bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of institutional prophylaxis guidelines on rates of pediatric venous thromboembolism following trauma—A multicenter study from the pediatric trauma society research committee
Authors: Labuz Daniel F. , Tobias Joseph , Selesner Leigh , Han XiaoYue , Cunningham Aaron , Marenco Christopher W. , Escobar Mauricio A. , Hazeltine Max D. , Cleary Muriel A. , Kotagal Meera , Falcone Richard A. , Vogel Adam M. , MacArthur Taleen , Klinkner Denise B. , Shah Aashka , Chernoguz Artur , Orioles Alberto , Zagel Alicia , Gosain Ankush , Knaus Maria , Hamilton Nicholas A. , Jafri Mubeen A.
Published: March 2023

BACKGROUND

A paucity of data exists with regard to the incidence, management, and outcomes of venous thromboembolism (VTE) in injured children. We sought to determine the impact of institutional chemoprophylaxis guidelines on VTE rates in a pediatric trauma population.

METHODS

A retrospective review of injured children (≤15 years) admitted between 2009 and 2018 at 10 pediatric trauma centers was performed. Data were gathered from institutional trauma registries and dedicated chart review. The institutions were surveyed as to whether they had chemoprophylaxis guidelines in place for high-risk pediatric trauma patients, and outcomes were compared based on the presence of guidelines using χ2 analysis (p < 0.05).

RESULTS

There were 45,202 patients evaluated during the study period. Three institutions (28,359 patients, 63%) had established chemoprophylaxis policies during the study period (“Guidelines”); the other seven centers (16,843 patients, 37%) had no such guidelines (“Standard”). There were significantly lower rates of VTE in the Guidelines group, but these patients also had significantly fewer risk factors. Among critically injured children with similar clinical presentations, there was no difference in VTE rate. Specifically within the Guidelines group, 30 children developed VTE. The majority (17/30) were actually not indicated for chemoprophylaxis based on institutional guidelines. Still, despite protocols only one VTE patient in the guidelines group who was indicated for intervention ended up receiving chemoprophylaxis prior to diagnosis. No consistent ultrasound screening protocol was in place at any institution during the study.

CONCLUSION

The presence of an institutional policy to guide chemoprophylaxis for injured children is associated with a decreased overall frequency of VTE, but this disappears when controlling for patient factors. However, the overall efficacy is impacted by a combination of deficits in guideline compliance and structure. Further prospective data are needed to help determine the ideal role for chemoprophylaxis and protocols in pediatric trauma.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level IV.
A Machine Learning Prediction Model for Immediate Graft Function After Deceased Donor Kidney Transplantation
Authors: Quinino Raquel M. , Agena Fabiana , Modelli de Andrade Luis Gustavo , Furtado Mariane , Chiavegatto Filho Alexandre D.P. , David-Neto Elias
Published: March 2023

Background.

After kidney transplantation (KTx), the graft can evolve from excellent immediate graft function (IGF) to total absence of function requiring dialysis. Recipients with IGF do not seem to benefit from using machine perfusion, an expensive procedure, in the long term when compared with cold storage. This study proposes to develop a prediction model for IGF in KTx deceased donor patients using machine learning algorithms.

Methods.

Unsensitized recipients who received their first KTx deceased donor between January 1, 2010, and December 31, 2019, were classified according to the conduct of renal function after transplantation. Variables related to the donor, recipient, kidney preservation, and immunology were used. The patients were randomly divided into 2 groups: 70% were assigned to the training and 30% to the test group. Popular machine learning algorithms were used: eXtreme Gradient Boosting (XGBoost), Light Gradient Boosting Machine, Gradient Boosting classifier, Logistic Regression, CatBoost classifier, AdaBoost classifier, and Random Forest classifier. Comparative performance analysis on the test dataset was performed using the results of the AUC values, sensitivity, specificity, positive predictive value, negative predictive value, and F1 score.

Results.

Of the 859 patients, 21.7% (n = 186) had IGF. The best predictive performance resulted from the eXtreme Gradient Boosting model (AUC, 0.78; 95% CI, 0.71–0.84; sensitivity, 0.64; specificity, 0.78). Five variables with the highest predictive value were identified.

Conclusions.

Our results indicated the possibility of creating a model for the prediction of IGF, enhancing the selection of patients who would benefit from an expensive treatment, as in the case of machine perfusion preservation.
Nonrapid Eye Movement Parasomnias
Authors: Augustine Ann
Published: March 2023

Non-REM parasomnias are often observed during childhood and adolescence, by which time they typically remit. For a small percentage, these nocturnal behaviors can persist into adulthood, or in some cases, present as a new onset in adults. Non-REM parasomnias (also known as disorders of arousal) can offer a diagnostic challenge in patients who have an atypical presentation where REM sleep parasomnias, nocturnal frontal lobe epilepsy, and overlap parasomnia should be considered as part of the differential. The purpose of this review is to discuss the clinical presentation, evaluation, and management of non-REM parasomnias. The neurophysiology behind non-REM parasomnias is considered, and this gives insights into their cause and the potential for treatment.
Measuring rhythms of vocal interactions: a proof of principle in harbour seal pups
Authors: Anichini Marianna , de Reus Koen , Hersh Taylor A. , Valente Daria , Salazar-Casals Anna , Berry Caroline , Keller Peter E. , Ravignani Andrea
Published: March 2023

Rhythmic patterns in interactive contexts characterize human behaviours such as conversational turn-taking. These timed patterns are also present in other animals, and often described as rhythm. Understanding fine-grained temporal adjustments in interaction requires complementary quantitative methodologies. Here, we showcase how vocal interactive rhythmicity in a non-human animal can be quantified using a multi-method approach. We record vocal interactions in harbour seal pups (
Phoca vitulina
) under controlled conditions. We analyse these data by combining analytical approaches, namely categorical rhythm analysis, circular statistics and time series analyses. We test whether pups' vocal rhythmicity varies across behavioural contexts depending on the absence or presence of a calling partner. Four research questions illustrate which analytical approaches are complementary versus orthogonal. For our data, circular statistics and categorical rhythms suggest that a calling partner affects a pup's call timing. Granger causality suggests that pups predictively adjust their call timing when interacting with a real partner. Lastly, the ADaptation and Anticipation Model estimates statistical parameters for a potential mechanism of temporal adaptation and anticipation. Our analytical complementary approach constitutes a proof of concept; it shows feasibility in applying typically unrelated techniques to seals to quantify vocal rhythmic interactivity across behavioural contexts.

This article is part of a discussion meeting issue ‘Face2face: advancing the science of social interaction’.
Face to face interactions in chimpanzee (
Pan troglodytes
) and human (
Homo sapiens
) mother–infant dyads
Authors: Amici Federica , Ersson-Lembeck Manuela , Holodynski Manfred , Liebal Katja
Published: March 2023

Human mothers interact with their infants in different ways. In Western, educated, industrialized, rich and democratic (WEIRD) societies, face-to-face interactions and mutual gazes are especially frequent, yet little is known about their developmental trajectories and if they differ from those of other primates. Using a cross-species developmental approach, we compared mother–infant interactions in 10 dyads of urban humans from a WEIRD society (
Homo sapiens
) and 10 dyads of captive zoo-based chimpanzees (
Pan troglodytes
), when infants were one, six and 12 months old. Results showed that face-to-face interactions with mutual gaze events were common in both groups throughout the infant's first year of life. The developmental trajectories of maternal and infants’ looks partially differed between species, but mutual gaze events were overall longer in humans than in chimpanzees. Mutual gazes were also more frequent in humans, peaking at six months in humans, while increasing with age in chimpanzees. The duration and frequency of mutual gazes varied across contexts in both groups, with mutual gazes being longer during caring/grooming and feeding contexts. These findings confirm that some aspects of early socio-cognitive development are shared by humans and other primates, and highlight the importance of combining developmental and cross-species approaches to better understand the evolutionary roots of parenting behaviour.

This article is part of a discussion meeting issue ‘Face2face: advancing the science of social interaction’.
Quirky conversations: how people with a diagnosis of schizophrenia do dialogue differently
Authors: Howes Christine , Lavelle Mary
Published: March 2023

People with a diagnosis of schizophrenia (PSz) have difficulty engaging in social interaction, but little research has focused on dialogues involving PSz interacting with partners who are unaware of their diagnosis. Using quantitative and qualitative methods on a unique corpus of triadic dialogues of PSz first social encounters, we show that turn-taking is disrupted in dialogues involving a PSz. Specifically, there are on average longer gaps between turns in groups which contain a PSz compared to those which do not, particularly when the speaker switch occurs from one control (C) participant to the other. Furthermore, the expected link between gesture and repair is not present in dialogues with a PSz, particularly for C participants interacting with a PSz. As well as offering some insights into how the presence of a PSz affects an interaction, our results also demonstrate the flexibility of our mechanisms for interaction.

This article is part of a discussion meeting issue ‘Face2face: advancing the science of social interaction’.
Beyond speaking: neurocognitive perspectives on language production in social interaction
Authors: Kuhlen Anna K. , Abdel Rahman Rasha
Published: March 2023

The human faculty to speak has evolved, so has been argued, for communicating with others and for engaging in social interactions. Hence the human cognitive system should be equipped to address the demands that social interaction places on the language production system. These demands include the need to coordinate speaking with listening, the need to integrate own (verbal) actions with the interlocutor's actions, and the need to adapt language flexibly to the interlocutor and the social context. In order to meet these demands, core processes of language production are supported by cognitive processes that enable interpersonal coordination and social cognition. To fully understand the cognitive architecture and its neural implementation enabling humans to speak in social interaction, our understanding of how humans produce language needs to be connected to our understanding of how humans gain insights into other people's mental states and coordinate in social interaction. This article reviews theories and neurocognitive experiments that make this connection and can contribute to advancing our understanding of speaking in social interaction.

This article is part of a discussion meeting issue ‘Face2face: advancing the science of social interaction’.
How video calls affect mimicry and trust during interactions
Authors: Diana Fabiola , Juárez-Mora Oscar E. , Boekel Wouter , Hortensius Ruud , Kret Mariska E.
Published: March 2023

Many social species, humans included, mimic emotional expressions, with important consequences for social bonding. Although humans increasingly interact via video calls, little is known about the effect of these online interactions on the mimicry of scratching and yawning, and their linkage with trust. The current study investigated whether mimicry and trust are affected by these new communication media. Using participant-confederate dyads (
n
= 27), we tested the mimicry of four behaviours across three different conditions: watching a pre-recorded video, online video call, and face-to-face. We measured mimicry of target behaviours frequently observed in emotional situations, yawn and scratch and control behaviours, lip-bite and face-touch. In addition, trust in the confederate was assessed via a trust game. Our study revealed that (i) mimicry and trust did not differ between face-to-face and video calls, but were significantly lower in the pre-recorded condition; and (ii) target behaviours were significantly more mimicked than the control behaviours. This negative relationship can possibly be explained by the negative connotation usually associated with the behaviours included in this study. Overall, this study showed that video calls might provide enough interaction cues for mimicry to occur in our student population and during interactions between strangers.

This article is part of a discussion meeting issue ‘Face2face: advancing the science of social interaction’.
Heritability and gene functions associated with sclerotia formation of Rhizoctonia solani AG-7 using whole genome sequencing and genome-wide association study
Authors: Lin Yu-Cheng , Liu Hsien-Hao , Tseng Min-Nan , Chang Hao-Xun
Published: March 2023

Sclerotia are specialized fungal structures formed by pigmented and aggregated hyphae, which can survive under unfavourable environmental conditions and serve as the primary inocula for several phytopathogenic fungi includingRhizoctonia solani. Among 154R.solanianastomosis group 7 (AG-7) isolates collected in fields, the sclerotia-forming capability regarding sclerotia number and sclerotia size varied in the fungal population, but the genetic makeup of these phenotypes remained unclear. As limited studies have focused on the genomics ofR. solaniAG-7 and the population genetics of sclerotia formation, this study completed the whole genome sequencing and gene prediction ofR. solaniAG-7 using the Oxford NanoPore and Illumina RNA sequencing. Meanwhile, a high-throughput image-based method was established to quantify the sclerotia-forming capability, and the phenotypic correlation between sclerotia number and sclerotia size was low. A genome-wide association study identified three and five significant SNPs associated with sclerotia number and size in distinct genomic regions, respectively. Of these significant SNPs, two and four showed significant differences in the phenotypic mean separation for sclerotia number and sclerotia size, respectively. Gene ontology enrichment analysis focusing on the linkage disequilibrium blocks of significant SNPs identified more categories related to oxidative stress for sclerotia number, and more categories related to cell development, signalling and metabolism for sclerotia size. These results indicated that different genetic mechanisms may underlie these two phenotypes. Moreover, the heritability of sclerotia number and sclerotia size were estimated for the first time to be 0.92 and 0.31, respectively. This study provides new insights into the heritability and gene functions related to the development of sclerotia number and sclerotia size, which could provide additional knowledge to reduce fungal residues in fields and achieve sustainable disease management.
SARS-CoV-2 post-vaccine surveillance studies in Australian children and adults with cancer: SerOzNET Quality of Life, Toxicity and Vaccine Beliefs Substudy Statistical Analysis Plan
Authors: Donoghue Mark W , Body Amy , Wakefield Claire , Ahern Elizabeth , Segelov Eva
Published: March 2023

COVID-19 disease is associated with higher morbidity and mortality in cancer patients. SerOzNET is a prospective cohort study of adults and children with cancer undergoing routine SARS-CoV-2 vaccination in Australia. Peripheral blood was collected and processed at multiple points (one pre-vaccination and five or more post-vaccination) to address the primary aim of the study to assess the serological and immunological responses to vaccination.

A secondary aim of the study was to “document patient response to vaccination using qualitative measures, including patient-reported outcomes, vaccine hesitancy survey and post-hoc toxicity recording” (body, et al.,2022). This statistical analysis plan describes the analysis of the data collected to address this aim. We will refer to this as the SerOzNET QoL Substudy.

We have no conflicts of interest to disclose.
Coronary microvascular resistance comparison of coronary branches with and without additional vascular diameter
Authors: Muroya Takahiro , Kawano Hiroaki , Yamamoto Fumi , Maemura Koji
Published: March 2023

Background

Measurement of coronary microvascular resistance (MR) is essential for diagnosing nonocclusive coronary artery ischemia, but whether coronary branches of different diameters can be similarly assessed using hyperemic microvascular resistance index (hMVRI) calculated from average peak velocity (APV) remains unclear.

Objectives

We investigated the relationship between coronary arteries of different diameters and hMVRI.

Method

Thirty patients with suspected angina pectoris and nonobstructive coronary stenosis with fractional flow reserve >0.8 underwent evaluation of all coronary arteries using a Doppler velocity and pressure-equipped guidewire. Vessel diameter (DQCA) was analyzed by quantitative coronary angiography (QCA). Coronary blood flow (CBFQCA) was calculated as πDQCA2/4 (0.5×APV) and hMVRI as distal coronary pressure (Pd) divided by CBFDQCAduring maximal hyperemia.

Results

The hMVRI was significantly higher for the right coronary artery (RCA) than for the left anterior descending artery (LAD), but no significant differences between arteries were seen for CBFQCAand hMVRIQCA. Although the correlation between CBFQCAand APV was weak in all arteries, CBFQCAdivided into three groups according to DQCAshowed very strong correlations with APV. Slopes of the straight line between APV and CBFQCAfor small-, middle-, and large-diameter groups were 0.48, 0.30, and 0,21, respectively, with slope decreasing as diameter increased. The correlation between APV and CBFQCAwas high for LAD and RCA, but weak for the left circumflex artery.

Conclusions

Evaluation of MR in coronary branches requires consideration of vessel diameter.
Continuous theta-burst stimulation of the contralesional primary motor cortex for promotion of upper limb recovery after stroke: a randomized controlled trial
Authors: Vink Jord JT , van Lieshout Eline CC , Otte Willem M , van Eijk Ruben PA , Kouwenhoven Mirjam , Neggers Sebastiaan FW , van der Worp H Bart , Visser-Meily Johanna MA , Dijkhuizen Rick M
Published: March 2023

Background

Despite improvements in acute stroke therapies and rehabilitation strategies, many stroke patients are left with long-term upper limb motor impairment. We assessed whether an inhibitory repetitive transcranial magnetic stimulation (rTMS) treatment paradigm started within three weeks after stroke onset promotes upper limb motor recovery.

Methods

Patients with ischemic stroke or intracerebral hemorrhage and unilateral upper limb motor impairment admitted to a single rehabilitation center were randomized to ten daily sessions of active or sham continuous theta burst stimulation (cTBS) of the contralesional primary motor cortex (M1) combined with standard upper limb therapy, started within three weeks after stroke onset. The primary outcome was the change in the Action Research Arm Test (ARAT) score from baseline (pre-treatment) at three months after stroke. Secondary outcomes included the score on the modified Rankin Scale (mRS) at three months and the length of stay (LOS) at the rehabilitation center. Statistical analyses were performed using mixed models for repeated measures.

Results

We enrolled 60 patients between April, 2017 and February, 2021, of whom 29 were randomized to active cTBS and 31 to sham cTBS. One patient randomized to active cTBS withdrew consent before the intervention and was excluded from the analyses. The mean difference in the change in ARAT score from baseline at three months post-stroke was 9.6 points (95%CI 1.2-17.9; p 0.0244) in favor of active cTBS. Active cTBS was associated with better scores on the mRS at three months (OR 0.2; 95%CI 0.1-0.8; p 0.0225) and with an 18 days shorter length of stay at the rehabilitation center than sham cTBS (95%CI 0.0-36.4; p 0.0494). There were no serious adverse events.

Conclusions

Ten daily sessions of cTBS of the contralesional M1 combined with upper limb training, started within three weeks after stroke onset, promote recovery of the upper limb, reduce disability and dependence and leads to earlier discharge from the rehabilitation center.

Trial registration

The trial was registered at the international clinical trials registry platform (https://trialsearch.who.int/) with unique identifier: NTR6133.
Parasitism and locomotory capacity calibrate the mitogenomic evolutionary rates in Bilateria
Authors: Jakovlić Ivan , Zou Hong , Ye Tong , Zhang Hong , Liu Xiang , Xiang Chuan-Yu , Wang Gui-Tang , Zhang Dong
Published: March 2023

The evidence that parasitic lineages exhibit elevated evolutionary rates is limited to Arthropoda and inconsistent. Similarly, the evidence that mitogenomic evolution is faster in species with low locomotory capacity (LC) is limited to a handful of animal lineages. We hypothesised that these two variables are associated and that LC is a major underlying factor driving the elevated evolutionary rates in parasites. We tested this hypothesis by studying mitogenomic evolutionary patterns in 10,911 bilaterian species classified according to their locomotory capacity and parasitic/free-living life history (LH). Evolutionary rates were significantly elevated in endoparasites, ectoparasites with reduced LC, and free-living lineages with reduced LC, but not in ectoparasites and parasitoids with high LC. Nematoda and Arachnida were the only lineages where parasitism was not associated with faster evolution. We propose that LC may also explain these two major outliers. Overall, the LH categorisation explained 35-37%, LC categorisation 26-28%, and together they explained 41-44% of the variance in branch lengths across the Bilateria. Our findings suggest that these two variables play a major role in calibrating the molecular clock in bilaterian animals.
The effects of mutations on gene expression and alternative splicing: a case study of EMS-induced heritable mutations in the microcrustaceanDaphnia
Authors: Snyman Marelize , Xu Sen
Published: March 2023

Understanding the relationship between mutations and their genomic and phenotypic consequences has been a longstanding goal of evolutionary biology. However, few studies have investigated the impact of mutations on gene expression and alternative splicing on the genome- wide scale. In this study, we aim to bridge this knowledge gap by utilizing whole-genome sequencing data and RNA sequencing data from 16 OPDaphniamutant lines to investigate the effects of EMS-induced mutations on gene expression and alternative splicing. Using rigorous analyses of mutations, expression changes, and alternative splicing, we show that trans-effects are the major contributor to the variance in gene expression and alternative splicing between the wildtype and mutant lines, whereas cis mutations only affected a limited number of genes and do not always alter gene expression. Moreover, we show that there is a significant association between DE genes and exonic mutations, indicating that exonic mutations are an important driver of altered gene expression.
Histology-based Prediction of Therapy Response to Neoadjuvant Chemotherapy for Esophageal and Esophagogastric Junction Adenocarcinomas Using Deep Learning
Authors: Hörst Fabian , Ting Saskia , Liffers Sven-Thorsten , Pomykala Kelsey L. , Steiger Katja , Albertsmeier Markus , Angele Martin K. , Lorenzen Sylvie , Quante Michael , Weichert Wilko , Egger Jan , Siveke Jens T. , Kleesiek Jens
Published: March 2023

Background

Quantifying treatment response to gastroesophageal junction (GEJ) adenocarcinomas is crucial to provide optimal therapeutic strategy. Routinely taken tissue samples provide an opportunity to enhance existing PET/CT-based therapy response evaluation. Our objective was to investigate if deep learning algorithms are capable to predict the therapy response of GEJ patients to neoadjuvant chemotherapy based on histological tissue samples.

Methods

This diagnostic study recruited 67 patients with GEJ I-III from the multicentric non-randomized MEMORI trial including 3 German university hospitals TUM (Munich), LMU (Munich), and UME (Essen). All patients underwent baseline PET/CT scans and esophageal biopsy before and 14-21 days after treatment initiation. Treatment response was defined as a ≥ 35% decrease in SUVmax from baseline. Several deep learning algorithms were developed to predict PET/CT-based responders and non-responders to neoadjuvant chemotherapy using digitized histopathological whole slide images.

Results

The resulting models were trained on TUM (n=25 pre-therapy, n=47 on-therapy) patients and evaluated on our internal validation cohort from LMU and UME (n=17 pre-therapy, n=15 on-therapy). Compared with multiple architectures, the best pre-therapy network achieves an area under the precision-recall curve (AUPRC) of 0.81 (95% confidence interval (CI), 0.61-1.00), area under the precision-recall curve (AUPRC) of 0.82 (95% CI, 0.61-1.00), balanced accuracy of 0.78 (95% CI, 0.60-0.94), and a Matthews correlation coefficient (MCC) of 0.55 (95% CI, 0.18-0.88). The best on-therapy network achieves an AUROC of 0.84 (95% CI, 0.64-1.00), AUPRC of 0.82 (95% CI, 0.56-1.00), balanced accuracy of 0.80 (95% CI, 0.63-1.00), and MCC of 0.71 (95% CI, 0.38-1.00), solving a task beyond the pathologists’ capabilities.

Conclusions

The findings suggest that the networks can predict treatment response using WSI with high accuracy even pre-therapy, suggesting morphological tissue biomarkers. Subject to further validation, this could lead to earlier therapy intensification compared to current PET/CT diagnostic system for non-responder.
Causal evidence for an ApoB-independent metabolomic risk profile associated with coronary artery disease
Authors: Ao Linjun , van Heemst Diana , Jukema J. Wouter , Rensen Patrick C.N. , van Dijk Ko Willems , Noordam Raymond
Published: March 2023

Background and aims

1-H nuclear magnetic resonance (1H-NMR) metabolomic measures in plasma have yielded significant insight into the pathophysiology of cardiometabolic disease, but their interrelated nature complicates causal inference and clinical interpretation. This study aimed to investigate the associations of unrelated1H-NMR metabolomic profiles with coronary artery disease (CAD), type 2 diabetes (T2D) and ischemic stroke (ISTR).

Methods

Principal component (PC) analysis was performed on 1681H-NMR metabolomic measures in 56,712 unrelated European participants from UK Biobank to retrieve unrelated PCs, which were used in multivariable-adjusted cox-proportional hazard models and genome-wide association analyses for Mendelian Randomization (MR). Two-sample MR analyses were conducted in three non-overlapping databases which were subsequently meta-analysed, resulting in combined sample sizes of 755,481 (128,728 cases), 1,017,097 (121,977 cases), and 1,002,264 (56,067 cases) for CAD, T2D, and ISTR, respectively.

Results

We identified six PCs which collectively explained 88% of the total variance. For CAD in particular, results from both multivariable-adjusted and MR analyses were generally directionally consistent. The pooled odds ratios (ORs) [95% CI] of per one-SD increase in genetically-influenced PC1 and PC3 (both characterized by distinct ApoB-associated lipoprotein profiles) were 1.04 [1.03, 1.05] and 0.94 [0.93, 0.96], respectively. In addition, the pooled OR for CAD of PC4, characterized by simultaneously decreased small HDL and increased large HDL, and independent of ApoB, was 1.05 [1.03, 1.07]. For the other outcomes, PC5 (characterized by increased amino acids) was associated with a higher risk of T2D and ISTR.

Conclusions

This study highlights the existence of an ApoB-independent lipoprotein profile driving CAD. Interestingly, this profile is characterized by a distinctive HDL sub-particle distribution, providing evidence for a role of HDL in the development of CAD.
Risk of cardiovascular events following COVID-19 in people with and without pre-existing chronic respiratory disease
Authors: Whittaker Hannah , Kallis Constantinos , Bolton Thomas , Wood Angela , Walker Samantha , Sheikh Aziz , Brownrigg Alex , Akbari Ashley , Sterniczuk Kamil , Quint Jennifer
Published: March 2023

Background

COVID-19 is associated with a higher risk of cardiovascular outcomes in the general population, but it is unknown whether people with pre-existing chronic respiratory disease (CRD) have a higher risk of cardiovascular events post-COVID-19 compared with the general population and, if so, what respiratory-related risk factors may modify this risk in these people.

Methods

Primary and secondary care data from the National Health Service and COVID-19-specific linked data were used to define a population of adults in England with COVID-19 (index date) between 01/01/2020-30/11/2021. Adjusted Cox Proportional Hazard regression was used to quantify the association between CRD, asthma-related factors, COPD-related factors, and risk of cardiovascular events. CRD included asthma, COPD, bronchiectasis, cystic fibrosis, or pulmonary fibrosis prior to COVID-19 diagnosis. Asthma-specific factors included baseline asthma control, exacerbations, and inhaled corticosteroid (ICS) dose. COPD-specific risk factors included baseline ICS prescriptions and exacerbations. Secondary objectives quantified the impact of COVID-19 hospitalisation and vaccine dose on cardiovascular outcomes.

Results

Of 3,670,455 people, those with CRD had a modest higher risk of cardiovascular events (HRadj1.11, 95%CI 1.07-1.14), heart failure (HRadj1.15, 1.09-1.21), and pulmonary emboli (HRadj1.20, 1.11-1.30) compared with people without CRD. In people with asthma, baseline exacerbations and high-dose ICS were associated with a higher risk of cardiovascular outcomes (HRadj1.24, 1.15-1.34 and 1.12, 1.01-1.24, respectively). In people with COPD, exacerbations were associated with a higher risk of cardiovascular outcomes (HRadj1.40, 1.28-1.52). Regardless of CRD, the risk of cardiovascular events was lower with increasing COVID-19 vaccine dose.

Conclusions

Higher risk of cardiovascular events following COVID-19 might be explained at least in part by the underlying CRD and severity of that condition. In addition, COVID-19 vaccines were beneficial to both people with and without CRD with regards to CV events.

Key Messages

Pre-existing chronic respiratory disease, asthma and COPD severity were associated with a higher risk of various types of cardiovascular outcomes following COVID-19. Regardless of having pre-existing chronic respiratory disease, COVID-19 vaccination reduced the risk of cardiovascular events following COVID-19.
Effectiveness of successive booster vaccine doses against SARS-CoV-2 related mortality in residents of Long-Term Care Facilities in the VIVALDI study
Authors: Stirrup Oliver , Shrotri Madhumita , Adams Natalie L. , Krutikov Maria , Azmi Borscha , Monakhov Igor , Tut Gokhan , Moss Paul , Hayward Andrew , Copas Andrew , Shallcross Laura
Published: March 2023

We evaluated the effectiveness of 1-3 booster vaccinations against SARS-CoV-2 related mortality among a cohort of 13407 older residents of long-term care facilities (LTCFs) participating in the VIVALDI study in England in 2022. Cox regression was used to estimate relative hazards of SARS-CoV-2 related death following booster vaccination relative to 2 doses (after 84+ days), stratified by previous SARS-CoV-2 infection and adjusting for age, sex and LTCF capacity. Each booster provided additional short-term protection relative to primary vaccination, with consistent pattern of waning to 45-75% reduction in risk beyond 112 days.
Geospatial assessment of the convergence of communicable and non-communicable diseases in South Africa
Authors: Cuadros Diego F. , Moreno Claudia M. , Tomita Andrew , Singh Urisha , Olivier Stephen , Castle Alison , Moosa Yumna , Edwards Johnathan A , Kim Hae-Young , Siedner Mark J , Wong Emily B , Tanser Frank
Published: March 2023

Background

Several low- and middle-income countries are undergoing a rapid epidemiological transition with a rising burden of non-communicable diseases (NCDs). South Africa (SA) is a country with one of the largest HIV epidemics worldwide and a growing burden of NCDs where the collision of these epidemics poses a major public health challenge.

Methods

Using data from a large nationally representative survey, the South Africa Demographic and Health Survey (SADHS 2016), we conducted a geospatial analysis of several diseases including HIV, tuberculosis (TB), cardiovascular, respiratory, and metabolic diseases to identify areas with a high burden of co-morbidity within the country. We explored the spatial structure of each disease and the associations between diseases using different spatial and visual data methodologies. We also assessed the individual-level co-occurrence of HIV and the other diseases included in the analysis.

Results

The spatial distribution for HIV prevalence showed that this epidemic is most intense in the eastern region of the country, mostly within the Gauteng, Mpumalanga, and Kwazulu-Natal provinces. In contrast, chronic diseases had their highest prevalence rates in the southern region of the country, particularly in the Eastern and Western Cape provinces. Individual-level analyses were consistent with the spatial correlations and found no statistically significant associations between HIV infection and the presence of any NCDs.

Conclusions

We found no evidence of geospatial overlap between the HIV epidemic and NCDs in SA. These results evidence the complex epidemiological landscape of the country, characterized by geographically distinct areas exhibiting different health burdens. The detailed description of the heterogenous prevalence of HIV and NCDs in SA reported in this study could be a useful tool to inform and direct policies to enhance targeted health service delivery according to the local health needs of each community.
Esm-1 mediates transcriptional polarization associated with diabetic kidney disease
Authors: Gaudet Alexandre , Zheng Xiaoyi , Kambham Neeraja , Bhalla Vivek
Published: March 2023

Background

Esm-1, endothelial cell-specific molecule-1, is a susceptibility gene for diabetic kidney disease (DKD) and is a cytokine- and glucose-regulated, secreted proteoglycan, that is notably expressed in kidney and attenuates inflammation and albuminuria.Esm1has restricted expression at the vascular tip during development but little is known about its expression pattern in mature tissues, and its precise effects in diabetes.

Methods

We utilized publicly available single-cell RNA sequencing data to explore the characteristics ofEsm1expression in 27,786 renal endothelial cells obtained from four adult human and three mouse databases. We validated our findings using bulk transcriptome data from an additional 20 healthy subjects and 41 patients with DKD and using RNAscope. Using correlation matrices, we relate Esm1 expression to the glomerular transcriptome and evaluated these matrices with systemic over-expression of Esm-1.

Results

In both mice and humans,Esm1is expressed in a subset of all renal endothelial cell types and represents a minority of glomerular endothelial cells. In patients,Esm1(+) cells exhibit a highly conserved enrichment for blood vessel development genes. With diabetes, these cells are fewer in number and profoundly shift expression to reflect chemotaxis pathways. Analysis of these gene sets highlight candidate genes such asIgfbp5for cross talk between cell types. We also find that diabetes induces correlations in the expression of large clusters of genes, within cell type-enriched transcripts.Esm1significantly correlates with a majority genes within these clusters, delineating a glomerular transcriptional polarization reflected by the magnitude ofEsm1deficiency. In diabetic mice, these gene clusters linkEsm1expression to albuminuria, and over-expression of Esm-1 reverses the expression pattern in many of these genes.

Conclusions

A comprehensive analysis of single cell and bulk transcriptomes demonstrates that diabetes correlates with lowerEsm1expression and with changes in the functional characterization ofEsm1(+) cells.Esm1is both a marker for glomerular transcriptional polarization, and a mediator that re-orients the transcriptional program in DKD.
Plasticity in parental behavior and vasopressin: Responses to co-parenting, pup age, and an acute stressor are experience-dependent
Authors: Hiura Lisa C. , Lazaro Vanessa A. , Ophir Alexander G.
Published: March 2023

The impact of variation in parental caregiving has lasting implications for the development of offspring. However, the ways in which parents impact each other in the context of caregiving is comparatively less understood, but can account for much of the variation observed in the postnatal environment. Prairie voles (Microtus ochrogaster) demonstrate a range of postnatal social groups, including biparental pairs and pups raised by their mothers alone. In addition to the challenges of providing parental care, prairie vole parents often experience acute natural stressors (e.g., predation, foraging demands, thermoregulation) that could alter the way co-parents interact. We investigated how variation in the experience of raising offspring impacts parental behavior and neurobiology by administering an acute handling stressor on prairie vole families of single mothers and biparental parents over the course of offspring postnatal development. Mothers and fathers exhibited robust behavioral plasticity in response to the age of their pups, but in sex-dependent ways. Pup-directed care from mothers did not vary as a function of their partner’s presence, but did covary with the number of hypothalamic vasopressin neurons in experience-dependent ways. The relationship between vasopressin neuron numbers and fathers’ behaviors was also contingent upon the stress handling manipulation, suggesting that brain-behavior associations exhibit stress-induced plasticity. These results demonstrate that the behavioral and neuroendocrine profiles of adults are sensitive to distinct and interacting experiences as a parent, and extend our knowledge of the neural mechanisms that may facilitate parental behavioral plasticity.
The eccDNA mediated spread and rapid evolution of herbicide resistance in pigweed interspecific hybrids
Authors: Koo Dal-Hoe , Sathishraj Rajendran , Nakka Sridevi , Ju Yoonha , Nandula Vijay K. , Jugulam Mithila , Friebe Bernd , Gill Bikram S.
Published: March 2023

Extrachromosomal circular DNAs (eccDNAs) are found in many eukaryotic organisms. The eccDNA-powered copy number variation plays diverse roles from oncogenesis in humans to herbicide resistance in crop weeds. Here we report interspecific eccDNA flow and its dynamic behavior in soma cells of natural populations and F1hybrids ofAmaranthussp. The glyphosate resistance (GR) trait is controlled by eccDNA-based amplification harboring the5-enolpyruvylshikimate-3-phosphate synthase(EPSPS) gene (EPSPS-eccDNA), the molecular target of glyphosate. We documented pollen-mediated transfer of eccDNA in experimental hybrids between GSA. tuberculatusx GRA. palmeri. Experimental hybridization and fluorescencein situhybridization (FISH) analysis revealed that theEPSPS-eccDNA present inA. spinosuswas derived from GRA. palmeriby natural hybridization. FISH analysis also revealed random chromosome anchoring and massiveEPSPS-eccDNA copy number variation in soma cells of weedy hybrids. The results suggest that eccDNAs are inheritable across compatible species contributing to genome plasticity and rapid adaptive evolution.
SnapHiC-G: identifying long-range enhancer-promoter interactions from single-cell Hi-C data via a global background model
Authors: Liu Weifang , Zhong Wujuan , Giusti-Rodríguez Paola , Wang Geoffery W. , Hu Ming , Li Yun
Published: March 2023

Harnessing the power of single-cell genomics technologies, single-cell Hi-C (scHi-C) and its derived technologies provide powerful tools to measure spatial proximity between regulatory elements and their target genes in individual cells. Using a global background model, we propose SnapHiC-G, a computational method to identify long-range enhancer-promoter interactions from scHi-C data. We applied SnapHiC-G to scHi-C datasets generated from mouse embryonic stem cells and human brain cortical cells and demonstrated that SnapHiC-G achieved high sensitivity in identifying long-range enhancer-promoter interactions. Moreover, SnapHiC-G can identify putative target genes for non-coding GWAS variants, and the genetic heritability of neuropsychiatric diseases is enriched for single nucleotide polymorphisms (SNPs) within SnapHiC-G-identified interactions in a cell-type-specific manner. In sum, SnapHiC-G is a powerful tool for characterizing cell-type-specific enhancer-promoter interactions from complex tissues and can facilitate the discovery of chromatin interactions important for gene regulation in biologically relevant cell types.
Inhibitory control of speech production in the human premotor frontal cortex
Authors: Zhao Lingyun , Silva Alexander B. , Kurteff Garret L. , Chang Edward F.
Published: March 2023

Natural speech is full of starts and stops. Here, we studied the neural mechanisms that underlie the inhibitory control of speech, specifically the ability to stop speaking on demand. We recorded direct cortical activity while participants made continuous speech production and were given a visual cue to stop speaking. Neural recordings revealed activity in the premotor frontal cortex associated with speech stopping. Cortical sites showing stop activity were largely distinct from sites involved in active speech production or, more specifically, encoding articulatory movements. Electrocortical stimulation mapping at many premotor sites with stop activity caused involuntary speech arrest, an immediate inability to speak or vocalize. Furthermore, many speech arrest sites did not co-localize with neural activity correlating with speech motor planning or execution, contrary to this long-assumed function in clinical brain mapping. Together, these results suggest a previously unknown premotor cortical network that underlies the inhibitory control of speech, which has significant implications for understanding the dynamics of normal and altered speech production, as well as clinical brain mapping.
Assessment of neutralization susceptibility of Omicron subvariants XBB.1.5 and BQ.1.1 against broad-spectrum neutralizing antibodies through epitopes mapping
Authors: Shah Masaud , Woo Hyun Goo
Published: March 2023

The emergence of new variants of the SARS-CoV-2 virus has posed a significant challenge in developing broadly neutralizing antibodies (nAbs) with guaranteed therapeutic potential. Some nAbs, such as Sotrovimab, have exhibited varying levels of efficacy against different variants, while others, such as Bebtelovimab and Bamlanivimab-etesevimab are ineffective against specific variants, including BQ.1.1 and XBB. This highlights the urgent need for developing broadly active mAbs providing prophylactic and therapeutic benefits to high-risk patients, especially in the face of the risk of reinfection from new variants. Here, we aimed to investigate the feasibility of redirecting existing mAbs against new variants of SARS-CoV-2, as well as to understand how BQ.1.1 and XBB.1.5 can evade broadly neutralizing mAbs. By mapping epitopes and escape sites, we discovered that the new variants evade multiple mAbs, including FDA-approved Bebtelovimab, which showed resilience against other Omicron variants. Our approach, which included simulations, free energy perturbations, and shape complementarity analysis, revealed the possibility of identifying mAbs that are effective against both BQ.1.1 and XBB.1.5. We identified two broad-spectrum mAbs, R200-1F9 and R207-2F11, as potential candidates with increased binding affinity to XBB.1.5 and BQ.1.1 compared to the wild-type virus. Additionally, we propose that these mAbs do not interfere with ACE2 and bind to conserved epitopes on the RBD that are not-overlapping, potentially providing a solution to neutralize these new variants either independently or as part of a combination (cocktail) treatment.
A subset of CD4+ effector memory T cells limit immunity to pulmonary viral infection and prevent tissue pathology via activation of latent TGFβ
Authors: McEntee CP , Houston S , Finlay CM , Rossi S , Liu G , Shaw TN , Casulli J , Fife M , Smedley C , Griffith TS , Pepper M , Hussell T , Hansbro PM , Schwartz J-M , Paidassi H , Travis MA
Published: March 2023

A rapid immune response to pathogen re-exposure underpins immunological memory, with protection against divergent pathogens such as heterologous or novel viral strains requiring cross­reactive memory T cells. Understanding the pathways that control memory T cell function is therefore important for the rational design of viral vaccines and will aid the discovery of therapies to boost anti-viral immunity. Here, we identify a sub-population of memory T cells that limit secondary immune responses to viral re-infection, which is crucial in preventing host tissue damage. We show that a population of CD4+effector memory T (TEM) cells activate the important immunoregulatory cytokine TGFβ, via expression of an integrin, αvβ8. Integrin αvβ8 expression marks a transcriptionally distinct sub-population of CD4+TEM, enriched for anti-inflammatory pathways. Loss of integrin αvβ8 on murine CD4+TEM, but not Foxp3+regulatory T cells (TREG), led to exacerbated virus-specific CD8+T cell responses following secondary influenza A virus (IAV) infection, which was associated with enhanced viral clearance. However, although accelerating clearance, loss of integrin αvβ8 expression on CD4+TEMresulted in enhanced lung pathology following secondary IAV infection, which was completely reversed by adoptive transfer of αvβ8+CD4+TEMcells. These data highlight a new pathway by which a distinct CD4+memory T cell subset restrains anti-viral immunity to prevent host tissue damage during secondary viral infection. Such pathways could be targeted therapeutically to either boost memory T-cell-mediated immunity or restrain host tissue damage during viral infection.
Hub taxa are keystone microbes during early succession
Authors: Rawstern Amanda H. , Hernandez Damian J. , Afkhami Michelle E.
Published: March 2023

Microorganisms underpin numerous ecosystem processes and support biodiversity globally, yet we understand surprisingly little about what structures environmental microbiomes themselves. Combining culturing, sequencing, and microbial networks, we identified ‘central’ (highly-connected, hub taxa), ‘intermediate’ (moderately-connected), and ‘peripheral’ (weakly/un-connected) microbes and experimentally evaluated their effects on soil microbiome assembly during early succession. Our results demonstrate central early colonizers significantly (1) enhanced biodiversity, (2) increased recruitment of additional influential, hub taxa, and (3) shaped microbiome assembly trajectories. This work elucidates fundamental principles of network theory in microbial ecology and demonstrates for the first time in nature that central, hub microbes are keystones.