bluuebunny/crossref_metadata_2025 huggingface dataset:
A new ensemble-based targeted observational method and its application in the TPOS 2020
Authors: Rao Weixun , Tang Youmin , Wu Yanling , Shen Zheqi , Song Xiangzhou , Li Xiaojing , Lian Tao , Chen Dake , Zhou Feng
Published: September 2023

Ensemble Kalman filter-based targeted observation is one of the best methods for determining the optimal observational array for oceanic buoy deployment. This study proposes a new algorithm suitable for a ‘cross-region and cross-variable’ approach by introducing a projection operator into the optimization process. A targeted observational analysis was conducted for El Niño–Southern Oscillation (ENSO) events in the tropical western Pacific for the Tropical Pacific Observation System (TPOS) 2020. The prediction target was at the Niño 3.4 region and the first 10 optimal observational sites detected reduced initial uncertainties by 70%, with the best observational array located where the Rossby wave signal dominates. At the vertical level, the most significant contribution was derived from observations near the thermocline. This study provides insights into understanding ENSO-related variability and offers a practical approach to designing an optimal mooring array. It serves as a scientific guidance for designing a TPOS observation network.
Species-specific ecological traits, phylogeny, and geography underpin vulnerability to population declines for North American birds
Authors: Stevens Henry C , Smith Adam C , Buechley Evan R , Şekercioğlu Çağan H , Shirey Vaughn , Rosenberg Kenneth V , La Sorte Frank A , Tallamy Douglas , Marra Peter P
Published: September 2023

Species declines and extinctions characterize the Anthropocene. Determining species vulnerability to decline, and where and how to mitigate threats, are paramount for effective conservation. We hypothesized that species with shared ecological traits also share threats, and therefore may experience similar population trends. Here, we used a Bayesian modeling framework to test whether phylogeny, geography, and 22 ecological traits predict regional population trends for 380 North American bird species. Groups like blackbirds, warblers, and shorebirds, as well as species occupying Bird Conservation Regions at more extreme latitudes in North America, exhibited negative population trends; whereas groups such as ducks, raptors, and waders, as well as species occupying more inland Bird Conservation Regions, exhibited positive trends. Specifically, we found that in addition to phylogeny and breeding geography, multiple ecological traits contributed to explaining variation in regional population trends for North American birds. Furthermore, we found that regional trends and the relative effects of migration distance, phylogeny, and geography differ between shorebirds, songbirds, and waterbirds. Our work provides evidence that multiple ecological traits correlate with North American bird population trends, but that the individual effects of these ecological traits in predicting population trends often vary between different groups of birds. Moreover, our results reinforce the notion that variation in avian population trends is controlled by more than phylogeny and geography, where closely related species within one region can show unique population trends due to differences in their ecological traits. We recommend that regional conservation plans, i.e. one-size-fits-all plans, be implemented only for bird groups with population trends under strong phylogenetic or geographic controls. We underscore the need to develop species-specific research and management strategies for other groups, like songbirds, that exhibit high variation in their population trends and are influenced by multiple ecological traits.
Impact of apolipoprotein A1 on tumor immune microenvironment, clinical prognosis and genomic landscape in hepatocellular carcinoma
Authors: Wang Ying , Chen Shipeng , Xiao Xiao , Yang Fan , Wang Jinhan , Zong Hui , Gao Yuzhen , Huang Chenjun , Xu Xuewen , Fang Meng , Zhang Xiaoyan , Gao Chunfang
Published: September 2023

Background

Current knowledge on apolipoprotein A1 (APOA1) in hepatocellular carcinoma (HCC) is fragmented and even contradictory. Multi-dimensional analyses are required to comprehensively elucidate its value and underlying mechanism.

Methods

We collected 49 RNA-seq datasets, 40 cell line types data and 70 scRNA pan-cancer datasets public available, including 17 HCC datasets (1754 tumor samples), and enrolled 73 pairs of HCC tissue and 516 blood samples independently from our clinics. APOA1 impacting on the HCC tumor microenvironment (TME) was analyzed using intensive data mining. Methylation sequencing, flow cytometry, quantitative PCR, western blot, immunohistochemistry and clinical chemistry assays were conducted for wet experimental investigation.

Results

The APOA1 ontology fingerprint indicated that it played various crucial biological roles in HCC, primarily involved in cholesterol efflux. Consistent findings at histology, serology, and clinical follow-up revealed that high APOA1 was a good prognosis indicator of HCC. Hypermethylation in the APOA1 promoter region was found in clinical samples which is in accordance with the reduction of APOA1 in HCC. The cell cycle, DNA replication, mismatch repair pathways, and tumor cell proliferation were less observed in the HCC APOA1high subgroup. The favorable immunoregulatory abilities of APOA1 showed interesting findings: a positive correlation between APOA1 and anti-tumor immune cells (NK, CD8+ T cells) and a negative association with immune cells exerting immunosuppressive effects, including M2 macrophages.

Conclusion

This is an integrative multidimensional exploration of APOA1 using bioinformatics and experiments. Both the prognostic value and anti-tumor effects based on APOA1 panoramic exploration in the HCC TME demonstrate a new potential clinical target for HCC assessment and intervention in the future.
Finding the Optimal Resistance Training Intensity for Your Bones: Protocol for a Randomized Controlled Trial
Authors: Giangregorio Lora M , Bleakney Robert R , Brien Sheila , Butcher Scotty J , Chan Brian C F , Chilibeck Philip D , Devries Michaela C , Funnell Larry , Jain Ravi , Keller Heather H , Milligan James , Mourtzakis Marina , O’Hare Bonny S , Thabane Lehana , Cheung Angela M
Published: September 2023

Objective

The purpose of this trial is to evaluate the effect of twice-weekly, moderate-to-high intensity progressive resistance training (PRT) for 1 year on lumbar spine bone mineral density (BMD) in individuals with low BMD, compared to attention control. Secondary analyses will examine if resistance training improves other health outcomes; if high intensity is more effective than moderate intensity resistance training for all outcomes; the cost of intervention versus benefit; the willingness to pay; and harms.

Methods

For this study, 324 men or postmenopausal women aged ≥50 years with a femoral neck, total hip, or lumbar spine BMD T-score of ≤−1, or a Fracture Risk Assessment Tool probability of ≥20% for major osteoporotic fracture or ≥ 3% for hip fracture are being recruited to participate in a randomized controlled trial with 1:1:1 randomization. Participants will be stratified by site (3 centers) to twice-weekly, supervised PRT at moderate intensity (about 10 repetitions maximum), to high intensity PRT (≤6 repetitions maximum), or to a home posture and balance exercise program (attention control) for 1 year (resistance training to comparator allocation ratio of 2:1). The primary outcome is lumbar spine BMD via dual-energy X-ray absorptiometry. Secondary outcomes include trabecular bone score, proximal femur and total hip BMD and structure, bone-free and appendicular lean mass, physical functioning, falls, fractures, glucose metabolism, cost per life-year gained, adverse events, and quality of life. Between-group differences will be tested in intention-to-treat and per-protocol analyses using analysis of covariance, chi-square tests, or negative binomial or logistic regression, adjusting for site and baseline values.

Impact

The Finding the Optimal Resistance Training Intensity For Your Bones trial will support decision making on resistance training for people at risk of fracture.
A reduction procedure and pipeline for the detection of trans-Neptunian objects using occultations
Authors: Nir Guy , Ofek Eran O , Zackay Barak
Published: September 2023

Kuiper belt objects smaller than a few kilometres are difficult to observe directly. They can be detected when they randomly occult a background star. Close to the ecliptic plane, each star is occulted once every tens of thousands of hours, and occultations typically last for less than a second. We present an algorithm, and companion pipeline, for detection of diffractive occultation events. Our approach includes: cleaning the data; an efficient and optimal matched filtering of the light curves with a template bank of diffractive occultations; treating the red-noise in the light curves; injection of simulated events for efficiency estimation; and applying data quality cuts. We discuss human vetting of the candidate events in a blinded way to reduce bias caused by the human-in-the-loop. We present Markov Chain Monte Carlo tools to estimate the parameters of candidate occultations, and test them on simulated events. This pipeline is used by the W-FAST. The methods discussed here can be applied to searches for other Trans-Neptunian objects, albeit with larger radii that correspond to a larger diffraction length scale.
Nontraumatic Spine Emergencies: A Primer for the On-Call Radiologist
Authors: Convery Emily , Cohen Benjamin A. , Patel Roshni R.
Published: September 2023

Myelopathy is defined as rapidly developing muscle weakness, sensory deficit, and loss of bowel and bladder sphincter control. The differential for atraumatic myelopathy includes both extrinsic and intrinsic causes, with the former including disc herniations with compressive myelopathy, osteomyelitis with epidural abscess, and leptomeningeal spread of disease whereas the latter includes acute inflammatory processes like Guillain-Barre syndrome or demyelinating disease, and spinal cord tumors.
Association of interpregnancy interval and risk of adverse pregnancy outcomes in woman by different previous gestational ages
Authors: Chen Peiran , Mu Yi , Liu Zheng , Wang Yanping , Li Xiaohong , Dai Li , Li Qi , Li Mingrong , Xie Yanxia , Liang Juan , Zhu Jun
Published: September 2023

Background:

With an increasing proportion of multiparas, proper interpregnancy intervals (IPIs) are urgently needed. However, the association between IPIs and adverse perinatal outcomes has always been debated. This study aimed to explore the association between IPIs and adverse outcomes in different fertility policy periods and for different previous gestational ages.

Methods:

We used individual data from China's National Maternal Near Miss Surveillance System between 2014 and 2019. Multivariable Poisson models with restricted cubic splines were used. Each adverse outcome was analyzed separately in the overall model and stratified models. The stratified models included different categories of fertility policy periods (2014–2015, 2016–2017, and 2018–2019) and infant gestational age in previous pregnancy (<28 weeks, 28–36 weeks, and ≥37 weeks).

Results:

There were 781,731 pregnancies enrolled in this study. A short IPI (≤6 months) was associated with an increased risk of preterm birth (OR [95% CI]: 1.63 [1.55, 1.71] for vaginal delivery [VD] and 1.10 [1.03, 1.19] for cesarean section [CS]), low Apgar scores and small for gestational age (SGA), and a decreased risk of diabetes mellitus in pregnancy, preeclampsia or eclampsia, and gestational hypertension. A long IPI (≥60 months) was associated with an increased risk of preterm birth (OR [95% CI]: 1.18 [1.11, 1.26] for VD and 1.39 [1.32, 1.47] for CS), placenta previa, postpartum hemorrhage, diabetes mellitus in pregnancy, preeclampsia or eclampsia, and gestational hypertension. Fertility policy changes had little effect on the association of IPIs and adverse maternal and neonatal outcomes. The estimated risk of preterm birth, low Apgar scores, SGA, diabetes mellitus in pregnancy, and gestational hypertension was more profound among women with previous term births than among those with preterm births or pregnancy loss.

Conclusion:

For pregnant women with shorter or longer IPIs, more targeted health care measures during pregnancy should be formulated according to infant gestational age in previous pregnancy.
Quercetin enhances decidualization through AKT-ERK-p53 signaling and supports a role for senescence in endometriosis
Authors: Delenko Julia , Xue Xiangying , Chatterjee Prodyot K , Hyman Nathaniel , Shih Andrew J , Adelson Robert P , Safaric-Tepes Polona , Gregersen Peter K , Metz Christine N
Published: September 2023

Quercetin, a flavonoid with senolytic activity, has attracted great interest as a therapy for fibrotic diseases such as pulmonary fibrosis, a disorder attributed to senescent pulmonary fibroblasts. Interestingly, quercetin has shown some benefit in pre-clinical models of endometriosis, an inflammatory condition characterized by senescent endometrial stromal cells and in severe cases, intraperitoneal fibrotic lesions and infertility. Quercetin exerts multiple biological activities but the signaling pathways underlying quercetin’s effects are not well-defined. In this report, we have analyzed the signaling pathways underlying quercetin’s action using menstrual effluent-derived endometrial stromal cells. We found that quercetin promotes decidualization, a well-defined differentiation process known to be defective in patients with endometriosis using cells obtained from endometriosis patients and unaffected controls. We show that quercetin substantially reduces the phosphorylation of multiple signaling molecules in the AKT and ERK1/2 pathways. In contrast, we observed striking phosphorylation of p53 and increased p53 protein expression. Furthermore, p53 inhibition blocks decidualization while p53 activation promotes decidualization. Finally, we provide evidence that quercetin increases apoptosis of endometrial stromal cells with a senescence phenotype. These data provide insight into mechanisms of action of quercetin in the setting of endometriosis and support studies to test senolytics for treating endometriosis.
Self-Focused Brain Predictors of Cognitive Behavioral Therapy Response in a Transdiagnostic Sample
Authors: Fang Angela , Baran Bengi , Feusner Jamie D. , Phan K. Luan , Beatty Clare C. , Crane Jessica , Jacoby Ryan J. , Manoach Dara S. , Wilhelm Sabine
Published: September 2023

Background

Effective biomarkers of cognitive behavioral therapy (CBT) response provide information beyond available behavioral or self-report measures and may optimize treatment selection for patients based on likelihood of benefit. No single biomarker reliably predicts CBT response. In this study, we evaluated patterns of brain connectivity associated with self-focused attention (SFA) as biomarkers of CBT response for anxiety and obsessive-compulsive disorders. We hypothesized that pre-treatment as well as pre- to post-treatment changes in functional connectivity would be associated with improvement during CBT in a transdiagnostic sample.

Methods

Twenty-seven patients with primary social anxiety disorder (n=14) and primary body dysmorphic disorder (n=13) were scanned before and after 12 sessions of CBT targeting their primary disorder. Eligibility was based on elevated trait SFA scores on the Public Self-Consciousness Scale. Seed-based resting state functional connectivity associated with symptom improvement was computed using a seed in the posterior cingulate cortex/precuneus that delineated a self-other functional network.

Results

At pre-treatment, stronger positive connectivity of the seed with the cerebellum, insula, middle occipital gyrus, postcentral gyrus, and precuneus/superior parietal lobule, and stronger negative connectivity with the putamen, were associated with greater clinical improvement. Between pre- to post-treatment, greater anticorrelation between the seed and precuneus/superior parietal lobule was associated with clinical improvement, although this did not survive thresholding.

Conclusions

Pre-treatment functional connectivity between regions involved in attentional salience, self-generated thoughts, and external attention predicted greater CBT response. Behavioral and self-report measures of SFA did not contribute to predictions, thus highlighting the value of neuroimaging-based measures of SFA.

Clinical Trials Registration

ClinicalTrials.gov Identifier:NCT02808702https://clinicaltrials.gov/ct2/show/NCT02808702
COVID-19-related school closures, United States, July 27, 2020 – June 30, 2022
Authors: Zviedrite Nicole , Jahan Ferdous , Moreland Sarah , Ahmed Faruque , Uzicanin Amra
Published: September 2023

As part of a multi-year project that monitored illness-related school closures, we conducted systematic daily online searches from July 27, 2020–June 30, 2022, to identify public announcements of COVID-19-related school closures (COVID-SCs) in the US lasting ≥1 day. We explored the temporospatial patterns of COVID-SCs and analyzed associations between COVID-SCs and national COVID-19 surveillance data. COVID-SCs reflected national surveillance data: correlation was highest between COVID-SCs and both new PCR test positivity (correlation coefficient, r = 0·73, CI: 0·56, 0·84) and new cases (r = 0·72, CI: 0·54, 0·83) in school year (SY) 2020-21, and with hospitalization rates among all ages (rs = 0·81, CI: [0·67, 0·89]) in SY 2021-22. The number of reactive COVID-SCs during SYs 2020-21 and 2021-22 greatly exceeded previously observed numbers of illness-related reactive school closures in the US, notably being nearly 5-fold greater than reactive closures observed during the 2009 H1N1 Pandemic (H1N1pdm09 virus).

Article summary line

COVID-19-related school closures occurred annually in the US and their temporal patterns mirror the general patterns of COVID-19 activity at the national level as observed through routine COVID-19 epidemiological surveillance.
Contrast sensitivity: a fundamental limit to vision restoration after V1 damage
Authors: Yang Jingyi , Saionz Elizabeth L. , Cavanaugh Matthew R. , Fahrenthold Berkeley K. , Melnick Michael D. , Tadin Duje , Briggs Farran , Carrasco Marisa , Huxlin Krystel R.
Published: September 2023

Stroke damage to the primary visual cortex (V1) causes severe visual deficits, which benefit from perceptual retraining. However, whereas training with high-contrast stimuli can locally restore orientation and direction discrimination abilities at trained locations, it only partially restores luminance contrast sensitivity (CS). Recent work revealed that high-contrast discrimination abilities may be preserved in the blind field of some patients early after stroke. Here, we asked if CS for orientation and direction discrimination is similarly preserved inside the blind field, to what extent, and whether it could benefit from a visual training intervention. Thirteen subacute (<3 months post-V1-stroke) and 12 chronic (>6 months post-V1-stroke) participants were pre-tested, then trained to discriminate either orientation or motion direction of Gabor patches of progressively lower contrasts. At baseline, more subacute than chronic participants could correctly discriminate the orientation of high-contrast Gabors in their blind field, but all failed to perform this task at lower contrasts, even when 10Hz flicker or motion direction were added. Training improved CS in a greater portion of subacute than chronic participants, but no-one attained normal CS, even when stimuli contained flicker or motion. We conclude that, unlike the near-complete training-induced restoration of high-contrast orientation and direction discrimination, there is limited capacity for restoring CS after V1 damage in adulthood. Our results suggest that CS involves different neural substrates and computations than those required for orientation and direction discrimination in V1-damaged visual systems.

Significance statement

Stroke-induced V1 damage in adult humans induces a rapid and severe impairment of contrast sensitivity for orientation and direction discrimination in the affected hemifield, although discrimination of high-contrast stimuli can persist for months. Adaptive training with Gabor patches of progressively lower contrasts improves contrast sensitivity for these discriminations in the blind-field of both subacute (<3 months post-stroke) and chronic (>6 months post-stroke) participants, although it fails to restore fully-normal contrast sensitivity. Nonetheless, more subacute than chronic stroke participants benefit from such training, particularly when discriminating the orientation of static, non-flickering targets. Thus, contrast sensitivity appears critically dependent on processing within V1, with perceptual training displaying limited potential to fully restore it after V1 damage.
Validating risk prediction models for multiple primaries and competing cancer outcomes in families with Li-Fraumeni syndrome using clinically ascertained data at a single institute
Authors: Nguyen Nam H. , Dodd-Eaton Elissa B. , Corredor Jessica L. , Woodman-Ross Jacynda , Green Sierra , Hernandez Nathaniel D. , Gutierrez Barrera Angelica M. , Arun Banu K. , Wang Wenyi
Published: September 2023

Purpose

There exists a barrier between developing and disseminating risk prediction models in clinical settings. We hypothesize this barrier may be lifted by demonstrating the utility of these models using incomplete data that are collected in real clinical sessions, as compared to the commonly used research cohorts that are meticulously collected.

Patients and methods

Genetic counselors (GCs) collect family history when patients (i.e., probands) come to MD Anderson Cancer Center for risk assessment of Li-Fraumeni syndrome, a genetic disorder characterized by deleterious germline mutations in theTP53gene. Our clinical counseling-based (CCB) cohort consists of 3,297 individuals across 124 families (522 cases of single primary cancer and 125 cases of multiple primary cancers). We applied our software suite LFSPRO to make risk predictions and assessed performance in discrimination using area under the curve (AUC), and in calibration using observed/expected (O/E) ratio.

Results

For prediction of deleteriousTP53mutations, we achieved an AUC of 0.81 (95% CI, 0.70 – 0.91) and an O/E ratio of 0.96 (95% CI, 0.70 – 1.21). Using the LFSPRO.MPC model to predict the onset of the second cancer, we obtained an AUC of 0.70 (95% CI, 0.58 – 0.82). Using the LFSPRO.CS model to predict the onset of different cancer types as the first primary, we achieved AUCs between 0.70 and 0.83 for sarcoma, breast cancer, or other cancers combined.

Conclusion

We describe a study that fills in the critical gap in knowledge for the utility of risk prediction models. Using a CCB cohort, our previously validated models have demonstrated good performance and outperformed the standard clinical criteria. Our study suggests better risk counseling may be achieved by GCs using these already-developed mathematical models.
Supervised Learning for CT Denoising and Deconvolution Without High-Resolution Reference Images
Authors: Missert Andrew D. , Hsieh Scott S. , Ferrero Andrea , McCollough Cynthia H.
Published: September 2023

Purpose

Convolutional neural networks (CNNs) have been proposed for super-resolution in CT, but training of CNNs requires high-resolution reference data. Higher spatial resolution can also be achieved using deconvolution, but conventional deconvolution approaches amplify noise. We develop a CNN that mitigates increasing noise and that does not require higher-resolution reference images.

Methods

Our model includes a noise reduction CNN and a deconvolution CNN that are separately trained. The noise reduction CNN is a U-Net, similar to other noise reduction CNNs found in the literature. The deconvolution CNN uses an autoencoder, where the decoder is fixed and provided as a hyperparameter that represents the system point spread function. The encoder is trained to provide a deconvolution that does not amplify noise. Ringing can occur from deconvolution but is controlled with a difference of gradients loss function term. Our technique was demonstrated on a variety of patient images and on ex vivo kidney stones.

Results

The noise reduction and deconvolution CNNs produced visually sharper images at low noise. In ex vivo mixed kidney stones, better visual delineation of the kidney stone components could be seen.

Conclusions

A noise reduction and deconvolution CNN improves spatial resolution and reduces noise without requiring higher-resolution reference images.
Comparison of disability level between Early and Late Onset Parkinson’s Disease using WHODAS 2
Authors: Nascimento Isaíra Almeida Pereira da Silva , Costa Nobrega Kátia Cirilo , Antunes Souza Bruno Rafael , Barone Isabela Carneiro , Checchio Giovanna , Ponciano Vitória Pereira , de Paula Clara Greif Cerveira , Possani Arieni Nunes , Penha Natália Cardoso , Helene André Frazão , Roque Antonio Carlos , Savica Rodolfo , Pimentel Piemonte Maria Elisa
Published: September 2023

Background

Parkinson’s disease (PD) is a degenerative neurological disorder that usually affects people over the age of 60. However, 10-20% of patients have an early onset of PD (EOPD).

Objectives

To compare disability levels according to the World Health Organization Disability Assessment Schedule 2.0 (WHODAS-2) between people with EOPD and those with late-onset PD (LOPD).

Methods

We conducted a cross-sectional study with 95 EOPD patients (mean-age 44.51±4.63, H&Y 1.93±0.93) and 255 LOPD patients (mean-age 63.01±7.99, H&Y 2.02±0.95). Demographic information, clinical characteristics, cognitive evaluation by Telephone-Montreal-Cognitive-Assessment (T-MoCA), functionality self-evaluation by WHODAS-2 and the Unified-Parkinson’s-Disease-Rating-Scale (MDS-UPDRS), parts I and II, were documented for each patient by an individual remote interview.

Results

Analysis showed a statistically significant difference between EOPD and LOPD in the cognition and activities of daily-living-related to work/school domains of WHODAS-2. T-MoCA scores confirmed more impaired cognition capacity in LOPD. The two groups had no significant differences in levodopa daily dosage, Hoehn and Yahr (H&Y) stages, disease time duration, and MDS-UPDRS I and II scores.

Conclusion

People living with EOPD face similar disability levels as those with LOPD, except for cognition, where LOPD patients exhibited higher levels of disability than EOPD and for work activities where the EOPD exhibited higher levels of disability than LODP. These results highlight the challenges faced by people with EOPD in interacting with society and living with the disease for a longer time. The WHODAS-2 can be a useful tool to assess disability and tailor interventions for people with PD of different age groups.
Representing multimorbid disease progressions using directed hypergraphs
Authors: Burke Jamie , Akbari Ashley , Bailey Rowena , Fasusi Kevin , Lyons Ronan A. , Pearson Jonathan , Rafferty James , Schofield Daniel
Published: September 2023

Objective

To introduce directed hypergraphs as a novel tool for assessing the temporal relationships between coincident diseases, addressing the need for a more accurate representation of multimorbidity and leveraging the growing availability of electronic healthcare databases and improved computational resources.

Methods

Directed hypergraphs offer a high-order analytical framework that goes beyond the limitations of directed graphs in representing complex relationships such as multimorbidity. We apply this approach to multimorbid disease progressions observed from two multimorbidity sub-cohorts of the SAIL Databank, after having been filtered according to the Charlson and Elixhauser comorbidity indices, respectively. After constructing a novel weighting scheme based on disease prevalence, we demonstrate the power of these higher-order models through the use of PageRank centrality to detect and classify the temporal nature of conditions within the two comorbidity indices.

Results

In the Charlson population, we found that chronic pulmonary disease (CPD), cancer and diabetes were conditions observed early in a patient’s disease progression (predecessors), with stroke and dementia appearing later on (successors) and myocardial infarction acting as a transitive condition to renal failure and congestive heart failure. In Elixhauser, we found renal failure, neurological disorders and arrhythmia were classed as successors and hypertension, depression, CPD and cancer as predecessors, with diabetes becoming a transitive condition in the presence of obesity and alcohol abuse. The dynamics of these and other conditions changed across age and sex but not across deprivation. Unlike the directed graph, the directed hypergraph could model higher-order disease relationships, which translated into stronger classifications between successor and predecessor conditions, alongside the removal of spurious results.

Conclusion

This study underscores the utility of directed hypergraphs as a powerful approach to investigate and assess temporal relationships among coincident diseases. By overcoming the limitations of traditional pairwise models, directed hypergraphs provide a more accurate representation of multimorbidity, offering insights that can significantly contribute to healthcare decision-making, resource allocation, and patient management. Further research holds promise for advancing our understanding of critical issues surrounding multimorbidity and its implications for healthcare systems.
Exact calculation of end-of-outbreak probabilities using contact tracing data
Authors: Bradbury NV , Hart WS , Lovell-Read FA , Polonsky JA , Thompson RN
Published: September 2023

A key challenge for public health policy makers is determining when an infectious disease outbreak has finished. Following a period without cases, an estimate of the probability that no further cases will occur in future (the end-of-outbreak probability) can be used to inform whether or not to declare an outbreak over. An existing quantitative approach, based on a branching process transmission model, allows the end-of-outbreak probability to be approximated from disease incidence time series, the offspring distribution and the serial interval of the pathogen (the Nishiura method). Here, we show how the end-of-outbreak probability under the same transmission model can be calculated exactly if data describing who-infected-whom (the outbreak transmission tree) are available alongside the disease incidence time series. When such data are available, for example from contact tracing studies, our novel approach (the traced transmission method) is straightforward to use. We demonstrate this by applying the traced transmission method to data from previous outbreaks of Ebola virus disease and Nipah virus infection. For both outbreak datasets considered, we find that the traced transmission method would have determined that the outbreak was over more quickly than the Nishiura method. This highlights that consideration of contact tracing data may allow stringent control interventions to be relaxed quickly at the end of an outbreak, with only a limited risk of outbreak resurgence.
Benefit-Risk Assessment of Medical Products Using Bayesian Multi-Criteria Augmented Decision Analysis for Clinical Development
Authors: Vuong Quang , Metcalfe Rebecca K , Harari Ofir , Mills Edward J , Park Jay JH
Published: September 2023

Multi-criteria decision analysis (MCDA) is a benefit-risk assessment tool that evaluates multiple competing benefit and risk endpoints simultaneously. MCDA has the potential to aid sponsors in making effective and informed go/no-go decisions for clinical development programs. MCDA involves assigning weights to benefit and risk endpoints based on their relative importance (i.e., utility weight) and using them to compute a single utility score that represents the overall benefit-risk profile of the treatment. However, to date, MCDA applications have not been appropriate for time-to-event data. In this paper, we introduce a novel framework known as Bayesian Multi-Criteria Augmented Decision Analysis (MCADA) that extends existing probabilistic MCDA methods to encompass time-to-event and ordinal outcomes while incorporating linear and novel non-linear functions in utility aggregation. This paper provides a comprehensive description of the statistical methodology behind the MCADA framework and demonstrates its application using a simulation study, as well as two clinical trials using IPD and aggregate data. Our simulation study found that MCADA generally achieves higher power than the existing MCDA methods due to avoidance of loss of information that occurs when survival and ordinal outcomes are dichotomized. Our two case studies show that the MCADA framework can be effectively used to produce a single utility score that reflects the overall benefit-risk profile of a treatment using both IPD and aggregate data from trials. MCADA broadens the horizon of the current MCDA framework by accommodating a wider range of data types and utility functions in the utility aggregation process.
Na+/K+ATPase-Cav1.2 nanodomain differentially regulates intracellular [Na+], [Ca2+] and local adrenergic signaling in cardiac myocytes
Authors: Karbowski Mariusz , Boyman Liron , Garber Libet , Joca Humberto C. , Verhoeven Nicolas , Coleman Andrew K. , Ward Christopher W. , Lederer W. Jonathan , Greiser Maura
Published: September 2023

Background

The intracellular Na+concentration ([Na+]i) is a crucial but understudied regulator of cardiac myocyte function. The Na+/K+ATPase (NKA) controls the steady-state [Na+]iand thereby determines the set-point for intracellular Ca2+. Here, we investigate the nanoscopic organization and local adrenergic regulation of the NKA macromolecular complex and how it differentially regulates the intracellular Na+and Ca2+homeostases in atrial and ventricular myocytes.

Methods

Multicolor STORM super-resolution microscopy, Western Blot analyses, and in vivo examination of adrenergic regulation are employed to examine the organization and function of Na+nanodomains in cardiac myocytes. Quantitative fluorescence microscopy at high spatiotemporal resolution is used in conjunction with cellular electrophysiology to investigate intracellular Na+homeostasis in atrial and ventricular myocytes.

Results

The NKAα1 (NKAα1) and the L-type Ca2+-channel (Cav1.2) form a nanodomain with a center-to center distance of ∼65 nm in both ventricular and atrial myocytes. NKAα1 protein expression levels are ∼3 fold higher in atria compared to ventricle. 100% higher atrial INKA, produced by large NKA “superclusters”, underlies the substantially lower Na+concentration in atrial myocytes compared to the benchmark values set in ventricular myocytes. The NKA’s regulatory protein phospholemman (PLM) has similar expression levels across atria and ventricle resulting in a much lower PLM/NKAα1 ratio for atrial compared to ventricular tissue. In addition, a huge PLM phosphorylation reserve in atrial tissue produces a high ß-adrenergic sensitivity of INKAin atrial myocytes. ß-adrenergic regulation of INKAis locally mediated in the NKAα1-Cav1.2 nanodomain via A-kinase anchoring proteins.

Conclusions

NKAα1, Cav1.2 and their accessory proteins form a structural and regulatory nanodomain at the cardiac dyad. The tissue-specific composition and local adrenergic regulation of this “signaling cloud” is a main regulator of the distinct global intracellular Na+and Ca2+concentrations in atrial and ventricular myocytes.
Electrostatic modulation of signaling at cell membrane: Waveform- and time-dependent electric control of ERK dynamics
Authors: Hu Minxi , Li Houpu , Zhu Kan , Guo Liang , Zhao Min , Zhan Huiwang , Devreotes Peter N. , Qing Quan
Published: September 2023

Different exogenous electric fields (EF) can guide cell migration, disrupt proliferation, and program cell development. Studies have shown that many of these processes were initiated at the cell membrane, but the mechanism has been unclear, especially for conventionally non-excitable cells. In this study, we focus on the electrostatic aspects of EF coupling with the cell membrane by eliminating Faradaic processes with dielectric-coated microelectrodes, and show that the ERK signaling pathway of epithelial cells (MCF10A) can be both inhibited and activated by AC EF with different amplitude thresholds, peaking times and refractory periods. Interestingly, the ERK responses were sensitive to the waveform and timing of EF stimulation pulses, depicting the characteristics of electrostatic and dissipative interactions. Blocker tests and correlated changes of active Ras on the cell membrane with ERK signals indicated that both EGFR and Ras were involved in the rich ERK dynamics induced by EF. We propose that the frequency-dependent dielectric relaxation process could be an important mechanism to couple EF energy to the cell membrane region and modulate membrane protein-initiated signaling pathways, which can be further explored to precisely control cell behavior and fate with high temporal and spatial resolution.
Short-term consumption of ultra-processed semi-synthetic diets impairs the sense of smell and brain metabolism in mice
Authors: Makhlouf Melanie , Souza Débora G. , Kurian Smija , Bellaver Bruna , Ellis Hillary , Kuboki Akihito , Al-Naama Asma , Hasnah Reem , Venturin Gianina Teribele , da Costa Jaderson Costa , Venugopal Neethu , Manoel Diogo , Reisert Johannes , Tordoff Michael G. , Zimmer Eduardo R. , Saraiva Luis R.
Published: September 2023

The prevalence of highly-palatable, ultra-processed food in our modern diet has exacerbated obesity rates and contributed to a global health crisis. While accumulating evidence suggests that chronic consumption of ultra-processed semi-synthetic food is detrimental to sensory and neural physiology, it is unclear whether its short-term intake has adverse effects. Here, we assessed how short-term consumption (<2 months) of three ultra-processed diets (one grain-based diet, and two semi-synthetic) influence olfaction and brain metabolism in mice. Our results demonstrate that short-term consumption of semi-synthetic diets, regardless of macronutrient composition, adversely affect odor-guided behaviors, physiological responses to odorants, transcriptional profiles in the olfactory mucosa and brain regions, and brain glucose metabolism and mitochondrial respiration. These findings reveal that even short periods of ultra-processed semi-synthetic food consumption are sufficient to cause early olfactory and brain abnormalities, which has the potential to alter food choices and influence the risk of developing metabolic disease.
Modelling cognitive outcomes in the UK Biobank: education, noradrenaline and frontoparietal networks
Authors: Bravo-Merodio Laura , Williams Jackie A. , Russ Dominic , Gkoutos Georgios , Brosnan Meadhbh , Bellgrove Mark A. , Chechlacz Magdalena
Published: September 2023

Cognitive reserve (CR) measured by proxies of life experiences is thought to account for the heterogeneity in cognitive ageing. One hypothesis is that cognitively enriched environments acting on the noradrenergic system strengthen the right fronto-parietal networks to facilitate cognitive reserve and maintain cognition throughout the lifetime. We used machine learning and mediation analysis to model interactions between neurobiological features (genetic variants in noradrenergic signalling, structural and functional fronto-parietal connectivity) and CR (by proxy of education) on cognitive outcomes (general cognitive ability score) in the UK Biobank cohort. We show that: (1) interactions between CR and neurobiological variables more fully explain cognitive outcomes than either factor alone; (2) among the neurobiological features selected using variable importance testing, measures of fronto-parietal connectivity are the strongest mediators of the effect of CR on cognitive outcomes. Our findings offer novel insights into neurobiological basis of CR by pointing to two between-networks connectivity measures, representing connections linking the default mode network with the right fronto-parietal network, and with the executive control network, as the key facilitators of CR.
“Dark taxonomy”: a new protocol for overcoming the taxonomic impediments for dark taxa and broadening the taxon base for biodiversity assessment
Authors: Meier Rudolf , Srivathsan Amrita , Oliveira Sarah Siqueira , Balbi Maria Isabel P.A. , Ang Yuchen , Yeo Darren , Kjærandsen Jostein , Amorim Dalton de Souza
Published: September 2023

We are entering the 6thmass extinction with little data for “dark taxa” although they comprise most species. Much of the neglect is due to the fact that conventional taxonomic methods struggle with handling thousands of specimens belonging to hundreds of species. We thus here propose a new strategy that we call “dark taxonomy.” It addresses (1) taxonomic impediments, (2) lack of biodiversity baselines, (3) and low impact of revisionary research. Taxonomic impediments are reduced by carrying out revisions at small geographic scales to keep the number of specimens low. The risk of taxonomic error is kept low by delimiting species based on two types of data. We then show that dark taxonomy can yield important biodiversity baseline data because it uses samples obtained with biomonitoring traps. Lastly, we argue that the impact of research can be improved by publishing two manuscripts addressing different readerships. The principles of dark taxonomy are illustrated by our taxonomic treatment of Singapore’s fungus gnats (Mycetophilidae) based only on Malaise trap samples. We show that a first batch of specimens (N=1,454) contains 120 species, of which 115 are new to science thus reducing taxonomic impediments by increasing the number of described Oriental species by 25%. Species delimitation started with using DNA barcodes to estimate the number of MOTUs before “LIT” (Large-scale Integrative Taxonomy) was used to obtain the species boundaries for the 120 species by integrating morphological and molecular data. To test the taxonomic completeness of the revision, we then analyzed a second batch of 1,493 specimens and found that >97% belonged to the 120 species described based on the first batch. Indeed, the second batch only contained 18 new and rare MOTUs; i.e. our study suggests that a single revision can simultaneously yield the names for all important species and relevant biodiversity baseline data. Overall, we believe that “dark taxonomy” can quickly ready a large unknown taxon for biomonitoring.
SpatialDDLS: An R package to deconvolute spatial transcriptomics data using neural networks
Authors: Mañanes Diego , Rivero-García Inés , Jimenez-Carretero Daniel , Torres Miguel , Sancho David , Torroja Carlos , Sánchez-Cabo Fátima
Published: September 2023

Spatial transcriptomics has changed our way to study tissue structure and cellular organization. However, there are still limitations in its resolution, and most available plaXorms do not reach a single cell resolution. To address this issue, we introduce SpatialDDLS, a fast neural network-based algorithm for cell type deconvolution of spatial transcriptomics data. SpatialDDLS leverages single-cell RNA sequencing (scRNA-seq) data to simulate mixed transcriptional profiles with predefined cellular composition, which are subsequently used to train a fully-connected neural network to uncover cell type diversity within each spot. By comparing it with two state-of-the-art spatial deconvolution methods, we demonstrate that SpatialDDLS is an accurate and faster alternative to the available state-of-the art tools.

Availability and implementation

The R package SpatialDDLS is available via CRAN-The Comprehensive R Archive Network:https://CRAN.R-project.org/package=SpatialDDLS. A detailed manual of the main functionalities implemented in the package can be found athttps://diegommcc.github.io/SpatialDDLS.

Contact

fscabo@cnic.es

Supplementary information

Supplementary data are available at Bioinformatics online.
PlasmidEC and gplas2: An optimised short-read approach to predict and reconstruct antibiotic resistance plasmids inEscherichia coli
Authors: Paganini Julian A. , Kerkvliet Jesse J. , Vader Lisa , Plantinga Nienke L. , Meneses Rodrigo , Corander Jukka , Willems Rob J.L. , Arredondo-Alonso Sergio , Schürch Anita C.
Published: September 2023

Accurate reconstruction ofEscherichia coliantibiotic resistance gene (ARG) plasmids from Illumina sequencing data has proven to be a challenge with current bioinformatic tools. In this work, we present an improved method to reconstructE. coliplasmids using short reads. We developed plasmidEC, an ensemble classifier that identifies plasmid-derived contigs by combining the output of three different binary classification tools. We showed that plasmidEC is especially suited to classify contigs derived from ARG plasmids with a high recall of 0.941. Additionally, we optimised gplas, a graph-based tool that bins plasmid-predicted contigs into distinct plasmid predictions. Gplas2 is more effective at recovering plasmids with large sequencing coverage variations and can be combined with the output of any binary classifier. The combination of plasmidEC with gplas2 showed a high completeness (median=0.818) and F1-score (median=0.812) when reconstructing ARG plasmids and exceeded the binning capacity of the reference-based method MOB-suite. In the absence of long read data, our method offers an excellent alternative to reconstruct ARG plasmids inE. coli.

Data Summary

No new sequencing data have been generated in this study. All genomes used in this research are publicly available at the GenBank and Sequence Read Archive of the National Center for Biotechnology Information. Accession numbers are specified in Supplementary Materials.

Scripts to reproduce the results reported in this manuscript can be accessed athttps://gitlab.com/jpaganini/ecoli-binary-classifier. The ensemble classifier, plasmidEC, is publicly available athttps://gitlab.com/mmb-umcu/plasmidEC(release 1.3.1), and gplas2 (release 1.0.0) can be found athttps://gitlab.com/mmb-umcu/gplas2.

Impact Statement

Escherichia colihas emerged as a highly pervasive multidrug resistant pathogen on a global scale. The dissemination of resistance is significantly influenced by plasmids, mobile genetic elements that facilitate the transfer of antimicrobial resistance genes within and between diverse bacterial species. Consequently, precise and high-throughput identification of plasmids is imperative for effective genomic surveillance of resistance. However, accurate plasmid reconstruction remains challenging with the use of affordable short-read sequencing data. In this work, we present a novel method to accurately predict and reconstructE. coliplasmids based on Illumina data. Additionally, we demonstrate that our approach outperforms the reference-based method MOB-suite, especially when reconstructing plasmids carrying antimicrobial resistance genes.