bluuebunny/crossref_metadata_2025_split huggingface dataset:
Linoleoyl-lysophosphatidylcholine suppresses immune-related adverse events due to immune checkpoint blockade
Authors: Mathews Ian T. , Saminathan Priyanka , Henglin Mir , Liu Mingyue , Nadig Namratha , Fang Camille , Mercader Kysha , Chee Serena J. , Campbell Allison M. , Patel Abhijit A. , Tiwari Saumya , Watrous Jeramie D. , Ramesh Karthik , Dicker Martina , Dao Khoi , Meyer Melissa A. , Jousilahti Pekka , Havulinna Aki S. , Niiranen Teemu , Salomaa Veikko , Joosten Leo A.B. , Netea Mihai G. , Zheng Pan , Kronenberg Mitchell , Patel Sandip Pravin , Gutkind J. Silvio , Ottensmeier Christian , Long Tao , Kaech Susan M. , Hedrick Catherine C. , Cheng Susan , Jain Mohit , Sharma Sonia 
Published: August 2024

AbstractImmune related adverse events (irAEs) after immune checkpoint blockade (ICB) therapy occur in a significant proportion of cancer patients. To date, the circulating mediators of ICB-irAEs remain poorly understood. Using non-targeted mass spectrometry, here we identify the circulating bio-active lipid linoleoyl-lysophosphatidylcholine (LPC 18:2) as a modulator of ICB-irAEs. In three independent human studies of ICB treatment for solid tumor, loss of circulating LPC 18:2 preceded the development of severe irAEs across multiple organ systems. In both healthy humans and severe ICB-irAE patients, low LPC 18:2 was found to correlate with high blood neutrophilia. Reduced LPC 18:2 biosynthesis was confirmed in preclinical ICB-irAE models, and LPC 18:2 supplementationin vivosuppressed neutrophilia and tissue inflammation without impacting ICB anti-tumor response. Results indicate that circulating LPC 18:2 suppresses human ICB-irAEs, and LPC 18:2 supplementation may improve ICB outcomes by preventing severe inflammation while maintaining anti-tumor immunity.
IBS stress reactivity phenotype is associated with blood transcriptome profiles and microstructural and functional brain changes
Authors: Labus Jennifer S , Delgadillo Desiree R. , Cole Steve , Wang Chencai , Naliboff Bruce , Chang Lin , Ellingson Benjamin M. , Mayer Emeran A. 
Published: August 2024

AbstractBackground & AimsClinical evidence suggests significant interindividual differences in stress reactivity (SR), but biological mechanisms and therapeutic implications of these differences are poorly understood. We aimed to identify the biological basis of increased SR by investigating associations between a psychometric-based phenotype with blood transcriptomics profiles of increased sympathetic nervous system (SNS) activation and brain imaging phenotypes in irritable bowel syndrome (IBS) participants and healthy controls (HCs).MethodsA cross-sectional observational study design, transcriptomics profiling, multimodal brain imaging, and psychosocial assessments were obtained in 291 female and male IBS participants and HCs. Prior to analyses, unsupervised clustering was applied to derive high and low SR subgroups across participants based on two measures of SR. General linear models tested for SR group differences in clinical and biological parameters. Exploratory analyses examined associations between SR group-specific brain alterations and gene expression.ResultsThe high, compared to low SR group showed greater cyclic AMP response element-binding protein (CREB) gene expression consistent with tonic SNS activity and proinflammatory changes in whole blood. Brain imaging showed neuroplastic changes in the high SR group consistent with an upregulation of ascending arousal systems and sensory processing and integration regions, and functional connectivity changes in the central autonomic network. SR moderated the sex difference in extraintestinal symptoms.ConclusionsThe findings support a model of tonically increased SNS activity as a plausible risk factor for increased autonomic reactivity to psychosocial stressors and low grade immune activation in both IBS and HCs, with a greater prevalence in IBS. These findings may have important implications for personalized treatment interventions in IBS.
Loss-of-function of the Zinc Finger Homeobox 4 (ZFHX4) gene underlies a neurodevelopmental disorder
Authors: Pérez Baca María del Rocío , Palomares Bralo María , Vanhooydonck Michiel , Hamerlinck Lisa , D’haene Eva , Leimbacher Sebastian , Jacobs Eva Z. , De Cock Laurenz , D’haenens Erika , Dheedene Annelies , Malfait Zoë , Vantomme Lies , Silva Ananilia , Rooney Kathleen , Santos-Simarro Fernando , Lleuger-Pujol Roser , García-Miñaúr Sixto , Losantos-García Itsaso , Menten Björn , Gestri Gaia , Ragge Nicola ,   ZFHX4 consortium, Sadikovic Bekim , Bogaert Elke , Syx Delfien , Callewaert Bert , Vergult Sarah 
Published: August 2024

Abstract8q21.11 microdeletions encompassing the gene encoding transcription factor ZFHX4, have previously been associated by us with a syndromic form of intellectual disability, hypotonia, decreased balance and hearing loss. Here, we report on 57 individuals, 52 probands and 5 affected family members, with protein truncating variants (n=36), (micro)deletions (n=20) or an inversion (n=1) affectingZFHX4with variable developmental delay and intellectual disability, distinctive facial characteristics, morphological abnormalities of the central nervous system, behavioral alterations, short stature, hypotonia, and occasionally cleft palate and anterior segment dysgenesis. The phenotypes associated with 8q21.11 microdeletions andZFHX4intragenic loss-of-function variants largely overlap, identifying ZFHX4 as the main driver for the microdeletion syndrome, although leukocyte-derived DNA shows a mild common methylation profile for (micro)deletions only. We identify ZFHX4 as a transcription factor that is increasingly expressed during human brain development and neuronal differentiation. Furthermore, ZFHX4 interacting factors identified via IP-MS in neural progenitor cells, suggest an important role for ZFHX4 in cellular and developmental pathways, especially during histone modifications, cytosolic transport and development. Additionally, using CUT&RUN, we observed that ZFHX4 binds with the promoter regions of genes with crucial roles in embryonic, neuron and axon development. Since loss-of-function variants inZFHX4are found with consistent dysmorphic facial features, we investigated whether the disruption ofzfhx4causes craniofacial abnormalities in zebrafish. First-generation (F0)zfhx4crispant zebrafish, (mosaic) mutant forzfhx4loss-of-function variants, have significantly shorter Meckel’s cartilages and smaller ethmoid plates compared to control zebrafish. Furthermore, behavioral assays show a decreased movement frequency in thezfhx4crispant zebrafish in comparison with control zebrafish larvae. Although further research is needed, ourin vivowork suggests a role for zfhx4 in facial skeleton patterning, palatal development and behavior.
Cost effectiveness of adopting a postoperative delirium risk prediction tool with non-pharmacological delirium prevention interventions for surgical patients
Authors: Graves Nicholas , Boettger Soenke , Zozmann Martin , Franziska Maja , Stocker Reto 
Published: August 2024

AbstractBackgroundPostoperative delirium arises among older surgical patients. Screening followed by prevention efforts are recommended. A risk prediction tool has been developed yet the performance and whether adoption is cost-effective are unknown.ObjectiveTo estimate the expected change to ‘total costs’ and ‘health benefits’ measured by quality adjusted life years from a decision to adopt PIPRA plus for screening purpose to find at-risk individuals who are then offered non-pharmacological interventions to reduce risks of postoperative delirium.DesignCost effectiveness modelling study that draws on a range of relevant data sources.SettingSwiss healthcare system.SubjectsSurgical inpatients aged 60 or older, excluding cardiac and intracranial surgeries.MethodsA decision tree model was used to capture the events likely to impact on cost and health outcomes. Information was harvested from a prospective before-after study and augmented with other relevant data sources. Probabilistic sensitivity analysis was undertaken to reveal the probability that adoption was cost effective against a stated maximum willingness to pay threshold for decision making in Switzerland.ResultsPatients in both phases of the study were similar. Costs were lower by 3075CHF (SD 997) per patient with the adoption of the risk screening tool and there was a modest gain to health benefits of 0.01 QALY (SD 0.026). There was a 100% probability that adoption would be cost saving and a 91% probability that adoption would be cost-effective.ConclusionsWe provide early-stage evidence that a decision to adopt the risk screening tool and offer risk reducing interventions will be cost-effective.Key pointsMany surgical patients suffer from post operative delirium.Screening and early intervention can reduce risks and improve outcomes.It is important to establish whether screening and early intervention is cost effective.
Dynamic and prognostic proteomic associations with FEV1decline in chronic obstructive pulmonary disease
Authors: Ruvuna Lisa , Hijazi Kahkeshan , Guzman Daniel E. , Guo Claire , Loureiro Joseph , Khokhlovich Edward , Morris Melody , Obeidat Ma’en , Pratte Katherine A. , DiLillo Katarina M. , Sharma Sunita , Kechris Katerina , Anzueto Antonio , Barjaktarevic Igor , Bleecker Eugene R. , Casaburi Richard , Comellas Alejandro , Cooper Christopher B. , DeMeo Dawn L. , Foreman Marilyn , Flenaugh Eric L. , Han MeiLan K. , Hanania Nicola A. , Hersh Craig P. , Krishnan Jerry A. , Labaki Wassim W. , Martinez Fernando J. , O’Neal Wanda K. , Paine Robert , Peters Stephen P. , Woodruff Prescott G. , Wells J Michael , Wendt Christine H. , Arnold Kelly B. , Barr R. Graham , Curtis Jeffrey L. , Ngo Debby , Bowler Russell P. ,   SPIROMICS, COPDGene and MESA-Lung Investigators
Published: August 2024

ABSTRACTRationaleIdentification and validation of circulating biomarkers for lung function decline in COPD remains an unmet need.ObjectiveIdentify prognostic and dynamic plasma protein biomarkers of COPD progression.MethodsWe measured plasma proteins using SomaScan from two COPD-enriched cohorts, the Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS) and Genetic Epidemiology of COPD (COPDGene), and one population-based cohort, Multi-Ethnic Study of Atherosclerosis (MESA) Lung. Using SPIROMICS as a discovery cohort, linear mixed models identified baseline proteins that predicted future change in FEV1(prognostic model) and proteins whose expression changed with change in lung function (dynamic model). Findings were replicated in COPDGene and MESA-Lung. Using the COPD-enriched cohorts, Gene Set Enrichment Analysis (GSEA) identified proteins shared between COPDGene and SPIROMICS. Metascape identified significant associated pathways.Measurements and Main ResultsThe prognostic model found 7 significant proteins in common (p < 0.05) among all 3 cohorts. After applying false discovery rate (adjusted p < 0.2), leptin remained significant in all three cohorts and growth hormone receptor remained significant in the two COPD cohorts. Elevated baseline levels of leptin and growth hormone receptor were associated with slower rate of decline in FEV1. Twelve proteins were nominally but not FDR significant in the dynamic model and all were distinct from the prognostic model. Metascape identified several immune related pathways unique to prognostic and dynamic proteins.ConclusionWe identified leptin as the most reproducible COPD progression biomarker. The difference between prognostic and dynamic proteins suggests disease activity signatures may be different from prognosis signatures.
Delineating Drug Class and Target-Specific Adverse Events of Kinase Inhibitors
Authors: Schweickart Annalise , Somani Juhi , Theisen Ryan , Sahni Navriti , Cichońska Anna , Rahman Rayees 
Published: August 2024

AbstractKinase inhibitors are a successful category of therapeutics used in treating diseases such as cancer, autoimmunity, and neurodegeneration. Despite their efficacy, these drugs often present clinically relevant adverse events that can limit their therapeutic utility or lead to their failure in clinical trials. The adverse event profile of a kinase inhibitor can be explained by its off- and on-target binding profile. Unfortunately, there are limited resources to couple inhibition of a specific kinase to clinical adverse events. Discerning which adverse events can be attributed to a specific kinase, and which are more generally caused by the kinase inhibitor drug class, is crucial for designing next-generation drugs that avoid toxicity and enhance clinical viability. By integrating adverse event incident data from the FDA Adverse Events Reporting Database with machine learning-predicted molecular binding profiles, we developed a statistical method that associates specific adverse events with potent inhibition of certain kinases. We also identify general adverse events inherent to the kinase inhibitor class. We validate our model through an extensive literature review of known kinase-adverse event pairs, comparison with the OnSIDES drug label side effect dataset, and prospective prediction of adverse events of recently approved kinase inhibitors. We show that our method can recapitulate well-established kinase-toxicity associations and identify previously unreported kinases associated with adverse events.
Hydrogen Sulfide (H₂S)-Producing Oral Bacteria May Protect Against COVID-19
Authors: Vaishnani Meghalbahen , Modi Anupama , Chauhan Kshipra , Parekh Bhavin 
Published: August 2024

AbstractCOVID-19 mortality rates have varied dramatically across the globe. Yet the reasons behind these disparities remain poorly understood. While recent research has linked gut microbes to these variations, the role of oral bacteria, a main port of entry for the coronavirus, remains unexplored.We investigated the relationship between oral microbiota and COVID-19 mortality rates across eightcountries. Raw sequencing data of 16S rRNA regions from oral microbiota in 244 healthy subjects from eight countries were obtained from public databases. We employed a generalized linear model (GLM) to predict COVID-19 mortality rates using oral microbiota composition. GLM revealed that high abundances of hydrogen sulfide (H₂S)-producing bacteria, particularly Treponema, predicted low COVID-19 mortality rates with a markedly low p-value. Unsupervised clustering using a combination of LIGER and t-SNE yielded four oral microbiome "orotypes." Orotypes enriched in H₂S-producing bacteria coincided with lower mortality rates, while orotypes harboring Haemophilus or Rothia were associated with increased vulnerability. To validate our findings, we analyzed influenza mortality data from the same countries, observing similar protective trends. Our findings suggest that oral bacteria-produced H₂S may serve as a critical initial defense against SARS-CoV-2 infection.H₂S from oral bacteria may prevent infection through antiviral activity, blocking ACE2 receptors, suppressing cytokines, and boosting antioxidants. This highlights the oral microbiome’s role in COVID-19 outcomes and suggests new preventive and therapeutic strategies.Graphical Abstract
Targeting OAS3 for reversing M2d infiltration and restoring anti-tumor immunity in pancreatic cancer
Authors: Zhang Shaopeng , Xu Ximo , Zhang Kundong , Lei Changzheng , Xu Yitian , Zhang Pengshan , Zhang Yuan , Gu Haitao , Huang Chen , Qiu Zhengjun 
Published: August 2024

AbstractAbundant infiltration of tumor-associated macrophages (TAMs) within the tumor stroma plays a pivotal role in inducing immune escape in pancreatic cancer (PC). Lactate serves as a direct regulator of macrophage polarization and functions, although the precise regulation mechanism remain inadequately understood. Our study revealed that PC cells promote macrophage polarization towards the M2d phenotype through high lactate secretion. M2d is characterized by elevated secretion of IL-10 and VEGF-A, which diminish CD8+T cells cytotoxicity and promote tumor neoangiogenesis simultaneously. Additionally, we identify 2,5’-oligoadenylate synthase 3 (OAS3) as an essential regulator of M2d polarization, upregulated by PC cells via lactate/METTL3/OAS3 axis. METTL3 mediated m6A modification on OAS3 mRNA correlates with increased OAS3 expression in TAMs, which is associated with poorer prognosis in PC patients. OAS3 deficiency in macrophages substantially impairs IL-10highVEGF-AhighM2d polarization and their pro-tumor functions while enhancing the therapeutic efficacy of gemcitabine (Gem) and anti-PD-L1 mAb in humanized mouse models. In conclusion, OAS3 presents as a promising immune therapeutic target for reversing IL-10highVEGF-AhighM2d infiltration and restoring CD8+T cell mediated anti-tumor immunity in pancreatic cancer.
The role of a structured community health worker network in achieving malaria elimination goals in the Dominican Republic: an impact evaluation amid COVID-19 Disruptions
Authors: Michelén Ströfer Nicole , Tejada Bueno Natalia , Santos Félix María Yinet , Cruz Raposo Jose Luis , Lana Justin T. , Turbé Valérian , Cohen Justin M. , Napier Harriet 
Published: August 2024

AbstractCommunity health workers (CHWs) can play a key role in malaria elimination through expanding access to malaria testing and treatment. The Dominican Republic, a low endemic country committed to eliminate malaria by 2025, implemented a structured malaria CHW network in the three main urban foci of Greater Santo Domingo. This research quantifies the networks’ contributions towards malaria elimination from its implementation in 2019 until 2022. The study highlights the impact of COVID-19 disruptions on CHWs’ performance and explores the network’s ability to bounce back from health systems’ shocks.The performance of a malaria CHW network in Greater Santo Domingo, Dominican Republic was evaluated using weekly data collected from CHWs and routinely collected surveillance data from the Ministry of Public Health (MoH). We assess performance of CHWs by analyzing key variables such as (1) reporting compliance, (2) household visitation rates, (3) malaria rapid diagnostic tests performed, (4) malaria cases detected, and (5) time between symptom onset and malaria diagnosis. To evaluate the impact of COVID-19 on the network, CHW’s performance indicators are evaluated across three time periods (prior to, during, and after COVID-19 interruptions).Results showed that over the evaluation period, reported malaria cases in study foci decreased from 1,243 cases in 2019 to 5 cases in 2023. CHWs diagnosed and treated over 43% of malaria cases in study foci before COVID-19 interruptions and 14% during interruptions. 83% of cases detected by CHWs were detected through active case detection, with 17% detected passively. CHWs detected malaria cases and initiated treatment 1.5 days earlier than health facilities and MoH personnel performing active case detection.This evaluation provides evidence that a structured CHW network with clearly defined responsibilities and management protocol can assume a large proportion of malaria case management service provision, contribute to early malaria case detection, and help curb local malaria transmission. It adds to a growing body of research on the feasibility and benefits of CHW-led proactive household visitation. Despite interruptions such as the COVID-19 pandemic, concerted investment can sustain CHW program gains.
Coaching visits and supportive supervision for primary care facilities to improve malaria service data quality in Ghana: an intervention case study
Authors: Asiedu Amos , Haws Rachel A. , Mohammed Wahjib , Boye-Doe Joseph , Agblanya Charles , Ntumy Raphael , Malm Keziah , Boateng Paul , Tetteh Gladys , Oseni Lolade 
Published: August 2024

AbstractEffective decision-making for malaria prevention and control depends on timely, accurate, and appropriately analyzed and interpreted data. Poor quality data reported into national health management information systems (HMIS) prevent managers at the district level from planning effectively for malaria in Ghana. We analyzed reports from data coaching visits and follow-up supervision conducted to 231 health facilities in six of Ghana’s 16 regions between February and November 2021. The visits targeted health workers’ knowledge and skills in malaria data recording, HMIS reporting, and how managers visualized and used HMIS data for planning and decision making. A before-after design was used to assess how data coaching visits affected data documentation practices and compliance with standards of practice, quality and completeness of national HMIS data, and use of facility-based malaria indicator wall charts for decision-making at health facilities. The percentage of health workers demonstrating good understanding of standards of practice in documentation, reporting and data use increased from 72 to 83% (p<0.05). At first follow-up, reliability of HMIS data entry increased from 29 to 65% (p<0.001); precision increased from 48 to 78% (p<0.001); and timeliness of reporting increased from 67 to 88% (p<0.001). HMIS data showed statistically significant improvement in data completeness (from 62 to 87% (p<0.001)) and decreased error rate (from 37 to 18% (p<0.001)) from baseline to post-intervention. By the second follow-up visit, 98% of facilities had a functional data management system (a 26-percentage-point increase from the first follow-up visit, p<0.0001), 77% of facilities displayed wall charts, and 63% reported using data for decision-making and local planning. There are few documented examples of data coaching to improve malaria surveillance and service data quality. Data coaching provides support and mentorship to improve data quality, visualization, and use, modeling how other malaria programs can use HMIS data effectively at the local level.
Utility of thromboelastography to assess the effect of anticoagulation reversal in intracranial hemorrhage
Authors: Zepeski A , Faine BA , Ghannam M , Olalde HM , Wendt L , Naidech A , Mohr NM , Leira EC 
Published: August 2024

ABSTRACTBackgroundIntracranial hemorrhage (ICH) is a serious complication associated with oral anticoagulant use and is associated with significant morbidity and mortality. Although anticoagulation reversal agents are utilized as standard of care, practitioners are limited in their ability to assess degree of anticoagulation reversal for direct oral anticoagulants (DOACs). There is a clinical need identify biomarkers to assess anticoagulation status in patients with DOAC-associated ICH to ensure hemostatic efficacy of anticoagulation reversal agents in the acute setting. The purpose of this study was to assess the utility of thromboelastography (TEG) to assess the impact of anticoagulation reversal in patients presenting to the emergency department (ED) with DOAC-associated ICH.MethodsWe conducted a prospective, observational cohort study in adult patients presenting to the ED with acute DOAC-associated ICH. Patients were excluded if last DOAC dose was >48 hours prior to hospital arrival, if they experienced polytrauma, were pregnant, incarcerated, had a history of hepatic failure or coagulopathy, or received anticoagulation reversal with products other than prothrombin complex concentrates (PCCs). We collected baseline TEG samples from participants prior to anticoagulation reversal, as well as 30-minutes, 12-hours, and 24-hours post-reversal. TEG samples were also collected from participants who transferred to our facility after reversal at ED presentation, as well as 12- and 24-hours post-reversal.ResultsPre-reversal TEG was collected on 10 participants prior to DOAC reversal. A significant decrease in TEG R-time was observed at 30 minutes post-reversal. R-time increased at 12- and 24-hours to baseline levels. Significant changes were not observed in K-time, clot strength, maximum amplitude, or coagulation index.ConclusionsTEG R-time may be able to detect a change in anticoagulation activity of DOACs in ICH after anticoagulation reversal. R-time decreases acutely after anticoagulation reversal and rebounds at 12- and 24-hours post-reversal.