bluuebunny/crossref_metadata_2025 huggingface dataset:
The evolution of UK sea-level projections
Authors: Weeks Jennifer H , Fung Fai , Harrison Benjamin J , Palmer Matthew D
Published: March 2023

The methods used to generate process-based global and local mean sea-level projections have evolved substantially over the last fifteen years, including improved process understanding, advances in ice-sheet modelling, the use of emulators and further development of high-end scenarios. During this time, two sets of UK national sea-level projections have been generated as part of the UK Climate Projections in 2009 (UKCP09; Lowe et al 2009) and in 2018 (UKCP18; Palmer et al 2018b). UKCP18 presented local mean sea-level projections for the UK coastline for the 21st century rooted in Coupled Model Intercomparison Project Phase 5 (CMIP5) models and in methods used in the Intergovernmental Panel on Climate Change (IPCC) Fifth Assessment Report (AR5), with an emulator-based methodology to provide extended projections to 2300 (Palmer et al 2018a; 2020). We compare UKCP18 global and local mean sea-level projections with those presented in the IPCC Sixth Assessment Report (AR6, IPCC 2021a). We find the likely range projections (characterising the central two-thirds of the distribution) are broadly similar at 2150 to within 0.1 m, except at Edinburgh, where the maximum difference is 0.22 m under medium emissions. Differences arise due to higher contributions from sterodynamic processes and the Antarctic ice sheet, and higher or lower vertical land movement, in AR6 compared to UKCP18. We also compare high-end sea-level rise estimates, presented in AR6 and UKCP09, finding reasonable global and UK local agreement over the 21st century. We explore future paths for UK sea-level science considering both user needs for information and developments in modelling capability. Future UK sea-level projections would benefit from updated high-end sea-level rise scenarios which extend beyond 2100 and continued efforts to build understanding of observed sea-level change drivers. Alongside close collaboration with user groups this would enhance the utility of local sea-level projections by UK coastal practitioners and decision-makers.
Improvements in Hypertension Control in the Rural Longitudinal HAALSI Cohort of South African Adults Aged 40 and Older, From 2014 to 2019
Authors: Abrahams-Gessel Shafika , Gómez-Olivé F Xavier , Tollman Stephen , Wade Alisha N , Du Toit Jacques D , Ferro Enrico G , Kabudula Chodziwadziwa W , Gaziano Thomas A
Published: March 2023

Background

Over half of the South African adults aged 45 years and older have hypertension but its effective management along the treatment cascade (awareness, treatment, and control) remains poorly understood.

Methods

We compared the prevalence of all stages of the hypertension treatment cascade in the rural HAALSI cohort of older adults at baseline and after four years of follow-up using household surveys and blood pressure data. Hypertension was a mean systolic blood pressure >140 mm Hg or diastolic pressure >90 mm Hg, or current use of anti-hypertension medication. Control was a mean blood pressure <140/90 mm Hg. The effects of sex and age on the treatment cascade at follow-up were assessed. Multivariate Poisson regression models were used to estimate prevalence ratios along the treatment cascade at follow-up.

Results

Prevalence along the treatment cascade increased from baseline (B) to follow-up (F): awareness (64.4% vs. 83.6%), treatment (49.7% vs. 73.9%), and control (22.8% vs. 41.3%). At both time points, women had higher levels of awareness (B: 70.5% vs. 56.3%; F: 88.1% vs. 76.7%), treatment (B: 55.9% vs. 41.55; F: 79.9% vs. 64.7%), and control (B: 26.5% vs. 17.9%; F: 44.8% vs. 35.7%). Prevalence along the cascade increased linearly with age for everyone. Predictors of awareness included being female, elderly, or visiting a primary health clinic three times in the previous 3 months, and the latter two also predicted hypertension control.

Conclusions

There were significant improvements in awareness, treatment, and control of hypertension from baseline to follow-up and women fared better at all stages, at both time points.
Coercion promotes alloparental care in cooperative breeders
Authors: Zöttl Markus , Schreier Tanja , Taborsky Michael
Published: March 2023

Members of social groups may negotiate among each other about the exchange of goods and services. If this involves asymmetries between interacting partners, for instance in condition, power, or expected payoffs, coercion may be involved in the bargain. Cooperative breeders are excellent models to study such interactions, because asymmetries are inherent in the relationship between dominant breeders and subordinate helpers. Currently it is unclear whether punishment is used to enforce costly cooperation in such systems. Here we investigated experimentally in the cooperatively breeding cichlid Neolamprologus pulcher whether alloparental brood care provided by subordinates is contingent on enforcement by dominant breeders. We manipulated first the brood care behavior of a subordinate group member and then the possibility of the dominant breeders to punish idle helpers. When subordinates were prevented from providing brood care, breeders increased their attacks on them, which triggered increased alloparental brood care by helpers as soon as this was again possible. In contrast, when the possibility to punish helpers was prevented, energetically costly alloparental brood care did not increase. Our results confirm predictions of the pay-to-stay mechanism causing alloparental care in this species and they suggest more generally that coercion can play an important role in the control of cooperation.
Exploiting parallelization in positional Burrows–Wheeler transform (PBWT) algorithms for efficient haplotype matching and compression
Authors: Wertenbroek Rick , Xenarios Ioannis , Thoma Yann , Delaneau Olivier
Published: March 2023

The positional Burrows–Wheeler transform (PBWT) data structure allows for efficient haplotype data matching and compression. Its performance makes it a powerful tool for bioinformatics. However, existing algorithms do not exploit parallelism due to inner dependencies. We introduce a new method to break the dependencies and show how to fully exploit modern multi-core processors.

Availability and implementation

Source code and applications are available at https://github.com/rwk-unil/parallel_pbwt.

Supplementary information

Supplementary data are available at Bioinformatics Advances online.
GEOfetch: a command-line tool for downloading data and standardized metadata from GEO and SRA
Authors: Khoroshevskyi Oleksandr , LeRoy Nathan , Reuter Vincent P , Sheffield Nathan C
Published: March 2023

Motivation

The Gene Expression Omnibus has become an important source of biological data for secondary analysis. However, there is no simple, programmatic way to download data and metadata from Gene Expression Omnibus (GEO) in a standardized annotation format.

Results

To address this, we present GEOfetch—a command-line tool that downloads and organizes data and metadata from GEO and SRA. GEOfetch formats the downloaded metadata as a Portable Encapsulated Project, providing universal format for the reanalysis of public data.

Availability and implementation

GEOfetch is available on Bioconda and the Python Package Index (PyPI).
kb_DRAM: annotation and metabolic profiling of genomes with DRAM in KBase
Authors: Shaffer Michael , Borton Mikayla A , Bolduc Ben , Faria José P , Flynn Rory M , Ghadermazi Parsa , Edirisinghe Janaka N , Wood-Charlson Elisha M , Miller Christopher S , Chan Siu Hung Joshua , Sullivan Matthew B , Henry Christopher S , Wrighton Kelly C
Published: March 2023

Microbial genome annotation is the process of identifying structural and functional elements in DNA sequences and subsequently attaching biological information to those elements. DRAM is a tool developed to annotate bacterial, archaeal, and viral genomes derived from pure cultures or metagenomes. DRAM goes beyond traditional annotation tools by distilling multiple gene annotations to genome level summaries of functional potential. Despite these benefits, a downside of DRAM is the requirement of large computational resources, which limits its accessibility. Further, it did not integrate with downstream metabolic modeling tools that require genome annotation. To alleviate these constraints, DRAM and the viral counterpart, DRAM-v, are now available and integrated with the freely accessible KBase cyberinfrastructure. With kb_DRAM users can generate DRAM annotations and functional summaries from microbial or viral genomes in a point-and-click interface, as well as generate genome-scale metabolic models from DRAM annotations.

Availability and implementation

For kb_DRAM users, the kb_DRAM apps on KBase can be found in the catalog at https://narrative.kbase.us/#catalog/modules/kb_DRAM. For kb_DRAM users, a tutorial workflow with all documentation is available at https://narrative.kbase.us/narrative/129480. For kb_DRAM developers, software is available at https://github.com/shafferm/kb_DRAM.
Interpretable meta-learning of multi-omics data for survival analysis and pathway enrichment
Authors: Cho Hyun Jae , Shu Mia , Bekiranov Stefan , Zang Chongzhi , Zhang Aidong
Published: March 2023

Motivation

Despite the success of recent machine learning algorithms’ applications to survival analysis, their black-box nature hinders interpretability, which is arguably the most important aspect. Similarly, multi-omics data integration for survival analysis is often constrained by the underlying relationships and correlations that are rarely well understood. The goal of this work is to alleviate the interpretability problem in machine learning approaches for survival analysis and also demonstrate how multi-omics data integration improves survival analysis and pathway enrichment. We use meta-learning, a machine-learning algorithm that is trained on a variety of related datasets and allows quick adaptations to new tasks, to perform survival analysis and pathway enrichment on pan-cancer datasets. In recent machine learning research, meta-learning has been effectively used for knowledge transfer among multiple related datasets.

Results

We use meta-learning with Cox hazard loss to show that the integration of TCGA pan-cancer data increases the performance of survival analysis. We also apply advanced model interpretability method called DeepLIFT (Deep Learning Important FeaTures) to show different sets of enriched pathways for multi-omics and transcriptomics data. Our results show that multi-omics cancer survival analysis enhances performance compared with using transcriptomics or clinical data alone. Additionally, we show a correlation between variable importance assignment from DeepLIFT and gene coenrichment, suggesting that genes with higher and similar contribution scores are more likely to be enriched together in the same enrichment sets.

Availability and implementation

https://github.com/berkuva/TCGA-omics-integration.
Targeting tumor heterogeneity: multiplex-detection-based multiple instance learning for whole slide image classification
Authors: Wang Zhikang , Bi Yue , Pan Tong , Wang Xiaoyu , Bain Chris , Bassed Richard , Imoto Seiya , Yao Jianhua , Daly Roger J , Song Jiangning
Published: March 2023

Motivation

Multiple instance learning (MIL) is a powerful technique to classify whole slide images (WSIs) for diagnostic pathology. The key challenge of MIL on WSI classification is to discover the critical instances that trigger the bag label. However, tumor heterogeneity significantly hinders the algorithm’s performance.

Results

Here, we propose a novel multiplex-detection-based multiple instance learning (MDMIL) which targets tumor heterogeneity by multiplex detection strategy and feature constraints among samples. Specifically, the internal query generated after the probability distribution analysis and the variational query optimized throughout the training process are utilized to detect potential instances in the form of internal and external assistance, respectively. The multiplex detection strategy significantly improves the instance-mining capacity of the deep neural network. Meanwhile, a memory-based contrastive loss is proposed to reach consistency on various phenotypes in the feature space. The novel network and loss function jointly achieve high robustness towards tumor heterogeneity. We conduct experiments on three computational pathology datasets, e.g. CAMELYON16, TCGA-NSCLC, and TCGA-RCC. Benchmarking experiments on the three datasets illustrate that our proposed MDMIL approach achieves superior performance over several existing state-of-the-art methods.

Availability and implementation

MDMIL is available for academic purposes at https://github.com/ZacharyWang-007/MDMIL.
More than a Bit of Fun: The Multiple Outcomes of a Bioblitz
Authors: Meeus Sofie , Silva-Rocha Iolanda , Adriaens Tim , Brown Peter M J , Chartosia Niki , Claramunt-López Bernat , Martinou Angeliki F , Pocock Michael J O , Preda Cristina , Roy Helen E , Tricarico Elena , Groom Quentin J
Published: March 2023

Bioblitzes are a popular approach to engage people and collect biodiversity data. Despite this, few studies have actually evaluated the multiple outcomes of bioblitz activities. We used a systematic review, an analysis of data from more than 1000 bioblitzes, and a detailed analysis of one specific bioblitz to inform our inquiry. We evaluated five possible bioblitz outcomes, which were creating a species inventory, engaging people in biological recording, enhancing learning about nature, discovering a species new to an area, and promoting an organization. We conclude that bioblitzes are diverse but overall effective at their aims and have advantages over unstructured biodiversity recording. We demonstrate for the first time that bioblitzes increase the recording activity of the participants for several months after the event. In addition, we provide evidence that bioblitzes are effective at bringing people and organizations together to build communities of professionals and amateurs, critical for conserving and protecting biodiversity.
Systematic evaluation of high-level visual deficits and lesions in posterior cerebral artery stroke
Authors: Robotham Ro Julia , Rice Grace E , Leff Alex P , Lambon Ralph Matthew A , Starrfelt Randi
Published: March 2023

Knowledge about the consequences of stroke on high-level vision comes primarily from single case studies of patients selected based on their behavioural profiles, typically patients with specific stroke syndromes like pure alexia or prosopagnosia. There are, however, no systematic, detailed, large-scale evaluations of the more typical clinical behavioural and lesion profiles of impairments in high-level vision after posterior cerebral artery stroke. We present behavioural and lesion data from the Back of the Brain project, to date the largest (N = 64) and most detailed examination of patients with cortical posterior cerebral artery strokes selected based on lesion location. The aim of the current study was to relate behavioural performance with faces, objects and written words to lesion data through two complementary analyses: (i) a multivariate multiple regression analysis to establish the relationships between lesion volume, lesion laterality and the presence of a bilateral lesion with performance and (ii) a voxel-based correlational methodology analysis to establish whether there are distinct or separate regions within the posterior cerebral artery territory that underpin the visual processing of words, faces and objects. Behaviourally, most patients showed more general deficits in high-level vision (n = 22) or no deficits at all (n = 21). Category-selective deficits were rare (n = 6) and were only found for words. Overall, total lesion volume was most strongly related to performance across all three domains. While behavioural impairments in all domains were observed following unilateral left and right as well as bilateral lesions, the regions most strongly related to performance mainly confirmed the pattern reported in more selective cases. For words, these included a left hemisphere cluster extending from the occipital pole along the fusiform and lingual gyri; for objects, bilateral clusters which overlapped with the word cluster in the left occipital lobe. Face performance mainly correlated with a right hemisphere cluster within the white matter, partly overlapping with the object cluster. While the findings provide partial support for the relative laterality of posterior brain regions supporting reading and face processing, the results also suggest that both hemispheres are involved in the visual processing of faces, words and objects.
Prediction of post-stroke motor recovery benefits from measures of sub-acute widespread network damages
Authors: Rivier Cyprien , Preti Maria Giulia , Nicolo Pierre , Van De Ville Dimitri , Guggisberg Adrian G , Pirondini Elvira
Published: March 2023

Following a stroke in regions of the brain responsible for motor activity, patients can lose their ability to control parts of their body. Over time, some patients recover almost completely, while others barely recover at all. It is known that lesion volume, initial motor impairment and cortico-spinal tract asymmetry significantly impact motor changes over time. Recent work suggested that disabilities arise not only from focal structural changes but also from widespread alterations in inter-regional connectivity. Models that consider damage to the entire network instead of only local structural alterations lead to a more accurate prediction of patients’ recovery. However, assessing white matter connections in stroke patients is challenging and time-consuming. Here, we evaluated in a data set of 37 patients whether we could predict upper extremity motor recovery from brain connectivity measures obtained by using the patient’s lesion mask to introduce virtual lesions in 60 healthy streamline tractography connectomes. This indirect estimation of the stroke impact on the whole brain connectome is more readily available than direct measures of structural connectivity obtained with magnetic resonance imaging. We added these measures to benchmark structural features, and we used a ridge regression regularization to predict motor recovery at 3 months post-injury. As hypothesized, accuracy in prediction significantly increased (R2 = 0.68) as compared to benchmark features (R2 = 0.38). This improved prediction of recovery could be beneficial to clinical care and might allow for a better choice of intervention.
Role of inflammation in neurological damage and regeneration following spinal cord injury and its therapeutic implications
Authors: Jin Yan , Song Yixing , Lin Jiaqi , Liu Tianqing , Li Guicai , Lai Biqin , Gu Yun , Chen Gang , Xing Lingyan
Published: March 2023

Spinal cord injury (SCI) is an incurable trauma that frequently results in partial or complete loss of motor and sensory function. Massive neurons are damaged after the initial mechanical insult. Secondary injuries, which are triggered by immunological and inflammatory responses, also result in neuronal loss and axon retraction. This results in defects in the neural circuit and a deficiency in the processing of information. Although inflammatory responses are necessary for spinal cord recovery, conflicting evidence of their contributions to specific biological processes have made it difficult to define the specific role of inflammation in SCI. This review summarizes our understanding of the complex role of inflammation in neural circuit events following SCI, such as cell death, axon regeneration and neural remodeling. We also review the drugs that regulate immune responses and inflammation in the treatment of SCI and discuss the roles of these drugs in the modulation of neural circuits. Finally, we provide evidence about the critical role of inflammation in facilitating spinal cord neural circuit regeneration in zebrafish, an animal model with robust regenerative capacity, to provide insights into the regeneration of the mammalian central nervous system.
Nuclear fragile X mental retardation-interacting protein 1-mediated ribophagy protects T lymphocytes against apoptosis in sepsis
Authors: Zhao Peng-Yue , Yao Ren-Qi , Zheng Li-Yu , Wu Yao , Li Yu-Xuan , Dong Ning , Li Jing-Yan , Du Xiao-Hui , Yao Yong-Ming
Published: March 2023

Background

Ribophagy is a selective autophagic process that specifically degrades dysfunctional or superfluous ribosomes to maintain cellular homeostasis. Whether ribophagy can ameliorate the immunosuppression in sepsis similar to endoplasmic reticulum autophagy (ERphagy) and mitophagy remains unclear. This study was conducted to investigate the activity and regulation of ribophagy in sepsis and to further explore the potential mechanism underlying the involvement of ribophagy in T-lymphocyte apoptosis.

Methods

The activity and regulation of nuclear fragile X mental retardation-interacting protein 1 (NUFIP1)-mediated ribophagy in T lymphocytes during sepsis were first investigated by western blotting, laser confocal microscopy and transmission electron microscopy. Then, we constructed lentivirally transfected cells and gene-defective mouse models to observe the impact of NUFIP1 deletion on T-lymphocyte apoptosis and finally explored the signaling pathway associated with T-cell mediated immune response following septic challenge.

Results

Both cecal ligation and perforation-induced sepsis and lipopolysaccharide stimulation significantly induced the occurrence of ribophagy, which peaked at 24 h. When NUFIP1 was knocked down, T-lymphocyte apoptosis was noticeably increased. Conversely, the overexpression of NUFIP1 exerted a significant protective impact on T-lymphocyte apoptosis. Consistently, the apoptosis and immunosuppression of T lymphocytes and 1-week mortality rate in NUFIP1 gene-deficient mice were significantly increased compared with those in wild-type mice. In addition, the protective effect of NUFIP1-mediated ribophagy on T lymphocytes was identified to be closely related to the endoplasmic reticulum stress apoptosis pathway, and PERK–ATF4–CHOP signaling was obviously involved in downregulating T-lymphocyte apoptosis in the setting of sepsis.

Conclusions

NUFIP1-mediated ribophagy can be significantly activated to alleviate T lymphocyte apoptosis through the PERK–ATF4–CHOP pathway in the context of sepsis. Thus, targeting NUFIP1-mediated ribophagy might be of importance in reversing the immunosuppression associated with septic complications.
Efficacy and safety of extracorporeal membrane oxygenation for burn patients: a comprehensive systematic review and meta-analysis
Authors: Heng Xue , Cai Peng , Yuan Zhiqiang , Peng Yizhi , Luo Gaoxing , Li Haisheng
Published: March 2023

Background

Respiratory and circulatory dysfunction are common complications and the leading causes of death among burn patients, especially in severe burns and inhalation injury. Recently, extracorporeal membrane oxygenation (ECMO) has been increasingly applied in burn patients. However, current clinical evidence is weak and conflicting. This study aimed to comprehensively evaluate the efficacy and safety of ECMO in burn patients.

Methods

A comprehensive search of PubMed, Web of Science and Embase from inception to 18 March 2022 was performed to identify clinical studies on ECMO in burn patients. The main outcome was in-hospital mortality. Secondary outcomes included successful weaning from ECMO and complications associated with ECMO. Meta-analysis, meta-regression and subgroup analyses were conducted to pool the clinical efficacy and identify influencing factors.

Results

Fifteen retrospective studies with 318 patients were finally included, without any control groups. The commonest indication for ECMO was severe acute respiratory distress syndrome (42.1%). Veno–venous ECMO was the commonest mode (75.29%). Pooled in-hospital mortality was 49% [95% confidence interval (CI) 41–58%] in the total population, 55% in adults and 35% in pediatrics. Meta-regression and subgroup analysis found that mortality significantly increased with inhalation injury but decreased with ECMO duration. For studies with percentage inhalation injury ≥50%, pooled mortality (55%, 95% CI 40–70%) was higher than in studies with percentage inhalation injury <50% (32%, 95% CI 18–46%). For studies with ECMO duration ≥10 days, pooled mortality (31%, 95% CI 20–43%) was lower than in studies with ECMO duration <10 days (61%, 95% CI 46–76%). In minor and major burns, pooled mortality was lower than in severe burns. Pooled percentage of successful weaning from ECMO was 65% (95% CI 46–84%) and inversely correlated with burn area. The overall rate of ECMO-related complications was 67.46%, and infection (30.77%) and bleedings (23.08%) were the two most common complications. About 49.26% of patients required continuous renal replacement therapy.

Conclusions

ECMO seems to be an appropriate rescue therapy for burn patients despite the relatively high mortality and complication rate. Inhalation injury, burn area and ECMO duration are the main factors influencing clinical outcomes.
Myocardial injury: where inflammation and autophagy meet
Authors: Liu Chunping , Liu Yanjiao , Chen Huiqi , Yang Xiaofei , Lu Chuanjian , Wang Lei , Lu Jiahong
Published: March 2023

Autophagy is a highly conserved bulk degradation mechanism that degrades damaged organelles, aged proteins and intracellular contents to maintain the homeostasis of the intracellular microenvironment. Activation of autophagy can be observed during myocardial injury, during which inflammatory responses are strongly triggered. Autophagy can inhibit the inflammatory response and regulate the inflammatory microenvironment by removing invading pathogens and damaged mitochondria. In addition, autophagy may enhance the clearance of apoptotic and necrotic cells to promote the repair of damaged tissue. In this paper, we briefly review the role of autophagy in different cell types in the inflammatory microenvironment of myocardial injury and discuss the molecular mechanism of autophagy in regulating the inflammatory response in a series of myocardial injury conditions, including myocardial ischemia, ischemia/reperfusion injury and sepsis cardiomyopathy.
Melatonin influences the biological characteristics of keloid fibroblasts through the Erk and Smad signalling pathways
Authors: Huang Shaobin , Deng Wuguo , Dong Yunxian , Hu Zhicheng , Zhang Yi , Wang Peng , Cao Xiaoling , Chen Miao , Cheng Pu , Xu Hailin , Zhu Wenkai , Tang Bing , Zhu Jiayuan
Published: March 2023

Background

Keloids are abnormal fibrous hyperplasias that are difficult to treat. Melatonin can be used to inhibit the development of certain fibrotic diseases but has never been used to treat keloids. We aimed to discover the effects and mechanisms of melatonin in keloid fibroblasts (KFs).

Methods

Flow cytometry, CCK-8 assays, western blotting, wound-healing assays, transwell assays, collagen gel contraction assays and immunofluorescence assays were applied to demonstrate the effects and mechanisms of melatonin in fibroblasts derived from normal skin, hypertrophic scars and keloids. The therapeutic potential of the combination of melatonin and 5-fluorouracil (5-FU) was investigated in KFs.

Results

Melatonin significantly promoted cell apoptosis and inhibited cell proliferation, migration and invasion, contractile capability and collagen production in KFs. Further mechanistic studies demonstrated that melatonin could inhibit the cAMP/PKA/Erk and Smad pathways through the membrane receptor MT2 to alter the biological characteristics of KFs. Moreover, the combination of melatonin and 5-FU remarkably promoted cell apoptosis and inhibited cell migration and invasion, contractile capability and collagen production in KFs. Furthermore, 5-FU suppressed the phosphorylation of Akt, mTOR, Smad3 and Erk, and melatonin in combination with 5-FU markedly suppressed the activation of the Akt, Erk and Smad pathways.

Conclusions

Collectively, melatonin may inhibit the Erk and Smad pathways through the membrane receptor MT2 to alter the cell functions of KFs, while combination with 5-FU could exert even more inhibitory effects in KFs through simultaneous suppression of multiple signalling pathways.
Efficacy and Safety of Advanced Therapies for Moderately to Severely Active Ulcerative Colitis at Induction and Maintenance: An Indirect Treatment Comparison Using Bayesian Network Meta-analysis
Authors: Panaccione Remo , Collins Eric B , Melmed Gil Y , Vermeire Severine , Danese Silvio , Higgins Peter D R , Kwon Christina S , Zhou Wen , Ilo Dapo , Sharma Dolly , Sanchez Gonzalez Yuri , Wang Si-Tien
Published: March 2023

Background

Given rapid innovation in advanced therapies for moderately to severely active ulcerative colitis (UC), we investigated their comparative efficacy and safety during induction and maintenance through network meta-analysis.

Methods

Using Bayesian methods, endpoints of clinical remission and clinical response per Full Mayo score, and endoscopic improvement were assessed in bio-naive and -exposed populations. Safety was assessed in overall populations by all adverse events (AEs), serious AEs, discontinuation due to AEs, and serious infections. Phase 3 randomized controlled trials were identified via systematic literature review, including the following advanced therapies: infliximab, adalimumab, vedolizumab, golimumab, tofacitinib, ustekinumab, filgotinib, ozanimod, and upadacitinib. Random effects models were used to address between-study heterogeneity. Intent-to-treat (ITT) efficacy rates were calculated by adjusting maintenance outcomes by likelihood of induction response.

Results

Out of 48 trials identified, 23 were included. Across all outcomes and regardless of prior biologic exposure, ITT efficacy rates were highest for upadacitinib, owing to its highest ranking for all efficacy outcomes in induction and for all but clinical remission during maintenance among bio-naive induction responders. For all advanced therapies versus placebo, there were no significant differences in serious AEs or serious infections across therapies. For all AEs, golimumab had higher odds versus placebo during maintenance; for discontinuation due to AEs, upadacitinib had lower odds versus placebo during induction, while ustekinumab and vedolizumab had lower odds versus placebo during maintenance.

Conclusions

Upadacitinib may be the most efficacious therapy for moderately to severely active UC based on ITT analyses, with similar safety across advanced therapies.
Phospholamban pentamerization increases sensitivity and dynamic range of cardiac relaxation
Authors: Funk Florian , Kronenbitter Annette , Hackert Katarzyna , Oebbeke Matthias , Klebe Gerhard , Barth Mareike , Koch Daniel , Schmitt Joachim P
Published: March 2023

Aims

A key event in the regulation of cardiac contraction and relaxation is the phosphorylation of phospholamban (PLN) that relieves the inhibition of the sarco/endoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a). PLN exists in an equilibrium between monomers and pentamers. While only monomers can inhibit SERCA2a by direct interaction, the functional role of pentamers is still unclear. This study investigates the functional consequences of PLN pentamerization.

Methods and results

We generated transgenic mouse models expressing either a PLN mutant that cannot form pentamers (TgAFA-PLN) or wild-type PLN (TgPLN) in a PLN-deficient background. TgAFA-PLN hearts demonstrated three-fold stronger phosphorylation of monomeric PLN, accelerated Ca2+ cycling of cardiomyocytes, and enhanced contraction and relaxation of sarcomeres and whole hearts in vivo. All of these effects were observed under baseline conditions and abrogated upon inhibition of protein kinase A (PKA). Mechanistically, far western kinase assays revealed that PLN pentamers are phosphorylated by PKA directly and independent of any subunit exchange for free monomers. In vitro phosphorylation of synthetic PLN demonstrated that pentamers even provide a preferred PKA substrate and compete with monomers for the kinase, thereby reducing monomer phosphorylation and maximizing SERCA2a inhibition. However, β-adrenergic stimulation induced strong PLN monomer phosphorylation in TgPLN hearts and sharp acceleration of cardiomyocyte Ca2+ cycling and haemodynamic values that now were indistinguishable from TgAFA-PLN and PLN-KO hearts. The pathophysiological relevance of PLN pentamerization was evaluated using transverse aortic constriction (TAC) to induce left ventricular pressure overload. Compared to TgPLN, TgAFA-PLN mice demonstrated reduced survival after TAC, impaired cardiac haemodynamics, failure to respond to adrenergic stimulation, higher heart weight, and increased myocardial fibrosis.

Conclusions

The findings show that PLN pentamerization greatly impacts on SERCA2a activity as it mediates the full range of PLN effects from maximum inhibition to full release of SERCA2a function. This regulation is important for myocardial adaptation to sustained pressure overload.
Pyruvate dehydrogenase kinase regulates vascular inflammation in atherosclerosis and increases cardiovascular risk
Authors: Forteza Maria J , Berg Martin , Edsfeldt Andreas , Sun Jangming , Baumgartner Roland , Kareinen Ilona , Casagrande Felipe Beccaria , Hedin Ulf , Zhang Song , Vuckovic Ivan , Dzeja Petras P , Polyzos Konstantinos A , Gisterå Anton , Trauelsen Mette , Schwartz Thue W , Dib Lea , Herrmann Joerg , Monaco Claudia , Matic Ljubica , Gonçalves Isabel , Ketelhuth Daniel F J
Published: March 2023

Aims

Recent studies have revealed a close connection between cellular metabolism and the chronic inflammatory process of atherosclerosis. While the link between systemic metabolism and atherosclerosis is well established, the implications of altered metabolism in the artery wall are less understood. Pyruvate dehydrogenase kinase (PDK)-dependent inhibition of pyruvate dehydrogenase (PDH) has been identified as a major metabolic step regulating inflammation. Whether the PDK/PDH axis plays a role in vascular inflammation and atherosclerotic cardiovascular disease remains unclear.

Methods and results

Gene profiling of human atherosclerotic plaques revealed a strong correlation between PDK1 and PDK4 transcript levels and the expression of pro-inflammatory and destabilizing genes. Remarkably, the PDK1 and PDK4 expression correlated with a more vulnerable plaque phenotype, and PDK1 expression was found to predict future major adverse cardiovascular events. Using the small-molecule PDK inhibitor dichloroacetate (DCA) that restores arterial PDH activity, we demonstrated that the PDK/PDH axis is a major immunometabolic pathway, regulating immune cell polarization, plaque development, and fibrous cap formation in Apoe−/− mice. Surprisingly, we discovered that DCA regulates succinate release and mitigates its GPR91-dependent signals promoting NLRP3 inflammasome activation and IL-1β secretion by macrophages in the plaque.

Conclusions

We have demonstrated for the first time that the PDK/PDH axis is associated with vascular inflammation in humans and particularly that the PDK1 isozyme is associated with more severe disease and could predict secondary cardiovascular events. Moreover, we demonstrate that targeting the PDK/PDH axis with DCA skews the immune system, inhibits vascular inflammation and atherogenesis, and promotes plaque stability features in Apoe−/− mice. These results point toward a promising treatment to combat atherosclerosis.
Diagnosis and Clinical Features of Perianal Lesions in Newly Diagnosed Crohn’s Disease: Subgroup Analysis from Inception Cohort Registry Study of Patients with Crohn’s Disease (iCREST-CD)
Authors: Yamamoto Takayuki , Nakase Hiroshi , Watanabe Kenji , Shinzaki Shinichiro , Takatsu Noritaka , Fujii Toshimitsu , Okamoto Ryuichi , Matsuoka Katsuyoshi , Yamada Akihiro , Kunisaki Reiko , Matsuura Minoru , Shiga Hisashi , Bamba Shigeki , Mikami Yohei , Shimoyama Takahiro , Motoya Satoshi , Torisu Takehiro , Kobayashi Taku , Ohmiya Naoki , Saruta Masayuki , Matsuda Koichiro , Matsumoto Takayuki , Maemoto Atsuo , Murata Yoko , Yoshigoe Shinichi , Nagasaka Shinya , Yajima Tsutomu , Hisamatsu Tadakazu ,   iCREST-CD Study Group, Nagahori Masakazu , Yukawa Tatsu , Saito Daisuke , Kawai Mikio , Masamune Atsushi , Nagasaka Mitsuo , Kazama Tomoe
Published: March 2023

Background and Aims

Perianal lesion is a refractory phenotype of Crohn’s disease [CD] with significantly diminished quality of life. We evaluated the clinical characteristics of perianal lesions in newly diagnosed CD patients and the impact of perianal lesions on the quality of life in Japanese patients with CD.

Methods

Patients newly diagnosed with CD after June 2016 were included between December 2018 and June 2020 from the Inception Cohort Registry Study of Patients with CD [iCREST-CD].

Results

Perianal lesions were present in 324 [48.2%] of 672 patients with newly diagnosed CD; 71.9% [233/324] were male. The prevalence of perianal lesions was higher in patients aged <40 years vs ≥40 years, and it decreased with age. Perianal fistula [59.9%] and abscess [30.6%] were the most common perianal lesions. In multivariate analyses, male sex, age <40 years and ileocolonic disease location were significantly associated with a high prevalence of perianal lesions, whereas stricturing behaviour and alcohol intake were associated with low prevalence. Fatigue was more frequent [33.3% vs 21.6%] while work productivity and activity impairment-work time missed [36.3% vs 29.5%] and activity impairment [51.9% vs 41.1%] were numerically higher in patients with than those without perianal lesions.

Conclusions

At the time of CD diagnosis, approximately half of the patients had perianal lesions; perianal abscesses and perianal fistulas were the most common. Young age, male sex, disease location and behaviour were significantly associated with the presence of perianal lesions. The presence of perianal lesion was associated with fatigue and impairment of daily activities.

Clinical trials registry

University Hospital Medical Information Network Clinical Trials Registry System [UMIN-CTR, UMIN000032237].
Successful percutaneous transvenous approach for pinch-off syndrome: a case report
Authors: Matta Anthony , Chavernac Pascal , Pouche Marion , Cantié Philippe
Published: March 2023

Background

Pinch-off syndrome is a rare late complication characterized by the occurrence of spontaneous fracture and embolization of a port-a-cath implanted via subclavian venous access. It may lead to serious cardiovascular outcomes.

Case presentation

We report a successful percutaneous transvenous removal of intravascular fractured port catheter embolized into the right ventricle by using the ‘lasso’ technique in an 85-year-old man with type B non-Hodgkin lymphoma undergoing chemotherapy and long estimated life expectancy.

Discussion

Knowledge of pinch-off syndrome among physicians is essential for early intervention, thereby preventing adverse events. Percutaneous approach seems an effective, safe, and simple procedure.
Longitudinal analysis of systemic ventricular function and atrioventricular valve function after the Fontan procedure
Authors: Dahmen Vincent , Heinisch Paul Philipp , Staehler Helena , Schaeffer Thibault , Burri Melchior , Röhlig Christoph , Klawonn Frank , Hager Alfred , Ewert Peter , Hörer Jürgen , Ono Masamichi
Published: March 2023

OBJECTIVES

This study aimed to determine the longitudinal change of systemic ventricular function and atrioventricular valve (AVV) regurgitation after total cavopulmonary connection (TCPC).

METHODS

In 620 patients who underwent TCPC between 1994 and 2021, 4219 longitudinal echocardiographic examinations of systemic ventricular function and AVV regurgitation were evaluated retrospectively.

RESULTS

The most frequent primary diagnosis was hypoplastic left heart syndrome in 172, followed by single ventricle in 131, tricuspid atresia in 95 and double inlet left ventricle (LV) in 91 patients. Dominant right ventricle (RV) was observed in 329 (53%) and dominant LV in 291 (47%). The median age at TCPC was 2.3 (1.8–3.4) years. Transplant-free survival at 5, 10 and 15 years after TCPC was 96.3%, 94.7% and 93.6%, respectively, in patients with dominant RV and 97.3%, 94.6% and 94.6%, respectively, in those with dominant LV (P = 0.987). Longitudinal analysis of systemic ventricular function was similar in both groups during the first 10 years postoperatively. Thereafter, systemic ventricular function worsened significantly in patients with dominant RV, compared with those with dominant LV (15 years: P = 0.007, 20 years: P = 0.03). AVV regurgitation was more frequent after TCPC in patients with dominant RV compared with those with dominant LV (P < 0.001 at 3 months, 3 years, 5 years, 10 years and 15 years, P = 0.023 at 20 years). There was a significant correlation between postoperative systemic ventricular dysfunction and AVV regurgitation (P < 0.001).

CONCLUSIONS

There were no transplant-free survival difference and no difference in ventricular function between dominant RV and dominant LV for the first 10 years after TCPC. Thereafter, ventricular function in dominant RV was inferior to that in dominant LV. The degree of AVV regurgitation was significantly higher in dominant RV, compared with dominant LV, and it was positively associated with ventricular dysfunction, especially in dominant RV.
Effects of exercise training on cardiac toxicity markers in women with breast cancer undergoing chemotherapy with anthracyclines: a randomized controlled trial
Authors: Antunes Pedro , Joaquim Ana , Sampaio Francisco , Nunes Célia , Ascensão António , Vilela Eduardo , Teixeira Madalena , Capela Andreia , Amarelo Anabela , Marques Cristiana , Viamonte Sofia , Alves Alberto , Esteves Dulce
Published: March 2023

Aims

Exercise training has been suggested to prevent anthracycline-related cardiac dysfunction, but clinicalbased evidence is scarce. We investigated the effects of a supervised exercise training programme (SETP) on cardiac toxicity markers in women with breast cancer (BC) receiving anthracycline-containing chemotherapy.

Methods and results

Ninety-three women with early-stage breast cancer were randomly allocated to a supervised exercise training programme (SETP) plus usual care group (Exercise, n = 47) or usual care alone group (UC, n = 46). The SETP consisted of three sessions per week, combining aerobic and resistance training, conducted concurrently across the anthracycline-containing chemotherapy length. The primary endpoint was the change in left ventricular ejection fraction (LVEF) from baseline to the end of anthracycline cycles. Secondary endpoints included global longitudinal strain (GLS) and other conventional echocardiographic parameters, cardiorespiratory fitness (estimated peak VO2), circulating biomarkers (NT-proBNP, hs-TnT), and safety of the SETP. The study endpoints were also assessed 3 months after the end of anthracycline cycles. All patients were prescribed four cycles of doxorubicin plus cyclophosphamide (AC). No significant between-group differences in LVEF change were seen at the end of AC [mean difference: 0.7%; 95% confidence interval (CI): −0.8, 2.3; P = 0.349] and 3 months after AC (1.1%; 95% CI: −0.5, 2.6; P = 0.196). Compared to the usual care (UC) group, the estimated peak VO2 increased in the Exercise group at the end of AC (1.6 mL O2·kg−1·min−1; 95% CI: 0.06, 3.1; P = 0.041) and 3 months after AC (3.1 mL O2·kg−1·min−1; 95% CI: 1.4, 4.7; P < 0.001). No between-group differences were found in the remaining secondary endpoints. No serious adverse events were observed during SETP.

Conclusion

Exercise training was safe during chemotherapy and significantly improved cardiorespiratory fitness. No significant effects were seen on cardiac toxicity markers (LVEF or GLS) as compared to the usual care.

Trial registration

Mama Move Gaia on treatment trial ISRCTN32617901
Development of the ¡Vamos por Mas! parenting program to prevent substance use among Chilean adolescents
Authors: Meyer Jessica K V , Ortiz de Rozas Amaia Bernard , Muñoz Ivan , Burmeister Catalina , Macchiavello Carlo , Lendzion Lauren , García-Huidobro Diego
Published: March 2023

In Chile, the prevalence of tobacco, alcohol and drug use among adolescents is very high. Decades of research indicate that parenting interventions reduce these risky behaviors. However, there are no parenting interventions validated in Chile to prevent adolescent substance use. This article reports the development of the ¡Vamos por Mas! (¡VxM!) program following the recommendations of the Medical Research Council’s framework for designing and evaluating complex interventions. After identifying key intervention components, a preliminary version of a substance-use prevention program was designed. The preliminary intervention targeted families with adolescents in fifth and sixth grade and had four components: personalized feedback, in-person workshops, virtual engagement, and family support, to deliver positive-youth development and family-strengthening content. Then, students, guardians, school staff and community experts from different school systems (N = 111) evaluated the preliminary version of the program through a convergent parallel mixed methods study, including focus groups (N = 14) and surveys (N = 101). In general, all participants had positive perceptions of the program and valued its purpose, strategies, objectives and contents. Suggestions included expanding the purpose to promote healthy relationships, focusing on schools with low and intermediate socioeconomic vulnerability, including self-control content, removing the personalized feedback component and adding two additional components: school partnership and external supervision, among other improvements. With this information, the final version of the ¡VxM! program was developed. After a rigorous intervention development process, the ¡VxM! program is ready to be piloted and evaluated in a randomized trial.
Identification of clade-wide putative cis-regulatory elements from conserved non-coding sequences in Cucurbitaceae genomes
Authors: Song Hongtao , Wang Qi , Zhang Zhonghua , Lin Kui , Pang Erli
Published: March 2023

Cis-regulatory elements regulate gene expression and play an essential role in the development and physiology of organisms. Many conserved non-coding sequences (CNSs) function as cis-regulatory elements. They control the development of various lineages. However, predicting clade-wide cis-regulatory elements across several closely related species remains challenging. Based on the relationship between CNSs and cis-regulatory elements, we present a computational approach that predicts the clade-wide putative cis-regulatory elements in 12 Cucurbitaceae genomes. Using 12-way whole-genome alignment, we first obtained 632 112 CNSs in Cucurbitaceae. Next, we identified 16 552 Cucurbitaceae-wide cis-regulatory elements based on collinearity among all 12 Cucurbitaceae plants. Furthermore, we predicted 3 271 potential regulatory pairs in the cucumber genome, of which 98 were verified using integrative RNA sequencing and ChIP sequencing datasets from samples collected during various fruit development stages. The CNSs, Cucurbitaceae-wide cis-regulatory elements, and their target genes are accessible at http://cmb.bnu.edu.cn/cisRCNEs_cucurbit/. These elements are valuable resources for functionally annotating CNSs and their regulatory roles in Cucurbitaceae genomes.