VIGS) to show that several HTGs of bacterial and plant origin are important for aphid growth and/or survival. Silencing the expression of fungal‐origin HTGs did not affect aphid survivorship but decreased aphid reproduction. Importantly, although there was uptake of plant‐expressed RNA by Coccinella septempunctata (seven‐spotted ladybugs) via the aphids that they consumed, we did not observe negative effects on ladybugs from aphid‐targeted VIGS constructs. To demonstrate that this approach is more broadly applicable, we also targeted five Bemisia tabaci (whitefly) HTGs using VIGS and demonstrated that knockdown of some of these genes affected whitefly survival. As functional HTGs have been identified in the genomes of numerous pest species, we propose that these HTGs should be explored further as efficient and safe targets for control of insect pests using plant‐mediated RNA interference.
Protein kinase MtCIPK12 modulates iron reduction in Medicago truncatula by regulating riboflavin biosynthesis
Authors: Wang Tianzuo , Wang Jing , Zhang Di , Chen Li , Liu Min , Zhang Xinxin , Schmidt Wolfgang , Zhang Wen‐Hao 
Published: December 2022

AbstractIron (Fe) is an essential micronutrient, and deficiency in available Fe is one of the most important limiting factors for plant growth. In some species including Medicago truncatula, Fe deficiency results in accumulation of riboflavin, a response associated with Fe acquisition. However, how the plant's Fe status is integrated to tune riboflavin biosynthesis and how riboflavin levels affect Fe acquisition and utilization remains largely unexplored. We report that protein kinase CIPK12 regulates ferric reduction by accumulation of riboflavin and its derivatives in roots of M. truncatula via physiological and molecular characterization of its mutants and over‐expressing materials. Mutations in CIPK12 enhance Fe accumulation and improve photosynthetic efficiency, whereas overexpression of CIPK12 shows the opposite phenotypes. The Calcineurin B‐like proteins CBL3 and CBL8 interact with CIPK12, which negatively regulates the expression of genes encoding key enzymes in the riboflavin biosynthesis pathway. CIPK12 negatively regulates Fe acquisition by suppressing accumulation of riboflavin and its derivatives in roots, which in turn influences ferric reduction activity by riboflavin‐dependent electron transport under Fe deficiency. Our findings uncover a new regulatory mechanism by which CIPK12 regulates riboflavin biosynthesis and Fe‐deficiency responses in plants.
A circuit‐based approach to modulate hypersexuality in Parkinson's disease
Authors: Mata‐Marín David , Pineda‐Pardo José Ángel , Michiels Mario , Pagge Cristina , Ammann Claudia , Martínez‐Fernández Raúl , Molina José Antonio , Vela‐Desojo Lydia , Alonso‐Frech Fernando , Obeso Ignacio 
Published: December 2022

AimImpulse‐control disorder is a common neuropsychiatric complication in Parkinson's disease (PD) under dopamine replacement therapy. Prior studies tested the balance between enhanced desire towards reward and cognitive control deficits, hypothesized to be biased towards the former in impulse control disorders. We provide evidence for this hypothesis by measuring behavioral and neural patterns behind the influence of sexual desire over response inhibition and tools towards functional restoration using repetitive transcranial stimulation in patients with hypersexuality as predominant impulsive disorder.MethodsThe effect of sexual cues on inhibition was measured with a novel erotic stop‐signal task under on and off dopaminergic medication. Task‐related functional and anatomical connectivity models were estimated in 16 hypersexual and 17 nonhypersexual patients with PD as well as in 17 healthy controls. Additionally, excitatory neuromodulation using intermittent theta‐burst stimulation (sham‐controlled) was applied over the pre‐supplementary motor area in 20 additional hypersexual patients with PD aiming to improve response inhibition.ResultsCompared with their nonhypersexual peers, patients with hypersexuality recruited caudate, pre‐supplementary motor area, ventral tegmental area, and anterior cingulate cortex while on medication. Reduced connectivity was found between pre‐supplementary motor area and caudate nucleus in hypersexual compared with nonhypersexual patients (while medicated), a result paralleled by compensatory enhanced anatomical connectivity. Furthermore, stimulation over the pre‐supplementary motor area improved response inhibition in hypersexual patients with PD when exposed to sexual cues.ConclusionThis study, therefore, has identified a specific fronto‐striatal and mesolimbic circuitry underlying uncontrolled sexual responses in medicated patients with PD where cortical neuromodulation halts its expression.
Intermittent high‐intensity exercise for pre‐ to established hypertension: A systematic review and meta‐analysis
Authors: Teixeira Jorge M. M. , Motta‐Santos Daisy , Milanovic Zoran , Pereira Rita L. , Krustrup Peter , Póvoas Susana 
Published: December 2022

ObjectiveTo determine the impact of intermittent high‐intensity exercise training ([IHIE], including high‐intensity interval training [HIIT] and recreational team sports [RTS]) on systolic (SBP) and diastolic blood pressure (DBP) in adults with pre‐ to established arterial hypertension.Data sourcesMEDLINE, Cochrane Library, Embase, and SPORTDiscus.Eligibility criteriaRandomized controlled trials (RCTs) comparing the impact of IHIE on BP versus a non‐exercise control.Data collection and analysisTwo authors independently conducted all procedures. Mean differences were calculated using random‐effects model. The certainty of the evidence was assessed with GRADE.ResultsTwenty‐seven RCTs (18 HIIT and 9 RTS) were analyzed, with median duration of 12 weeks. Participants' (n = 946) median age was 46 years. Overall, IHIE decreased SBP (−3.29 mmHg; 95% CI: −5.19, −1.39) and DBP (−2.62 mmHg; 95% CI: −3.79, −1.44) compared to the control group. IHIE elicited higher decreases in office SBP and DBP of hypertensive subjects (SBP: −7.13 mmHg, [95% CI: −10.12, −4.15]; DBP: −5.81 mmHg, [95% CI: −7.94, −3.69]) than pre‐hypertensive (SBP: −2.14 mmHg, [95% CI: −4.36, −0.08]; DBP: −1.83 mmHg, [95% CI: −2.99, −0.67]). No significant differences were found between HIIT (SBP: −2.12 mmHg, [95% CI: −4.78, −0.54]; DBP: −1.89 mmHg, [95% CI: −3.32, −0.48]) and RTS (SBP: −4.18 mmHg, [95% CI: −7.19, −2.43]; DBP: −4.04 mmHg, [95% CI: −6.00, −2.09]). These findings present low/very low certainty of evidence. No adverse cardiovascular events were reported.ConclusionsIHIE appears to be safe and to promote substantial decreases in BP, particularly in patients with hypertension. However, the certainty of evidence was low/very low.ProtocolCRD42020163575.
Epidemiological study of ticks harbouring Aeromonas hydrophila in areas endemic and non‐endemic to Japanese‐spotted fever
Authors: Kondo Makoto , Matsushima Yoshiaki , Nakanishi Takehisa , Iida Shohei , Habe Koji , Yamanaka Keiichi 
Published: December 2022

AbstractObjectivesAeromonas spp. often cause life‐threatening diseases, including necrotizing fasciitis, which may lead to septic shock and ultimately death. Aeromonas infections are believed to be transmitted via minor wounds or the consumption of fresh fish. However, after the detection of Aeromonas hydrophila in ticks in areas endemic to Japanese‐spotted fever (JSF), a novel transmission route of A. hydrophila (i.e., via tick bites) has been proposed. We investigated the prevalence of A. hydrophila in ticks in areas endemic and not endemic to JSF in the Mie Prefecture, Japan.MethodsWe collected ticks from endemic and nonendemic areas in summer and winter and assessed them for presence of A. hydrophila using polymerase chain reaction.ResultsSix A. hydrophila isolates were obtained from 95 ticks in endemic areas, whereas one A. hydrophila isolate was obtained from 142 ticks in non‐endemic areas, in summer. All ticks that harboured A. hydrophila were Haemaphysalis longicornis (H.L); these ticks were almost at the larval stage and also carried Rickettsia spp. in the endemic area. In contrast, 51 and 41 ticks in the endemic and non‐endemic areas were captured in winter, respectively; A. hydrophila was not detected in these.ConclusionsThis study revealed the prevalence of tick‐borne A. hydrophila. Therefore, the risk of transmission of A. hydrophila via a tick bite should be considered in the following conditions: areas abundant in H. L. harbouring Rickettsia spp., in areas endemic for JSF, presence of ticks in the larval stage and during the summer season.
Optimising intravenous salbutamol in children: a phase 2 study
Authors: Walsh Sandra , Pan Shan , Sheng Yucheng , Kloprogge Frank , Standing Joe F , Anderson Brian J , Ramnarayan Padmanabhan 
Published: December 2022

ObjectiveThe β2-agonists such as salbutamol are the mainstay of asthma management. Pharmacokinetic–pharmacodynamic (PKPD) models to guide paediatric dosing are lacking. We explored the relationship between salbutamol dose, serum concentration, effectiveness and adverse effects in children by developing a PKPD model.DesignA prospective cohort study of children admitted to hospital with acute asthma, who received intravenous salbutamol.SettingChildren were recruited in two cohorts: the emergency departments of two London hospitals or those retrieved by the Children’s Acute Transport Service to three London paediatric intensive care units.PatientsPatients were eligible if aged 1–15 years, admitted for acute asthma and about to receive or receiving intravenous salbutamol.InterventionsTreatment was according to local policy. Serial salbutamol plasma levels were taken. Effectiveness measurements were recorded using the Paediatric Asthma Severity Score (PASS). Toxicity measurements included lactate, pH, glucose, heart rate, blood pressure and arrhythmias. PKPD modelling was performed with non-linear mixed-effect models.Main outcomesFifty-eight children were recruited with 221 salbutamol concentration measurements from 54 children. Median (range) age was 2.9 (1.1–15.2) years, and weight was 13.6 (8–57.3) kg. Ninety-five PASS measurements and 2078 toxicity measurements were obtained.ResultsA two-compartment PK model adequately described the time course of salbutamol–plasma concentrations. An EMAX(maximum drug effect) concentration–effect relationship described PASS and toxicity measures. PKPD simulations showed an infusion of 0.5 µg/kg/min (maximum 20 µg/min) for 4 hours after bolus achieves >90% maximal bronchodilation for 12 hours.ConclusionsA paediatric PKPD model for salbutamol is described. An infusion of 0.5 µg/kg/min after bolus achieves effective bronchodilation. Higher rates are associated with greater tachycardia and hyperglycaemia.
Correlation of lung function with ultra-low-dose CT-detected lung parenchymal abnormalities: a cohort study of 1344 asbestos exposed individuals
Authors: Brims Fraser , Harris Edward JA , Kumarasamy Chellan , Ringuet Amie , Adler Brendan , Franklin Peter , de Klerk Nick , Musk Bill , Murray Conor 
Published: December 2022

IntroductionDeliberate exposure to medical ionising radiation should be as low as reasonably practicable but the reduction of radiation from CT should be balanced against diagnostic image quality. The ability of ultra-low-dose CT (uLDCT: similar radiation to chest X-ray) to demonstrate low contrast abnormalities (emphysema and interstitial lung abnormality (ILA)) is unclear.The aim of this cross-sectional study was to analyse the lung parenchymal findings from uLDCT scans against physiological measures of respiratory function.MethodsWA Asbestos Review Programme participants were eligible if they had an uLDCT scan and lung function assessment between Janary and December 2018. All scans were performed using a single CT machine and reported using a standardised, semiquantitative synoptic report which includes emphysema and linear fibrosis (ILA) scores.ResultsOf 1344 participants, median (IQR) age was 72.0 (65.0–78.0) years, the majority were males (84.9%) with mixed occupational asbestos exposure (68.1%). There were 721 (53.6%) with no abnormality, 158 (11.8%) with emphysema, 465 (34.6%) with ILA. Mean radiation dose was 0.12 mSv. There was statistically significant between group differences for all physiological parameters of lung function compared with controls. For instance, the emphysema score significantly correlated with obstructive forced expiratory volume in 1 s (FEV1)/forced vital capacity ratio (r=0.512), per cent predicted FEV1(r=0.24) and lower diffusion of carbon monoxide (DLCO) (r=0.337). Multivariate modelling demonstrated that increasing age, emphysema and fibrosis scores predicted reduced DLCO (adjusted R2=0.30).DiscussionuLDCT-detected parenchymal lung abnormalities correlate strongly with significant changes on lung function testing suggesting the observed CT abnormalities are of physiological and clinical significance.
Impact of occupational asthma on health and employment status: a long-term follow-up study
Authors: Mason Paola , Liviero Filippo , Paccagnella Eleonora Rachele , Biasioli Marco , Maestrelli Piero , Frigo Anna Chiara 
Published: December 2022

ObjectivesThe aim of this study was to assess the predictors of a favourable prognosis of occupational asthma (OA) and the employment status of patients with OA at least 2 years after diagnosis.MethodsWe collected data from 204 patients who had a diagnosis of OA confirmed by a positive specific inhalation challenge. We defined OA remission as meeting the following three criteria: no asthma symptoms, no antiasthma therapy for the last year and having normal lung function at the end of follow-up. A logistic regression analysis was performed to estimate the effects of the covariates.ResultsAt 10.6±7.8-year follow-up, 60 of 204 possible patients participated in the study, and among them 17 showed OA remission. When compared with the 43 patients with persistent OA, these patients exhibited at diagnosis younger age (p=0.0039), shorter duration of symptomatic exposure (p=0.0512), better lung function expressed by higher forced vital capacity (FVC%) predicted (p=0.0164), forced expiratory volume in 1 s (FEV1) % predicted (p=0.0066) and FEV1/FVC% (p=0.0132), and less bronchial hyper-responsiveness (p=0.0118). Nevertheless, in the multivariable model, no variables were significantly associated with OA remission. At follow-up, three individuals have retired; among the remaining 57 workers, 91.2% were still employed and 43.8% of them had continued working in the same factory after ceasing exposure to the causative agent.ConclusionsThis monocentric study did not identify a strong predictor of OA remission, but documented a high employment rate and a good job preservation over a long timeframe after diagnosis of OA mainly induced by low molecular weight agents.