bluuebunny/crossref_metadata_2025 huggingface dataset:
UPTAKE OF REPRODUCTIVE, MATERNAL AND NEWBORN HEALTH IN THE CONTEXT OF COVID-19 PANDEMIC IN KENYA
Authors: Jebet Joyce , Muia Ruth , Ongeso Abednego , Omuga Blasio , Omoni Grace , Wagoro Miriam
Published: January 2024

Background

The outbreak of COVID 19 in 2019 lead to destabilization of all sectors globally including access to health care. The strain on the health care system as a result of the disease outbreak led to a shift in operations in the health care system. Maternal and neonatal care was affected as women and their families could not freely access health care owing to the restrictions to curb the spread of COVID 19. This led to a risk of a reversal in the gains made in maternal and neonatal health, prompting the need to strengthen community midwifery.

Aim

The aim of this study was to strengthen community reproductive, maternal and newborn health in the context of COVID-19 pandemic in Kenya.

Materials and methods

This is part of an interventional study that sought to strengthen community maternal and neonatal health services. A baseline survey was conducted to assess the uptake of reproductive, maternal and neonatal care services in one sub-county in Kilifi and Kitui, where five wards in each sub-county were selected. An interviewer administered questionnaire was used to collect data. The sample size for the two Counties was 414.

Results

There was a total of 378 respondents mostly comprising a rural population 75.7% (n=286). Outpatient and COVID 19 services (tests and vaccine) were most sought 37.5% (n= 137) and 29.9% (n=109) respectively. Antenatal care services were sought by 26% (n=95) of the respondents, postnatal care 9% (n=33) and skilled birth attendance 8.8% (n=32).

Conclusion

The most utilized health facility services were outpatient and COVID 19 services. Antenatal care was also sought, however skilled birth attendance and postnatal care services were least sought.
Evaluation of the impact of concentration and extraction methods on the targeted sequencing of human viruses from wastewater
Authors: Jiang Minxi , Wang Audrey L.W. , Be Nicholas A. , Mulakken Nisha , Nelson Kara L. , Kantor Rose S.
Published: January 2024

Sequencing human viruses in wastewater is challenging due to their low abundance compared to the total microbial background. This study compared the impact of four virus concentration/extraction methods (Innovaprep, Nanotrap, Promega, Solids extraction) on probe-capture enrichment for human viruses followed by sequencing. Different concentration/extraction methods yielded distinct virus profiles. Innovaprep ultrafiltration (following solids removal) had the highest sequencing sensitivity and richness, resulting in the successful assembly of most near-complete human virus genomes. However, it was less sensitive in detecting SARS-CoV-2 by dPCR compared to Promega and Nanotrap. Across all preparation methods, astroviruses and polyomaviruses were the most highly abundant human viruses, and SARS-CoV-2 was rare. These findings suggest that sequencing success can be increased by using methods that reduce non-target nucleic acids in the extract, though the absolute concentration of total extracted nucleic acid, as indicated by Qubit, and targeted viruses, as indicated by dPCR, may not be directly related to targeted sequencing performance. Further, using broadly targeted sequencing panels may capture viral diversity but risks losing signals for specific low-abundance viruses. Overall, this study highlights the importance of aligning wet lab and bioinformatic methods with specific goals when employing probe-capture enrichment for human virus sequencing from wastewater.

Synopsis

Four concentration/extraction methods combined with probe-capture sequencing of human viruses in raw wastewater were compared. Innovaprep ultrafiltration with solids removal had the best performance for human virus detection sensitivity, richness, and recovery of near-complete genomes.
Bifidobacterium longummodifies a nutritional intervention for stunting in Zimbabwean infants
Authors: Gough Ethan K , Edens Thaddeus J , Carr Lynnea , Robertson Ruairi C , Mutasa Kuda , Ntozini Robert , Chasekwa Bernard , Geum Hyun Min , Baharmand Iman , Gill Sandeep K , Mutasa Batsirai , Mbuya Mduduzi N N , Majo Florence D , Tavengwa Naume , Francis Freddy , Tome Joice , Evans Ceri , Kosek Margaret , Prendergast Andrew J , Manges Amee R ,   the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) Trial Team
Published: January 2024

Child stunting is an indicator of chronic undernutrition and reduced human capital. Small-quantity lipid-based nutrient supplements (SQ-LNS) has been widely tested to reduce stunting, but has modest effects. The infant intestinal microbiome may contribute to stunting, and is partly shaped by mother and infant histo-blood group antigens (HBGA). We investigated whether mother-infant fucosyltransferase status, which governs HBGA, and the infant gut microbiome modified the impact of SQ-LNS on stunting at age 18 months among Zimbabwean infants in the SHINE Trial (NCT01824940). We found that mother-infant fucosyltransferase discordance andBifidobacterium longummodified SQ-LNS efficacy. Infant age-related microbiome shifts inB. longumsubspecies dominance frominfantis, a proficient human milk oligosaccharide utilizer, tosuisorlongum, proficient plant-polysaccharide utilizers, were partly influenced by discordance in mother-infant FUT2+/FUT3-phenotype, suggesting that a “younger” microbiome at initiation of SQ-LNS reduces its benefits on stunting in areas with a high prevalence of linear growth restriction.
Effectiveness of a bedaquiline, linezolid, clofazimine “core” for multidrug-resistant tuberculosis
Authors: Zeng Chengbo , Hernán Miguel A. , Trevisi Letizia , Sauer Sara , Mitnick Carole D. , Hewison Catherine , Bastard Mathieu , Khan Palwasha , Seung Kwonjune J. , Rich Michael L. , Law Stephanie , Kikvidze Marina , Kirakosyan Ohanna , Miankou Alexey , Thit Phone , Mamsa Shahid , Janmohamed Aleeza , Melikyan Nara , Ahmed Saman , Vargas Dante , Binegdie Amsalu Bekele , Temirova Kulbaram , Oyewusi Lawrence , Philippe Kerline , Vilbrun Stalz C. , Khan Uzma , Huerga Helena , Franke Molly F. ,   endTB Observational Study Team
Published: January 2024

Rationale

Treatment outcomes may be compromised among patients with multidrug- or rifampicin-resistant tuberculosis with additional fluoroquinolone resistance. Evidence is needed to inform optimal treatment for these patients.

Objectives

We compared the effectiveness of longer individualized regimens comprised of bedaquiline for 5 to 8 months, linezolid, and clofazimine to those reinforced with at least 1 third-tier drug and/or longer duration of bedaquiline.

Methods

We emulated a target trial to compare the effectiveness of initiating and remaining on the core regimen to one of five regimens reinforced with (1) bedaquiline for ≥9 months, (2) bedaquiline for ≥9 months and delamanid, (3) imipenem, (4) a second-line injectable, or (5) delamanid and imipenem. We included patients in whom a fluoroquinolone was unlikely to be effective based on drug susceptibility testing and/or prior exposure. Our analysis consisted of cloning, censoring, and inverse-probability weighting to estimate the probability of successful treatment.

Measurements and Main Results

Adjusted probabilities of successful treatment were high across regimens, ranging from 0.75 (95%CI:0.61, 0.89) to 0.84 (95%CI:0.76, 0.91). We found no substantial evidence that any of the reinforced regimens improved effectiveness of the core regimen, with ratios of treatment success ranging from 1.01 for regimens reinforced with bedaquiline ≥9 months (95%CI:0.79, 1.28) and bedaquiline ≥9 months plus delamanid (95%CI:0.81, 1.31) to 1.11 for regimens reinforced by a second-line injectable (95%CI:0.92, 1.39) and delamanid and imipenem (95%CI:0.90, 1.41).

Conclusions

High treatment success underscores the effectiveness of regimens comprised of bedaquiline, linezolid, and clofazimine, highlighting the need for expanded access to these drugs.
Large-Scale Mendelian Randomization Study Reveals Circulating Blood-based Proteomic Biomarkers for Psychopathology and Cognitive Task Performance
Authors: Bhattacharyya Upasana , John Jibin , Lam Max , Fisher Jonah , Sun Benjamin , Baird Denis , Chen Chia-Yen , Lencz Todd
Published: January 2024

Background

Research on peripheral (e.g., blood-based) biomarkers for psychiatric illness has typically been low-throughput in terms of both the number of subjects and the range of assays performed. Moreover, traditional case-control studies examining blood-based biomarkers are subject to potential confounds of treatment and other exposures common to patients with psychiatric illnesses. Our research addresses these challenges by leveraging large-scale, high-throughput proteomics data and Mendelian Randomization (MR) to examine the causal impact of circulating proteins on psychiatric phenotypes and cognitive task performance.

Methods

We utilized plasma proteomics data from the UK Biobank (3,072 proteins assayed in 34,557 European-ancestry individuals) and deCODE Genetics (4,719 proteins measured across 35,559 Icelandic individuals). Significant proteomic quantitative trait loci (both cis-pQTLs and trans-pQTLs) served as MR instruments, with the most recent GWAS for schizophrenia, bipolar disorder, major depressive disorder, and cognitive task performance (all excluding overlapping UK Biobank participants) as phenotypic outcomes.

Results

MR revealed 109 Bonferroni-corrected causal associations (44 novel) involving 88 proteins across the four phenotypes. Several immune-related proteins, including interleukins and complement factors, stood out as pleiotropic across multiple outcome phenotypes. Drug target enrichment analysis identified several novel potential pharmacologic repurposing opportunities, including anti-inflammatory agents for schizophrenia and bipolar disorder and duloxetine for cognitive performance.

Conclusions

Identification of causal effects for these circulating proteins suggests potential biomarkers for these conditions and offers insights for developing innovative therapeutic strategies. The findings also indicate substantial evidence for the pleiotropic effects of many proteins across different phenotypes, shedding light on the shared etiology among psychiatric conditions and cognitive ability.
GWAS of ∼30,000 samples with bone mineral density at multiple skeletal sites and its clinical relevance on fracture prediction, genetic correlations and prioritization of drug targets
Authors: Qian Yu , Xia Jiangwei , Wang Pingyu , Xie Chao , Lin Hong-Li , Li Gloria Hoi-Yee , Yuan Cheng-Da , Qiu Mo-Chang , Fang Yi-Hu , Yu Chun-Fu , Cai Xiang-Chun , Khederzadeh Saber , Zhao Pian-Pian , Yang Meng-Yuan , Zhong Jia-Dong , Li Xin , Guan Peng-Lin , Gu Jia-Xuan , Gai Si-Rui , Yi Xiang-Jiao , Tao Jian-Guo , Chen Xiang , Miao Mao-Mao , Chen Guo-Bo , Xu Lin , Xie Shu-Yang , Tian Geng , Yue Hua , Li Guangfei , Xiao Wenjin , Karasik David , Xu Youjia , Yang Liu , Cheung Ching-Lung , Huang Fei , Zhang Zhenlin , Zheng Hou-Feng
Published: January 2024

We conducted genome-wide association studies (GWAS) of dual-energy X-ray absorptiometry (DXA)-derived bone mineral density (BMD) traits at 11 skeletal sites, within over 30,000 European individuals from the UK Biobank. A total of 92 unique and independent loci were identified for 11 DXA-derived BMD traits and fracture, including five novel loci (harboring genes such asABCA1,CHSY1,CYP24A1,SWAP70, andPAX1) for six BMD traits. These loci exhibited evidence of association in both males and females, which could serve as independent replication. We demonstrated that polygenic risk scores (PRSs) were independently associated with fracture risk. Although incorporating multiple PRSs (metaPRS) with the clinical risk factors (i.e., the FRAX model) exhibited the highest predictive performance, the improvement was marginal in fracture prediction. The metaPRS were capable of stratifying individuals into different trajectories of fracture risk, but clinical risk factors played a more significant role in the stratification. Additionally, we uncovered genetic correlation and shared polygenicity between head BMD and intracranial aneurysm. Finally, by integrating gene expression and GWAS datasets, we prioritized genes (e.g.ESR1andSREBF1) encoding druggable human proteins along with their respective inhibitors/antagonists. In conclusion, this comprehensive investigation revealed a new genetic basis for BMD and its clinical relevance on fracture prediction. More importantly, it was suggested that head BMD was genetically correlated with intracranial aneurysm. The prioritization of genetically supported targets implied the potential repurposing drugs (e.g. the n-3 PUFA supplement targeting SREBF1) for the prevention of osteoporosis.
Connecting genomic results for psychiatric disorders to human brain cell types and regions reveals convergence with functional connectivity
Authors: Yao Shuyang , Harder Arvid , Darki Fahimeh , Chang Yu-Wei , Li Ang , Nikouei Kasra , Volpe Giovanni , Lundström Johan N , Zeng Jian , Wray Naomi , Lu Yi , Sullivan Patrick F , Hjerling-Leffler Jens
Published: January 2024

Understanding the temporal and spatial brain locations etiological for psychiatric disorders is essential for targeted neurobiological research. Integration of genomic insights from genome-wide association studies with single-cell transcriptomics is a powerful approach although past efforts have necessarily relied on mouse atlases. Leveraging a comprehensive atlas of the adult human brain, we prioritized cell types via the enrichment of SNP-heritabilities for brain diseases, disorders, and traits, progressing from individual cell types to brain regions. Our findings highlight specific neuronal clusters significantly enriched for the SNP-heritabilities for schizophrenia, bipolar disorder, and major depressive disorder along with intelligence, education, and neuroticism. Extrapolation of cell-type results to brain regions reveals important patterns for schizophrenia with distinct subregions in the hippocampus and amygdala exhibiting the highest significance. Cerebral cortical regions display similar enrichments despite the known prefrontal dysfunction in those with schizophrenia highlighting the importance of subcortical connectivity. Using functional MRI connectivity from cases with schizophrenia and neurotypical controls, we identified brain networks that distinguished cases from controls that also confirmed involvement of the central and lateral amygdala, hippocampal body, and prefrontal cortex. Our findings underscore the value of single-cell transcriptomics in decoding the polygenicity of psychiatric disorders and offer a promising convergence of genomic, transcriptomic, and brain imaging modalities toward common biological targets.
Restoration of upper-extremity function after task-oriented, intention-driven functional electrical stimulation therapy using a wearable sleeve in adults with chronic stroke: a case series
Authors: Baumgart Ian W. , Darrow Michael J. , Tacca Nicholas J. , Dunlap Collin F. , Colachis Samuel C. , Kamath Ashwini , Schlink Bryan R. , Putnam Philip T. , Branch Joshua , Friedenberg David A. , Wengerd Lauren R. , Meyers Eric C.
Published: January 2024

Background

Functional electrical stimulation (FES) has been recognized for decades as a method to retrain the motor system after stroke. Benefits of FES rehabilitation can be enhanced by combining task-oriented therapy, dubbed FES therapy (FEST). Furthermore, by synchronizing FES with the user’s volitional motor intention and incorporating multiple trained tasks FES can be better integrated into common task-oriented rehabilitation practice. Using wearable FES technology, we tested therapy incorporating these elements in two chronic stroke survivors.

Methods

Our group has developed the NeuroLife® Sleeve, a wearable forearm sleeve that contains a high-density grid of embedded FES electrodes, that may be controlled by an operator or by the wearer’s own electromyographic (EMG) signals. During eight weeks of FEST, intention-driven FES enabling multiple movements was delivered via operator control twice weekly and EMG control once weekly.

Results

At the end of the therapy period, subjects A and B had both improved their scores: Box and Blocks Test (A: +5, B: +7), the Action Arm Research Test (A: +7, B: +12), the Fugl Meyer Upper Extremity section (A: +11, B: +9), and the 9-Hole Peg Test (A: 158 sec, B: 54 sec, both previously unable). All score improvements persisted over the 10-week follow-up period despite greatly reduced (>80%) effective dose of FES.

Conclusions

This case series provides additional evidence that intention-driven FEST drives long-lasting motor recovery in chronic stroke survivors. The NeuroLife Sleeve enabled this therapy through the easily donned wearable sleeve interface, control schemes for pairing FES with motor intention, and efficient transitions between tasks with programmable FES placement and parameters.
SEETrials: Leveraging Large Language Models for Safety and Efficacy Extraction in Oncology Clinical Trials
Authors: Lee Kyeryoung , Paek Hunki , Huang Liang-Chin , Hilton C Beau , Datta Surabhi , Higashi Josh , Ofoegbu Nneka , Wang Jingqi , Rubinstein Samuel M , Cowan Andrew J , Kwok Mary , Warner Jeremy L. , Xu Hua , Wang Xiaoyan
Published: January 2024

Background

Initial insights into oncology clinical trial outcomes are often gleaned manually from conference abstracts. We aimed to develop an automated system to extract safety and efficacy information from study abstracts with high precision and fine granularity, transforming them into computable data for timely clinical decision-making.

Methods

We collected clinical trial abstracts from key conferences and PubMed (2012-2023). The SEETrials system was developed with four modules: preprocessing, prompt modeling, knowledge ingestion and postprocessing. We evaluated the system’s performance qualitatively and quantitatively and assessed its generalizability across different cancer types— multiple myeloma (MM), breast, lung, lymphoma, and leukemia. Furthermore, the efficacy and safety of innovative therapies, including CAR-T, bispecific antibodies, and antibody-drug conjugates (ADC), in MM were analyzed across a large scale of clinical trial studies.

Results

SEETrials achieved high precision (0.958), recall (sensitivity) (0.944), and F1 score (0.951) across 70 data elements present in the MM trial studies Generalizability tests on four additional cancers yielded precision, recall, and F1 scores within the 0.966-0.986 range. Variation in the distribution of safety and efficacy-related entities was observed across diverse therapies, with certain adverse events more common in specific treatments. Comparative performance analysis using overall response rate (ORR) and complete response (CR) highlighted differences among therapies: CAR-T (ORR: 88%, 95% CI: 84-92%; CR: 95%, 95% CI: 53-66%), bispecific antibodies (ORR: 64%, 95% CI: 55-73%; CR: 27%, 95% CI: 16-37%), and ADC (ORR: 51%, 95% CI: 37-65%; CR: 26%, 95% CI: 1-51%). Notable study heterogeneity was identified (>75%I2heterogeneity index scores) across several outcome entities analyzed within therapy subgroups.

Conclusion

SEETrials demonstrated highly accurate data extraction and versatility across different therapeutics and various cancer domains. Its automated processing of large datasets facilitates nuanced data comparisons, promoting the swift and effective dissemination of clinical insights.
Evaluating Large Language Models in Echocardiography Reporting: Opportunities and Challenges
Authors: Chao Chieh-Ju , Banerjee Imon , Arsanjani Reza , Ayoub Chadi , Tseng Andrew , Delbrouck Jean-Benoit , Kane Garvan C. , Lopez-Jimenez Francisco , Attia Zachi , Oh Jae K , Erickson Bradley , Fei-Fei Li , Adeli Ehsan , Langlotz Curtis
Published: January 2024

Background

The increasing need for diagnostic echocardiography (echo) tests presents challenges in preserving the quality and promptness of reports. While Large Language Models (LLMs) have proven effective in summarizing clinical texts, their application in echo remains underexplored.

Aims

To evaluate open-source LLMs in echo report summarization.

Methods

Adult echo studies conducted at the Mayo Clinic from January 1, 2017, to December 31, 2017, were categorized into two groups: development (all Mayo locations except Arizona) and Arizona validation sets. We adapted open-source LLMs (Llama-2, MedAlpaca, Zephyr, and Flan-T5) using In-Context Learning (ICL) and Quantized Low-Rank Adaptation (QLoRA) fine-tuning for echo report summarization from “Findings” to “Impressions.” Against cardiologist-generated Impressions, the models’ performance was assessed both quantitatively with automatic metrics and qualitatively by cardiologists.

Results

The development dataset included 97,506 reports from 71,717 unique patients, predominantly male (55.4%), with an average age of 64.3±15.8 years. EchoGPT, a QLoRA fine-tuned Llama-2 model, outperformed other LLMs with win rates ranging from 87% to 99% in various automatic metrics, and produced reports comparable to cardiologists in qualitative review (significantly preferred in conciseness (p< 0.001), with no significant preference in completeness, correctness, and clinical utility). Correlations between automatic and human metrics were fair to modest, with the best being RadGraph F1 scores versus clinical utility (r=0.42) and automatic metrics showed insensitivity (0-5% drop) to changes in measurement numbers.

Conclusions

EchoGPT can generate draft reports for human review and approval, helping to streamline the workflow. However, scalable evaluation approaches dedicated to echo reports remains necessary.

Clinical Perspectives

1. What is new?

This study evaluated multiple open-source LLMs and different model adaptation methods in echocardiography report summarization.

The resulting system, EchoGPT, can generate echo reports comparable in quality to cardiologists.

Future metrics for echo report quality should emphasize factual correctness, especially on numerical measurements.

2. What are the clinical implications?

EchoGPT system demonstrated the potential of introducing LLMs into echocardiography practice to generate draft reports for human review and approval.
A framework for detecting causal effects of risk factors at an individual level based on principles of Mendelian randomization: Applications to modelling individualized effects of lipids on coronary artery disease
Authors: Shi Yujia , Xiang Yong , Ye Yuxin , He Tingwei , Sham Pak-Chung , So Hon-Cheong
Published: January 2024

Mendelian Randomization (MR), a method that employs genetic variants as instruments for causal inference, has gained popularity in assessing the causal effects of risk factors. However, almost all MR studies primarily concentrate on the population’saveragecausal effects. With the advent of precision medicine, theindividualizedtreatment effect (ITE) is often of greater interest. For instance, certain risk factors may pose a higher risk to some individuals compared to others, and the benefits of a treatment may vary among individuals. This highlights the importance of considering individual differences in risk and treatment response.

We propose a new framework that expands the concept of MR to investigateindividualizedcausal effects. We presented several approaches for estimating Individualized Treatment Effects (ITEs) within this MR framework, primarily grounded on the principles of the”R-learner”. To evaluate the existence of causal effect heterogeneity, we proposed two permutation testing methods. We employed Polygenic Risk Scores (PRS) as the instrument and demonstrated that the removal of potentially pleiotropic SNPs could enhance the accuracy of ITE estimates. The validity of our approach was substantiated through comprehensive simulations.

We applied our framework to study the individualized causal effect of various lipid traits, including Low-Density Lipoprotein Cholesterol (LDL-C), High-Density Lipoprotein Cholesterol (HDL-C), Triglycerides (TG), and Total Cholesterol (TC), on the risk of Coronary Artery Disease (CAD) using data from the UK Biobank. Our findings indicate that an elevated level of LDL-C is causally linked to increased CAD risks, with the effect demonstrating significant heterogeneity. Similar results were observed for TC. We also revealed clinical factors contributing to the heterogeneity of ITE based on Shapley value analysis. Furthermore, we identified clinical factors contributing to the heterogeneity of ITEs through Shapley value analysis. This underscores the importance of individualized treatment plans in managing CAD risks.
Procedural Volume and Outcomes with Atrial Fibrillation Ablation: A Report from the NCDR AFib Ablation Registry
Authors: Kattel Sharma , Tan Zhen , Lin Zhenqiu , Mszar Reed , Sanders Prashanthan , Zeitler Emily P. , Zei Paul C. , Bunch T Jared , Mansour Moussa , Akar Joseph , Curtis Jeptha P. , Friedman Daniel J. , Freeman James V
Published: January 2024

Background

Hospital and physician procedure volumes have been associated with outcomes for several cardiac procedures; however, this has not been well defined for atrial fibrillation (AF) ablation in the contemporary practice.

Objective

To determine the association between hospital and physician procedural volume and success for AF ablation and the risk of major adverse events (MAE).

Methods

Procedures reported to the NCDR AFib Ablation Registry between July 2019 and June 2022 were included. Physician and hospital procedural volumes were annualized and stratified into quartiles (Q) to compare success and MAE. Three level hierarchical (patient, hospital and physician) generalized linear models were used to assess the adjusted relationship between procedural volume and the likelihood of procedural outcomes.

Results

A total of 70,296 first time AF ablation at 186 hospitals across the United States were included. The mean age was 66.1 ± 10.3 years, 36% were women, the mean CHA2DS2-VASc score was 2.7±1.6, and 57.4% of patients had paroxysmal AF. The median annual procedural volume for hospitals and physicians were 230 (IQR:144.7-307.2) and 66 (IQR: 44.7-97.5), respectively. Overall, acute procedural success was 98.5 % and the MAE rate was 1.0%. With Q4 (highest) hospital volume as a reference, the adjusted likelihood of procedural success was significantly lower for Q1 (OR: 0.44, CI: 0.29-0.68), Q2 (OR: 0.50, CI: 0.33-0.75) and Q3 (OR: 0.60, CI: 0.40-0.89). Similarly, for physician, procedural success was less among Q1 (OR: 0.38, CI: 0.28-0.51), Q2 (OR: 0.51, CI: 0.38-0.69) and Q3 (OR: 0.55, CI: 0.42-0.72). With MAE, compared with Q4, there was an inverse relationship between procedural volume for hospitals in Q1 (OR: 1.78, CI: 1.26-2.51) but not Q2 (OR: 1.06, CI: 0.77-1.46) or Q3 (OR: 1.19, CI: 0.89-1.58) and for physicians in Q1 (OR: 1.93, CI: 1.44-2.58) and Q2 (OR: 1.49, CI: 1.13-1.97) but not in Q3 (OR: 1.22, CI: 0.94-1.58). An adjusted MAE ≤ 1% was predicted by an annual volume of approximately 190 for hospitals and 60 for physicians.

Conclusion

In this national cohort, hospital and physician AF ablation procedural volumes were directly related to acute procedural success and inversely related to rates of MAE.

Condensed Abstract

The relationship between atrial fibrillation (AF) ablation procedure volume and outcomes is not well defined in contemporary practice. In this national cohort of 70,296 patients undergoing first time AF ablation, acute procedural success was relatively high (98.5%) and risk of major adverse event remained low (1.0%). Greater hospital and physician procedure volume was associated with higher procedural success. There was an inverse relationship between hospital and physician procedural volume and the risk of major adverse events.
DeepResBat: deep residual batch harmonization accounting for covariate distribution differences
Authors: An Lijun , Zhang Chen , Wulan Naren , Zhang Shaoshi , Chen Pansheng , Ji Fang , Ng Kwun Kei , Chen Christopher , Zhou Juan Helen , Yeo B.T. Thomas ,   Alzheimer’s Disease Neuroimaging Initiative,   Australian Imaging Biomarkers and Lifestyle Study of Aging
Published: January 2024

Pooling MRI data from multiple datasets requires harmonization to reduce undesired inter-site variabilities, while preserving effects of biological variables (or covariates). The popular harmonization approach ComBat uses a mixed effect regression framework that explicitly accounts for covariate distribution differences across datasets. There is also significant interest in developing harmonization approaches based on deep neural networks (DNNs), such as conditional variational autoencoder (cVAE). However, current DNN approaches do not explicitly account for covariate distribution differences across datasets. Here, we provide mathematical results, suggesting that not accounting for covariates can lead to suboptimal harmonization. We propose two DNN-based covariate-aware harmonization approaches: covariate VAE (coVAE) and DeepResBat. The coVAE approach is a natural extension of cVAE by concatenating covariates and site information with site- and covariate-invariant latent representations. DeepResBat adopts a residual framework inspired by ComBat. DeepResBat first removes the effects of covariates with nonlinear regression trees, followed by eliminating site differences with cVAE. Finally, covariate effects are added back to the harmonized residuals. Using three datasets from three continents with a total of 2787 participants and 10085 anatomical T1 scans, we find that DeepResBat and coVAE outperformed ComBat, CovBat and cVAE in terms of removing dataset differences, while enhancing biological effects of interest. However, coVAE hallucinates spurious associations between anatomical MRI and covariates even when no association exists. Future studies proposing DNN-based harmonization approaches should be aware of this false positive pitfall. Overall, our results suggest that DeepResBat is an effective deep learning alternative to ComBat. Code for DeepResBat can be found here:https://github.com/ThomasYeoLab/CBIG/tree/master/stable_projects/harmonization/An2024_DeepResBat.
Single and Multi-Site Cortical Stimulation Related to Human Sensorimotor Function
Authors: Ryun Seokyun , Chung Chun Kee
Published: January 2024

Somatosensory feedback is crucial for precise control of our body and thereby affects various sensorimotor-related brain areas for movement control. Electrical stimulation on the primary somatosensory cortex (S1) elicits various artificial somatosensations. However, replicating the spatiotemporal dynamics of somatosensory feedback and fine control of elicited somatosensation are still challenging. Furthermore, how and where the somatosensory feedback interacts with neural activity for sensorimotor processing is unclear. Here, we replicate the spatiotemporal dynamics of somatosensory feedback and control the quality of elicited somatosensation using multi-site direct cortical stimulation (DCS). We also investigate how and where the neural feedback activity interacts with neural activity for motor processing by stimulating the downstream areas of the S1. We found that multi-site DCS on the S1 elicits different sensations simultaneously. Using the artificial feedback, blindfolded patients could efficiently perform a DCS-guided reach-and-grasp task successfully. Interestingly, we also found that multi-site DCS close to each other elicits different qualities of somatosensation in the same body part. Additionally, we found that DCS on the ventral premotor area (vPM) can affect hand grasping with eliciting artificial sensation of the hand. Throughout this study, we showed that semi-invasive, macro-level, and multi-site DCS can precisely elicit/modulate somatosensations in human. We suggest that activation of multiple cortical areas elicits simultaneous and independent somatosensations and that interplay among the stimulated sites can change the somatosensation quality. Finally, the results of vPM stimulation indicate that vPM has a critical role in function-specific sensorimotor interactions, such as hand grasping.
Changes in microglia chromatin accessibility in aged female mice
Authors: Ansere Victor A. , Tooley Kyla B. , Srividya Kottapalli , Hoolehan Walker , Pham Kevin D. , Ocañas Sarah R. , Freeman Willard M.
Published: January 2024

Aged female microglia display a more inflammatory and disease-associated phenotype compared to age-matched males. Epigenetic mechanisms, such as chromatin accessibility, are key drivers of microglial plasticity and phenotypes necessary for development, priming, and immune activation. Therefore, alterations in chromatin accessibility patterns can potentially regulate the neuroimmune responses and phenotypes observed in female microglia with aging, but to date have not been assessed. In this study, hippocampal microglia chromatin accessibility in young (4-5 months) and old (23-24 months) female mice was interrogated by Assay for Transposable Accessible Chromatin using Sequencing (ATAC-Seq). Cx3cr1-cre/ERT2+: NuTRAP mice were used to tag microglia and enable INTACT (isolation of nuclei tagged in specific cell types) collection of microglia-specific nuclei. With aging, loci specific gains and losses in chromatin accessibility were observed. Notably, changes in chromatin accessibility were skewed, with aged female microglia having more regions gaining accessibility than loosing accessibility. These changes were under-represented in the proximal promoter region (≤1kb) of genes but were enriched in intergenic regions. Regions that gained accessibility were more concentrated around genes responsible for myeloid cell differentiation and the regulation of immune and inflammatory responses. In contrast, regions that became less accessible were closest to genes involved in neuronal and synaptic function. In addition, X Chromosome accessibility changes were less common compared to autosomal changes, which argues against increased X Chromosome escape from inactivation with aging in female microglia. Overall, our data demonstrate age-related chromatin accessibility changes in female microglia, which may be regulated within enhancers and distal regulatory elements, and that these changes have potential downstream implications for the inflammatory phenotype of microglia in aging female mice.
Genome-wide allele frequency changes reveal that dynamic metapopulations evolve differently
Authors: Angst Pascal , Haag Christoph R. , Ben-Ami Frida , Fields Peter D. , Ebert Dieter
Published: January 2024

Background

Two important characteristics of metapopulations are extinction– (re)colonization dynamics and gene flow between subpopulations. These processes can cause strong shifts in genome-wide allele frequencies that are generally not observed in “classical” (large, stable, panmictic) populations. Subpopulations founded by one or a few individuals, the so-called propagule model, are initially expected to show intermediate allele frequencies at polymorphic sites until natural selection and genetic drift drive allele frequencies toward a mutation-selection-drift equilibrium characterized by a negative exponential-like distribution of the site frequency spectrum (SFS).

Results

We followed changes in SFS distribution in a natural metapopulation of the cyclically parthenogenetic pond-dwelling microcrustaceanDaphnia magnausing biannual pool-seq samples collected over a five-year period from 118 ponds occupied by subpopulations of known age. As expected under the propagule model, SFSs in newly founded subpopulations trended toward intermediate allele frequencies and shifted toward right skewed distributions as the populations aged. Immigration and subsequent hybrid vigor altered this dynamic.

Conclusions

The analysis of SFS dynamics is a powerful approach to understand evolution in metapopulations. It allowed us to disentangle evolutionary processes occurring in a natural metapopulation, where many subpopulations evolve in parallel. Thereby, stochastic processes like founder and immigration events lead to a pattern of subpopulation divergence, while genetic drift, leads to converging SFS distributions in the persisting subpopulations. The observed processes are well explained by the propagule model and highlight that metapopulations evolve differently from classical populations.
Multi-faceted roles of β-arrestins in G protein-coupled receptors endocytosis
Authors: Liu Junke , Xue Li , Ravier Magalie , Inoue Asuka , Drube Julia , Hoffmann Carsten , Trinquet Eric , Dupuis Elodie , Prézeau Laurent , Pin Jean-Philippe , Rondard Philippe
Published: January 2024

Internalization plays a crucial role in regulating the density of cell surface receptors and has been demonstrated to regulate intracellular signaling. Dysregulation of this process has been implicated in various diseases. The vast majority of GPCRs were considered to adopt one way for internalization. We challenged this conventional view by showing that multiple pathways converge to regulate the internalization of a specific receptor, based on an unparalleled characterization of 60 GPCR internalization profiles, both in the absence and presence of individual β-arrestins (βarrs). Furthermore, we revealed the internalization mechanism of the glucagon-like peptide-1 receptor (GLP-1R), a class B GPCR pivotal in promoting insulin secretion from pancreatic beta cells to maintain glucose homeostasis. GLP-1R can undergo agonist-induced internalization without βarrs, but can recruit and form stable complexes with βarrs. We found that GLP-1R recruits clathrin adaptor protein-2 for agonist-induced internalization in both βarr-dependent and -independent manners. These results provide a valuable resource for GPCR signaling and reveal the plasticity of different GPCRs to employ or not βarrs in the clathrin-mediated internalization.
Claustrum projections to the anterior cingulate modulate nociceptive and pain-associated behaviour
Authors: Faig Christian A. , Kim Gloria H. K. , Do Alison D. , Dworsky-Fried Zoë , Jackson Jesse , Taylor Anna M. W.
Published: January 2024

The anterior cingulate cortex (ACC) processes nociceptive information and pain unpleasantness. The claustrum is a subcortical region that provides robust feed-forward inhibition onto the ACC, suggesting this circuit could play a role in modulating pathological states such as pain. However, the function of this circuit in the context of acute and chronic inflammatory pain is unclear. Here, we show that claustrocingulate neurons exhibit a bimodal pattern of activation following acute pain but are suppressed during states of chronic inflammatory pain. Molecular lesion and chemogenetic suppression of claustrocingulate neurons increased acute nociception but interfered with pain learning. Activation of this pathway rescued mechanical allodynia associated with chronic pain. Together, these results suggest claustrocingulate neurons are a critical component of the pain neuromatrix, and dysregulation of this connection may contribute to chronic pain.
Gene therapy targeting sustained FGF23-ERK signaling alleviates kidney inflammation
Authors: Salas-Bastos Adrian , Bardet Claire , Kopper Klaudia , Jauze Louisa , Collaud Fanny , Francois Amandine , Chen Gaozhi , Mohammadi Moosa , Stockmann Christian , Sommer Lukas , Loffing Johannes , Ronzitti Giuseppe , Pathare Ganesh
Published: January 2024

Fibroblast growth factor 23 (FGF23) levels are highly elevated in patients with chronic kidney disease (CKD); however, whether it serves merely as a biomarker or actively contributes to kidney inflammation remains unclear. Full-length FGF23 is cleaved into C-terminal FGF23 (cFGF23), which acts as a natural antagonist of FGF23 by inhibiting its binding to the FGF receptor (FGFR) and the co-receptor Klotho. Here, we show that chronically elevated FGF23 levels in a mouse model Hyp-Duk cause sustained-ERK signaling and an inflammatory and immune responses in the kidney. cFGF23, delivered via adeno-associated virus (AAV) gene therapy, successfully mitigated sustained-ERK signaling and kidney inflammation in Hyp-Duk mice. On the other hand, acute physiological FGF23 levelsin vitroelicited transient-ERK signaling with the expression of canonical early-ERK targets (EGR1, JUNB, FOSB). Consistent within vivofindings, prolonged pathological FGF23 treatmentin-vitrorevealed sustained-ERK signaling with upregulation of late-ERK targets (ETV4/5, SPRED1/2, SPRY2/4) and unique inflammatory and immune gene signatures. These effects were significantly mitigated by FGFR and ERK inhibitors, as well as by recombinant cFGF23 treatment. In summary, chronically high levels of FGF23 induce kidney inflammation through the FGFR-Klotho complex and sustained-ERK activation, which are successfully mitigated by cFGF23 gene therapy.

KEY POINTS

Fibroblast growth factor 23 (FGF23) levels are highly elevated in patients with chronic kidney disease (CKD). FGF23 is also a potential biomarker for CKD and related cardiovascular disorders, although its role in disease progression remains unclear.

Our study identifies that chronically elevated FGF23 levels induce sustained-ERK signalingin-vitroandin-vivo, leading to inflammation and immune signaling pathways in the kidney.

These untoward effects of FGF23 were significantly suppressed by gene therapy using the C-terminal peptide of FGF23 (cFGF23), a natural FGF23 antagonist, warranting further investigation to confirm its clinical potential in CKD.
ER and SOCE Ca2+signals are not required for directed cell migration in human microglia
Authors: Granzotto Alberto , McQuade Amanda , Chadarevian Jean Paul , Davtyan Hayk , Sensi Stefano L. , Parker Ian , Blurton-Jones Mathew , Smith Ian
Published: January 2024

The central nervous system (CNS) is constantly surveilled by microglia, highly motile and dynamic cells deputed to act as the first line of immune defense in the brain and spinal cord. Alterations in the homeostasis of the CNS are detected by microglia that respond by migrating toward the affected area. Understanding the mechanisms controlling directed cell migration of microglia is crucial to dissect their responses to neuroinflammation and injury. We used a combination of pharmacological and genetic approaches to explore the involvement of calcium (Ca2+) signaling in the directed migration of induced pluripotent stem cell (iPSC)-derived microglia challenged with a purinergic stimulus. This approach mimics cues originating from injury of the CNS. Unexpectedly, simultaneous imaging of microglia migration and intracellular Ca2+changes revealed that this phenomenon does not require Ca2+signals generated from the endoplasmic reticulum (ER) and store-operated Ca2+entry (SOCE) pathways. Instead, we find evidence that human microglial chemotaxis to purinergic signals is mediated by cyclic AMP in a Ca2+-independent manner. These results challenge prevailing notions, with important implications in neurological conditions characterized by perturbation in Ca2+homeostasis.
CD62L-selected umbilical cord blood universal CAR T cells
Authors: Georgiadis Christos , Nickolay Lauren , Syed Farhatullah , Zhan Hong , Gkazi Soragia Athina , Etuk Annie , Abramowski-Mock Ulrike , Preece Roland , Cuber Piotr , Adams Stuart , Ottaviano Giorgio , Qasim Waseem
Published: January 2024

Umbilical cord blood (UCB) T cells exhibit distinct naïve ontogenetic profiles and may be an attractive source of starting cells for the production of chimeric antigen receptor (CAR) T cells. Pre-selection of UCB-T cells on the basis of CD62L expression was investigated as part of a machine-based manufacturing process, incorporating lentiviral transduction, CRISPR-Cas9 editing, T-cell expansion and depletion of residual TCRαβ T cells. This provided stringent mitigation against the risk of graft versus host disease (GVHD), and was combined with simultaneous knockout of CD52 to enable persistence of edited T cells in combination with preparative lymphodepletion using Alemtuzumab. Under compliant manufacturing conditions, two cell banks were generated with high levels of CAR19 expression and minimal carriage of TCRαβ T cells. Sufficient cells were cryopreserved in dose-banded aliquots at the end of each campaign to treat dozens of potential recipients. Molecular characterisation captured vector integration sites and CRISPR editing signatures and functional studies, includingin vivopotency studies in humanised mice, confirmed anti-leukaemic activity comparable to peripheral blood-derived universal CAR19 T cells. Machine manufactured UCB derived T cells banks offer an alternative to autologous cell therapies and could help widen access to CAR T cells.
EasyGrid: a versatile platform for automated cryo-EM sample preparation and quality control
Authors: Gemin Olivier , Armijo Victor , Hons Michael , Bissardon Caroline , Linares Romain , Bowler Matthew W. , Wolff Georg , Kovalev Kirill , Babenko Anastasiia , Salo Veijo T. , Schneider Sarah , Rossi Christopher , Lecomte Léa , Deckers Thibault , Lauzier Kévin , Janocha Robert , Felisaz Franck , Sinoir Jérémy , Galej Wojciech , Mahamid Julia , Müller Christoph W. , Eustermann Sebastian , Mattei Simone , Cipriani Florent , Papp Gergely
Published: January 2024

Imaging biological macromolecules in their native state with single-particle cryo-electron microscopy (cryo-EM) orin situcryo-electron tomography (cryo-ET) requires optimized approaches for the preparation and vitrification of biological samples. Here, we describe EasyGrid, a versatile technology enabling systematic, tailored and advanced sample preparation for cellular and structural biology. This automated, standalone platform combines in-line plasma treatment, microfluidic dispensing, blot-less sample spreading, jet-based vitrification and on-the-fly grid quality control using light interferometry to streamline cryo-EM sample optimization. With EasyGrid, we optimized grid preparation for different purified macromolecular complexes and subsequently determined their structure with cryo-EM. We also demonstrated how the platform allows better vitrification of large, mammalian cells compared to standard plunge-freezing. Automated sample preparation with EasyGrid establishes an advanced, high-throughput platform for both single-particle cryo-EM and cellular cryo-ET sample preparation.