bluuebunny/crossref_metadata_2025 huggingface dataset:
A sensory approach to turbidity: How sources and levels shape aquatic light environments and fish visual ecology
Authors: Garcia Anna , Sibeaux Adelaide , Burt de Perera Theresa , Newport Cait
Published: October 2024

Turbidity is a ubiquitous source of sensory pollution that is likely to impact the appearance of the visual stimuli that animals rely on for survival and reproduction. Understanding how different turbidity sources impact the appearance of the ambient light environment is the foundational first step towards predicting whether and how animals will cope with the global increases in the severity and frequency of high turbidity events caused by anthropogenic disturbance. Here, we measured how four common turbidity sources (algae, bentonite, calcium carbonate, and kaolin), and variable turbidity levels, changed the appearance of the ambient light environment. We measured total number of photons (luminance), hue, chroma, and image contrast, and we evaluated the effect of each turbidity source and level on settling rate, pH, and KH. Both turbidity source and turbidity level impacted the appearance of the ambient light environment. With increasing turbidity level, calcium carbonate and kaolin increased luminance while algae decreased luminance, bentonite caused the greatest change in hue, and algae caused the greatest change in chroma. This demonstrates that the impacts of different turbidity sources on the ambient light environment are not uniform, giving a potential explanation for the discrepancies between studies on the effects of turbidity on fish behaviour. Consideration of the effect of specific turbidity sources on ambient light is crucial for the design of experiments that seek to investigate how changes in turbidity impact the perception of important visual information, which underpins the survival and reproductive success of aquatic organisms around the world.

Summary Statement

Different turbidity sources and levels uniquely affect aquatic light environments and fish visual perception, emphasizing the need for these factors when interpreting fish behaviour and the ecological consequences of turbidity.
Expectation generation and its effect on subsequent pain and visual perception
Authors: Botvinik-Nezer Rotem , Geuter Stephan , Lindquist Martin A. , Wager Tor D.
Published: October 2024

Bayesian accounts of perception, such as predictive processing, suggest that perceptions integrate expectations and sensory experience, and thus assimilate to expected values. Furthermore, more precise expectations should have stronger influences on perception. We tested these hypotheses in a paradigm that manipulates both the mean value and the precision of cues within-person. Forty-five participants observed cues–presented as ratings from 10 previous participants–with varying cue means, variances (precision), and skewness across trials. Participants reported expectations regarding the painfulness of thermal stimuli or the visual contrast of flickering checkerboards. Subsequently, similar cues were each followed by a visual or noxious thermal stimulus. While perceptions assimilated to expected values in both modalities, cues’ precision mainly affected visual ratings. Furthermore, behavioral and computational models revealed that expectations were biased towards extreme values in both modalities, and towards low-pain cues specifically. fMRI analysis revealed that the cues affected systems related to higher-level affective and cognitive processes–including assimilation to the cue mean in a neuromarker of endogenous contributions to pain and in the nucleus accumbens, and activity consistent with aversive prediction-error-like encoding in the periaqueductal gray during pain perception–but not systems related to early perceptual processing. Our findings suggest that predictive processing theories should be combined with mechanisms such as selective attention to better fit empirical findings, and that expectation generation and its perceptual effects are mostly modality-specific and operate on higher-level processes rather than early perception.
On the patterns of genetic intra-tumour heterogeneity before and after treatment
Authors: Stein Alexander , Werner Benjamin
Published: October 2024

Genetic intra-tumour heterogeneity (gITH) is a universal property of all cancers. It emerges from the interplay of cell division, mutation accumulation and selection with important implications for the evolution of treatment resistance. Theoretical and data-driven approaches extensively studied gITH in ageing somatic tissues or cancers at detection. Yet, the expected patterns of gITH during and after treatment are less well understood. Here, we use stochastic birth-death processes to investigate the expected patterns of gITH across different treatment scenarios. We consider homogeneous treatment response with shrinking, growing and stable disease, and follow up investigating heterogeneous treatment response with sensitive and resistant cell types. We derive analytic expressions for the site frequency spectrum, the total mutational burden and the single-cell mutational burden distribution that we validate with computer simulations. We find that the SFS after homogeneous treatment response retains its characteristic power-law tail, while emergent resistant clones cause peaks corresponding to their sizes. The frequency of the largest resistant clone is subdominant and independent of the population size at detection, whereas the relative total number of resistant cells increases with detection size. Furthermore, the growth dynamics under treatment determine whether the total mutational burden is dominated by preexisting or newly acquired mutations, suggesting different possible treatment strategies.
Convergent depression of activity-dependent bulk endocytosis in rodent models of autism spectrum disorders
Authors: Bonnycastle Katherine , Kind Peter C. , Cousin Michael A.
Published: October 2024

The key pathological mechanisms underlying autism spectrum disorders (ASDs) remain relatively undetermined, potentially due to the heterogenous nature of the condition. Targeted studies of a series of monogenic ASDs have revealed postsynaptic dysfunction as a central conserved mechanism. Presynaptic dysfunction is emerging as an additional disease locus in neurodevelopmental disorders, however it is unclear whether this dysfunction drives ASDs or is an adaptation to the altered brain microenvironment. To determine this, we performed a high content analysis of key stages of the synaptic vesicle lifecycle in a series of preclinical models of monogenic ASDs. These models were specifically selected to have perturbations in a diverse palette of genes that were expressed either at the pre- or post-synapse. However, all models displayed a common trait of hyperexcitability. We determined that SV fusion events and SV cargo trafficking were unaffected in all models investigated. However, a key convergent phenotype was revealed, a depression in activity-dependent bulk endocytosis (ADBE). This suggests that the depression in ADBE is a homeostatic mechanism to correct hyperexcitability in the ASD brain.
Male is the default sex: functional significance of the sex determination cascade in horned dung beetles
Authors: Mitchell London C. , Moczek Armin P. , Nadolski Erica M.
Published: October 2024

Sex-specific trait expression represents a striking dimension of morphological variation within and across species. The mechanisms instructing sex-specific organ development have been well studied in a small number of insect model systems, suggesting striking conservation in some parts of the somatic sex determination pathway while hinting at possible evolutionary lability in others. However, further resolution of this phenomenon necessitates additional taxon sampling, particularly in groups in which sexual dimorphisms have undergone significant elaboration and diversification. Here, we functionally investigate the somatic sex determination pathway in the gazelle dung beetleDigitonthophagus gazella, an emerging model system in the study of the development and evolution of sexual dimorphisms. We find that RNA interference (RNAi) targetingtransformer1 (tra1)caused chromosomal females to develop morphological traits largely indistinguishable from those normally only observed in males, and thattra1RNAiis sufficient to induce splicing of the normally male-specific isoform ofdoublesexin chromosomal females, while leaving males unaffected. Further,intersexRNAiwas found to phenocopy previously described RNAi phenotypes ofdoublesexin female but not male beetles. These findings match predictions derived from models of the sex determination cascade as developed largely through studies inDrosophila melanogaster. In contrast,transformer2RNAiresulted in larval mortality and was not sufficient to affectdoublesexsplicing, whereas RNAi targetingSex-lethaland two putative orthologs ofhermaphroditeyielded no obvious phenotypic modifications in either males or females, raising the possibility that the function of a subset of sex determination genes may be derived in Diptera and thus non-representative of their roles in other holometabolous orders. Our results help illuminate how the differential evolutionary lability of the somatic sex determination pathway has contributed to the extraordinary morphological diversification of sex-specific trait expression found in nature.
Gasdermin D is activated but does not drive neurodegeneration in SOD1G93Amodel of ALS: Implications for targeting pyroptosis
Authors: Gunner Georgia , Basu Himanish , Lu Yueting , Bergstresser Matthew , Neel Dylan , Choi So Yoen , Chiu Isaac M.
Published: October 2024

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, microgliosis, and neuroinflammation. While pyroptosis, an inflammatory form of programmed cell death, has been implicated in ALS, the specific role of Gasdermin D (GSDMD) – the primary executioner of pyroptosis – remains unexplored. In this study, we examined the function of GSDMD in the well-established SOD1G93Amouse model of ALS. Our results showed robust GSDMD activation in the spinal cords of SOD1G93Aanimals across two strain backgrounds, with elevated expression in Iba1+ microglia. To explore its role in disease progression, we bred B6.SOD1G93Amice onto a GSDMD-deficient background. In comparing SOD1G93A;Gsdmd+/+ and SOD1G93A;Gsdmd−/− mice, we found thatGsdmdloss did not affect disease onset, weight loss, or grip strength decline in either male or female animals. Notably, GSDMD deficiency resulted in a modest but statistically significant increase in mortality in SOD1G93Amice. Moreover, GSDMD absence had minimal impact on astrogliosis, microgliosis and motor neuron loss. These findings show that while GSDMD is activated in the ALS mouse model, its loss does not mitigate key ALS behavioral phenotypes, gliosis or motor neuron loss. This study provides insights into the potential therapeutic relevance of targeting pyroptosis and inflammatory pathways in ALS.
Contribution of rat insular cortex to stimulus-guided action
Authors: Tensaouti Yacine , Morel Louis , Parkes Shauna L.
Published: October 2024

Anticipating rewards is fundamental for decision-making. Animals often use cues to assess reward availability and to make predictions about future outcomes. The gustatory region of the insular cortex (IC), the so-called gustatory cortex, has a well-established role in the representation of predictive cues, such that IC neurons encode both a general form of outcome expectation as well as anticipatory outcome-specific knowledge. Here, we used Pavlovian-instrumental transfer (PIT) in male rats to assess if the IC is also required for predictive cues to exert both a general and specific influence over instrumental actions. Chemogenetic inhibition of IC abolished the ability of a reward-predictive stimulus to energize instrumental responding for reward. This deficit in general transfer was evident whether the same or different outcomes were used in the Pavlovian and instrumental conditioning phases. We observed a similar deficit in specific PIT, such that rats with IC inhibition failed to use a reward-predictive stimulus to guide choice toward actions that deliver the same food reward. Finally, we show that rats with IC inhibition also fail to show outcome-selective reinstatement. Together, these data suggest a crucial role for IC in the representation of appetitive outcomes, and particularly in using this representation to guide instrumental action.

SIGNIFICANCE STATEMENT

Animals frequently use cues to infer the availability of rewards and to make predictions about future outcomes. The influence of these predictive cues on behaviour can be studied using Pavlovian-instrumental transfer (PIT), in which Pavlovian outcome expectancies can elevate (general PIT) or selectively guide (specific PIT) instrumental actions. In the current study, we show that chemogenetic inhibition of the gustatory region of insular cortex (IC) abolishes both general and specific transfer, as well as the selectivity of outcome-induced reinstatement. These results demonstrate a critical role for the IC in the representation of appetitive outcomes and significantly contribute to a broader understanding of the cortical bases of PIT.
Rapid, interpretable, data-driven models of neural dynamics using Recurrent Mechanistic Models
Authors: Burghi Thiago B. , Ivanova Maria , Morozova Ekaterina , Wang Huaxinyu , Marder Eve , O’Leary Timothy
Published: October 2024

Obtaining predictive models of a neural system is notoriously challenging. Detailed models suffer from excess model complexity and are difficult to fit efficiently. Simplified models must negotiate a tradeoff between tractability, predictive power and ease of interpretation. We present a new modelling paradigm for estimating predictive mechanistic-like models of neurons and small circuits that navigates these issues using methods from systems theory. The key insight is that membrane currents can be modelled using two scalable system components optimized for learning: linear state space models, and nonlinear artificial neural networks (ANNs). Combining these components, we construct two types of membrane currents: lumped currents, which are flexible, and data-driven conductance-based currents, which are interpretable. The resulting class of models — which we call Recurrent Mechanistic Models (RMMs) — can be trained in a matter of seconds to minutes on intracellular recordings during an electrophysiology experiment, representing a step change in performance over previous approaches. As a proof-of-principle, we use RMMs to learn the dynamics of two groups of neurons, and their synaptic connections, in the Stomatogastric Ganglion (STG), a well-known central pattern generator. We show that RMMs are efficiently trained using teacher forcing and multiple shooting. Due to their reliability, efficiency and interpretability, RMMs enable qualitatively new kinds of experiments using predictive models in closed-loop neurophysiology and online estimation of neural properties in living preparations.

Significance Statement

Our ability to understand the nervous system has been hindered by the difficulty of constructing good predictive models of neurons and circuits. This difficulty persists despite vast accumulated knowledge of how the basic components of the nervous system work, marking a gap in our ability to explain neural dynamics in terms of underlying mechanisms. This work describes a new data-driven modelling approach for neurons and small circuits that combines predictive power with mechanistic interpretation.
Prefrontal representations of retrospective spatial working memory in a rodent radial maze task
Authors: Taliaferro Joshua Paul , Posani Lorenzo , Greenwald Julia , Lim Sean , McGowan Josephine Cecelia , Pekarskaya Elizabeth , Lacefield Clay , Fusi Stefano , Kellendonk Christoph
Published: October 2024

Working memory is the cognitive capacity for temporarily holding information in mind for processing or use. It has been theorized to depend upon executive and mnemonic subcomponents, although the contextual mapping of these subcomponents is not complete. Perturbations of prefrontal cortex (PFC) delay activity disrupt spatial working memory performance in rodent tasks. However, recordings of unperturbed PFC delay activity do not consistently contain mnemonic representations of spatial information in these tasks, calling into question the role that mnemonic PFC representations play in freely-moving spatial working memory. We hypothesized that increasing task complexity might increase the likelihood of mnemonic PFC representation emergence. We therefore used an automated eight-arm radial maze to implement a novel match-to-sample rodent spatial working memory task with seven options on each trial, and recorded calcium activity in PFC neurons during task performance. We found that the delay-phase activity of PFC neurons indeed contained mnemonic representations of spatial information at the population level. These representations were retrospective rather than prospective, and—surprisingly—were more evident on error trials. Together with previous results, these observations suggest that in freely-moving spatial working memory tasks, PFC mnemonic representations emerge to empower deviation from a routine behavioral strategy.

Significance Statement

Prefrontal cortex (PFC) activity is necessary for optimal performance of freely-moving spatial working memory tasks in rodents. Despite this, PFC representations of retrospective actions or stimuli—one quintessential working memory hallmark—are only variably observed during task delays, complicating our understanding of the PFC’s role in spatial working memory. Here, we examine cellular-resolution PFC activity in a high-optionality match-to-sample radial maze task and find retrospective delay representations. Strikingly, these delay representations are more evident in error trials. This suggests that in the freely-moving context, explicit PFC representations of retrospective information support deviations from an entrained behavioral strategy, rather than equally supporting all spatial working memory-based behavior.
Orthrus: Towards Evolutionary and Functional RNA Foundation Models
Authors: Fradkin Philip , Shi Ruian , Isaev Keren , Frey Brendan J. , Morris Quaid , Lee Leo J. , Wang Bo
Published: October 2024

In the face of rapidly accumulating genomic data, our ability to accurately pre-dict key mature RNA properties that underlie transcript function and regulation remains limited. Pre-trained genomic foundation models offer an avenue to adapt learned RNA representations to biological prediction tasks. However, existing genomic foundation models are trained using strategies borrowed from textual or visual domains that do not leverage biological domain knowledge. Here, we intro-duce Orthrus, a Mamba-based mature RNA foundation model pre-trained using a novel self-supervised contrastive learning objective with biological augmentations. Orthrus is trained by maximizing embedding similarity between curated pairs of RNA transcripts, where pairs are formed from splice isoforms of 10 model organ-isms and transcripts from orthologous genes in 400+ mammalian species from the Zoonomia Project. This training objective results in a latent representation that clusters RNA sequences with functional and evolutionary similarities. We find that the generalized mature RNA isoform representations learned by Orthrus significantly outperform existing genomic foundation models on five mRNA prop-erty prediction tasks, and requires only a fraction of fine-tuning data to do so. Finally, we show that Orthrus is capable of capturing divergent biological function of individual transcript isoforms.
Early disruption of entorhinal dopamine in a knock-in model of Alzheimer’s disease
Authors: Nakagawa Tatsuki , Xie Jiayun L. , Savadkohighodjanaki Marjan , Zhang Yutian J. , Jun Heechul , Cao Kai , Ichii Ayana , Lee Jason Y. , Soma Shogo , Medhat Yasmeen K. , Saido Takaomi C. , Igarashi Kei M
Published: October 2024

The entorhinal cortex (EC) is a critical brain area for memory formation, while also the region exhibiting the earliest histological and functional alterations in Alzheimer’s disease (AD). The EC thus has been long hypothesized as one of the originating brain areas of AD pathophysiology, although circuit mechanisms causing its selective vulnerability remain poorly understood. We found that dopamine neurons projecting their axons to the lateral EC (LEC), critical for memory formation in healthy brains, become dysfunctional and cause memory impairments in early AD brains. In amyloid precursor protein knock-in mice with associative memory impairment, LEC dopamine activity and associative memory encoding of LEC layer 2/3 neurons were disrupted in parallel from the early pathological stage. Optogenetic reactivation of LEC dopamine fibers, as well as L- DOPA treatment, rescued associative learning behavior. These results suggest that dysfunction of LEC-projecting dopamine neurons underlies memory impairment in AD from early stages, pointing to a need for clinical investigation of LEC dopamine in AD patients.
The Xenopus respiratory system reveals common tetrapod mechanisms for growth, regeneration and healing
Authors: Perry Shiri Kult , Shaidani Nikko-Ideen , Horb Marko E , Shubin Neil
Published: October 2024

In recent years, we have seen a significant increase in our understanding of the mechanisms of development, regeneration, and healing of the respiratory system. However, most of these studies have been limited by their focus on mammalian systems. Here, we aimed to identify the underlying molecular mechanisms that are active during lung growth and tissue repair in amphibians, specifically Xenopus tropicalis (X. tropicalis). First, we analyzed the stem cell composition and signaling pathways that are active in epithelial and mesenchymal cells during lung growth. Then, we established a protocol for lung injury to assess the types of stem cells underlying tissue repair. In mammals, Sftpc+ (AT2) cells are alveolar stem cells that can differentiate to Krt8+ cells during lung homeostasis and post-injury repair. In this study, we identified Sftpc+ cells and Krt8+ cells, along with the activity of key developmental signaling pathways, Hippo and Wnt, during lung maturation at post-metamorphosis stages. We then established a protocol for lung injury using chemically induced injury with bleomycin, which damages the lung through oxidative stress. The results show an elevation in collagen post-injury, indicating bleomycin’s effect in causing lung fibrosis.X. tropicalisfroglets survived 42 days post-injury, with a continuous decrease in fibrosis. To explore this effect, we analyzed the distribution of lung stem cells; Sox9 protein levels and Sftp gene expression were downregulated at the alveoli 42 days post-injury. The decrease in stem cell marker expression 42 days post-injury suggests they are differentiating as part of the healing process. Nevertheless, we could still detect them after a few weeks of healing. These results suggest thatX. tropicalishas a regenerative capacity for lung tissue repair and that the same signaling pathways and stem cells are active in both amphibians and mammalian lungs during lung growth, regeneration, and healing. These findings show for the first time the physiological similarities between the anuran and the mammalian lung during growth and tissue repair processes, suggestingX. tropicalisas a potential animal model to study lung regeneration.
Single-nucleus transcriptomics of wing sexual dimorphism and scale cell specialization in sulphur butterflies
Authors: Loh Ling S. , Hanly Joseph J. , Carter Alexander , Chatterjee Martik , Tsimba Martina , Shodja Donya N. , Livraghi Luca , Day Christopher R. , Reed Robert D. , McMillan W. Owen , Wray Gregory A. , Martin Arnaud
Published: October 2024

The evolution of sexual secondary characteristics necessitates regulatory factors that confer sexual identity to differentiating tissues and cells. InColias eurythemebutterflies, males exhibit two specialized wing scale types — UV-iridescent (UVI) and lanceolate scales — absent in females and likely integral to male courtship behavior. This study investigates the regulatory mechanisms and single-nucleus transcriptomics underlying these two sexually dimorphic cell types during wing development. We show that Doublesex (Dsx) expression is itself dimorphic and required to repress the UVI cell state in females, while unexpectedly, UVI activation in males is independent from Dsx. In the melanic marginal band, Dsx is required in each sex to enforce the presence of lanceolate scales in males, and their absence in females. Single-nucleus RNAseq reveals that UV-iridescent and lanceolate scale cell precursors each show distinctive gene expression profiles at 40% of pupal development, with marker genes that include regulators of transcription, cell signaling, cytoskeletal patterning, and chitin secretion. Both male-specific cell types share a low expression of theBric-a-brac(Bab) transcription factor, a key repressor of the UVI fate. Bab ChIP-seq profiling suggests that Bab binds the cis-regulatory regions of gene markers associated to UVI fate, including potential effector genes involved in the regulation of cytoskeletal processes and chitin secretion, and loci showing signatures of recent selective sweeps in an UVI-polymorphic population. These findings open new avenues for exploring wing patterning and scale development, shedding light on the mechanisms driving the specification of sex-specific cell states and the differentiation of specialized cell ultrastructures.
The potential impact of declining development assistance for healthcare on population health: projections for Malawi
Authors: Molaro Margherita , Revill Paul , Chalkley Martin , Mohan Sakshi , Mangal Tara , Colbourn Tim , Collins Joseph H. , Graham Matthew M. , Graham William , Janoušková Eva , Manthalu Gerald , Mnjowe Emmanuel , Mulwafu Watipaso , Murray-Watson Rachel , Twea Pakwanja D. , Phillips Andrew N. , She Bingling , Tamuri Asif U. , Nkhoma Dominic , Mfutso-Bengo Joseph , Hallett Timothy B.
Published: October 2024

Development assistance for health (DAH) to Malawi will likely decrease as a fraction of GDP in the next few decades. Given the country’s significant reliance on DAH for the delivery of its healthcare services, estimating the impact that this could have on health projections for the country is particularly urgent. We use the Malawi-specific, individual-based “all diseases – whole health-system”Thanzi La Onsemodel to estimate the impact this could have on health system capacities, proxied by the availability of human resources for health, and consequently on population health outcomes. We estimate that the projected changes in DAH could result in a 7-15.8% increase in disability-adjusted life years compared to a scenario where health spending as a percentage of GDP remains unchanged. This could cause a reversal of gains achieved to date in many areas of health, although progress against HIV/AIDS appears to be less vulnerable. The burden due to non-communicable diseases, on the other hand, is found to increase irrespective of yearly growth in health expenditure, if assuming current reach and scope of interventions. Finally, we find that greater health expenditure will improve population health outcomes, but at a diminishing rate.
How improvements to drug effectiveness impact mass drug administration for control and elimination of schistosomiasis
Authors: Ellis John R. , Mutono Nyamai , Vasconcelos Andreia , Thumbi SM , Hollingsworth T. Déirdre , Anderson Roy M.
Published: October 2024

Schistosomiasis affects more than 230 million people worldwide. Control and elimination of this parasitic infection is based on mass drug administration of praziquantel (PZQ), which has been in use for several decades. Because of the limitations of the efficacy of PZQ especially against juvenile worms, and the threat of the emergence of resistance, there is a need to consider alternative formulations or delivery methods, or new drugs that could be more efficacious. We use an individual-based stochastic model of parasite transmission to investigate the effects of possible improvements to drug efficacy. We consider an increase in efficacy compared to PZQ, as well as additional efficacy against the juvenile life stage of schistosome parasites in the human host, and a slow-release formulation that would provide long-lasting efficacy for a period of time following treatment.

Analyses suggest a drug with a high efficacy of 99%, or with efficacy lasting 24 weeks after treatment, are the two most effective individual improvements to the drug profile of PZQ. A drug with long lasting efficacy is most beneficial when MDA coverage is low. However, when prevalence of infection has already been reduced to a low level, a high efficacy is the most important factor to accelerate interruption of transmission. Our results indicate that increased efficacy against juvenile worms can only result in modest benefits, but the development of a new drug formulation with higher efficacy against adult worms or long-lasting efficacy would create an improvement to the community impact over the currently used formulation.

Author summary

The World Health Organization has set the target of elimination of schistosomiasis as a public health problem by 2030. Currently, praziquantel is the sole drug used in mass drug administration (MDA) for schistosomiasis, raising concerns about the potential evolution of resistance and whether an improved drug profile would be necessary to achieve elimination and the more ambitious goal of interruption of transmission. We present the results from an individual-based stochastic mathematical model that simulates schistosome transmission and the impact of MDA. Three potential improvements to the properties of the drug are considered: improved efficacy, long lasting efficacy post a single treatment and improved efficacy against the juvenile life stage of the schistosome. Our findings reveal that with good coverage, an improved drug efficacy is best at reducing prevalence and achieving interruption of transmission. However, when MDA quality is compromised due to low coverage, infrequent treatment or high rates of non-adherence, then a long-lasting efficacy performs best. There is only a modest benefit of improved drug efficacy against juvenile schistosomes. These results highlight the importance of good MDA program and inform future drug development aims.
High Prevalence of Unrecognized Actionable Cardiac Arrhythmias in Patients with Moderate to Severe Chronic Obstructive Pulmonary Disease
Authors: Coleman Kristie M. , Wolf RN. Elliot , Varrias Dimitrios , Schwartz Jacob , Garcia Brenda , Roselli Victoria , Lam Betty , Leavitt Jonas , Sharma Nikhil , Dumchin Gregory , Altschul Erica , Oks Margarita , Mina Bushra , Mountantonakis Stavros E.
Published: October 2024

Background

Patients with chronic obstructive pulmonary disease (COPD) are at high risk for developing arrhythmias due to hypoxemia, right heart failure, and the use of beta-agonist inhalers. Symptoms related to arrhythmias can often be masked or confounded by symptoms related to COPD exacerbation and remain undiagnosed. With this study, we identify the incidence of actionable arrhythmias in patients with no prior cardiology follow-up and moderate-severe COPD with continuous monitoring.

Methods

An automatic referral for electrophysiology (EP) consult was generated in patients with moderate-severe COPD if they endorsed one of the following: palpitations, dizziness, abnormal ECG, or near syncope. Eligible patients underwent ILR implantation after evaluation with an EP specialist and were followed via remote monitoring for 12 months. A control group of patients without COPD matched for age, sex, and implant indication were randomly selected in a 3:1 ratio. Actionable arrhythmias, defined as arrhythmias that correlated with symptoms triggered by the patient, necessitating EP intervention, were recorded for both groups.

Results

In this prospective cohort study, 21 patients with COPD were enrolled and compared to 63 controls. COPD patients experienced a significantly higher rate of actionable arrhythmias compared to the controls (48% vs 11%, p<0.001). EP interventions in response to actionable arrhythmias included eight patients initiated on anticoagulation, three catheter ablations, one implantable cardiac defibrillator, and one permanent pacemaker implanted. In multivariate analysis, COPD was an independent predictor of actionable arrhythmias (aOR 4.3, 95% CI 1.2-15.2, p=0.02) when adjusting for chronic kidney disease and all-cause readmissions.

Conclusion

Continuous monitoring was highly effective in diagnosing significant arrhythmic events in patients with moderate-severe COPD. Awareness should be raised about the high arrhythmic risk in this population and the role of continuous monitoring should be evaluated in larger studies.

Abstract Figure

WHAT IS KNOWN?

Patients with COPD are at greater risk for developing cardiac arrhythmias, which may propagate COPD exacerbations.

WHAT THE STUDY ADDS

Quantification of incidence of actionable arrhythmias in patients with moderate to severe COPD using continuous monitoring for the 1sttime.

Multivariate analysis which determines whether this phenomenon is due to demographic confounders, comorbidities, treatment modalities or an independent association.

Detailed presentation of the type or arrhythmias, COPD exacerbations and healthcare utilization, emphasizing the need for arrhytmia surveillance in this vulnerable patient population.
Prospective Quantification of Tricuspid Regurgitation with Echocardiography vs 4D Flow Cardiac Magnetic Resonance
Authors: Sularz Agata , Negm Ahmed S. , Chavez-Ponce Alejandra , El Shaer Ahmed , Liu Chia-Hao , Bird Jared , Oh Jae , Pislaru Sorin , Collins Jeremy D. , Alkhouli Mohamad
Published: October 2024

Introduction

Cardiac magnetic resonance (CMR) is a valuable tool in the assessment of valvular disease. However, its utilization in tricuspid regurgitation (TR) evaluation has been limited. We sought to compare TR grading with 4D-CMR and transthoracic echocardiography (TTE).

Methods

We prospectively recruited patients with ≥moderate TR on TTE to undergo multiparametric CMR with integrated cardiac function and 4D flow assessments using a 1.5-T scanner (Siemens Somatom Aera, Erlangen, Germany). Patients with other severe valvulopathy, end-stage renal disease, or pacemakers were excluded. TR was graded severe on CMR when TR volume ≥45 mL, and/or TR fraction ≥50%. The weighted kappa test was used to assess the agreement in overall TR grading on TTE and MR.

Results

Fifty-two patients were enrolled (mean age 78.5±7.6 years, 53.8% men). The median interval between CMR and TTE was 2 days (IQR=1-37). The agreement between TTE and CMR-derived TR volume was fair (kappa = 0.28, 95%CI 0.13-0.45), with only 10 of 31 patients (32%) with ≥severe TR on TTE meeting severe TR volume criterion on CMR (TR volume ≥45 ml). There was no agreement between TTE and CMR-derived TR fraction (kappa=0.04, 95%CI 0.13-0.46) with only 3 of 31 patients (13%) with ≥severe TR on TTE meeting severe TR criterion on CMR (TR fraction ≥50%).

Conclusion

Grading of TR was frequently discordant between TEE and 4D-MRI. Further studies are needed to elucidate the clinical impact of concordant/discordant TR grading on multi-modality imaging.
Cochlear implants with dexamethasone-eluting electrode arrays reduce foreign body response in a murine model of cochlear implantation and human subjects
Authors: Rahman Muhammad Taifur , Mostaert Brian , Eckard Peter , Fatima Shakila Mahmuda , Scheperle Rachel , Razu Ibrahim , Hunger Bryce , Olszewski Rafal T. , Gu Shoujun , Garcia Cristina , Khan Nashwaan Ali , Bennion Douglas M , Oleson Jacob , Kirk Jonathon R. , Enke Ya Lang , Gay Robert D. , Morell Robert J. , Hirose Keiko , Hoa Michael , Claussen Alexander D. , Hansen Marlan R.
Published: October 2024

The inflammatory foreign body response (FBR) following cochlear implantation (CI) can negatively impact CI outcomes, including increased electrode impedances. This study aims to investigate the long-term efficacy of dexamethasone eluting cochlear implant and locally delivered dexamethasone, a potent anti-inflammatory glucocorticoid on the intracochlear FBR and electrical impedance post-implantation in a murine model and human subjects. The left ears of CX3CR1+/GFPThy1+/YFP(macrophage-neuron dual reporter) mice were implanted with dexamethasone-eluting cochlear implants (Dex-CI) or standard implant (Standard-CI) while the right ear served as unoperated control. Another group of dual reporter mice was implanted with a standard CI electrode array followed by injection of dexamethasone in the middle ear to mimic current clinical practice (Dex-local). Mouse implants were electrically stimulated with serial measurement of electrical impedance. Human subjects were implanted with either standard or Dex-CI followed by serial impedance measurements. Dex-CI reduced electrical impedance in the murine model and human subjects and inflammatory FBR in the murine model for an extended period. Dex-local in the murine model is ineffective for long-term reduction of FBR and electrode impedance. Our data suggest that dexamethasone eluting arrays are more effective than the current clinical practice of locally applied dexamethasone in reducing FBR and electrical impedance.
Integrative multi-ethnic Mendelian randomisation identifies tissue-specific causal genes for Coronary Artery Disease and interactions with post-acute Covid
Authors: Jaros Rachel , O’Sullivan Justin M.
Published: October 2024

Coronary artery disease (CAD) is highly heritable and remains the leading cause of mortality worldwide. Understanding the genetic and mechanistic underpinnings of CAD is crucial for early risk assessment and intervention. We conducted a transcriptome-wide Mendelian randomisation (MR) study, utilising unbiased tissue-specific gene regulatory networks, to identify genes causally associated with CAD in European and East Asian populations. We identified 291 tissue and ancestry-specific genes implicated in CAD, including 98 novel protein-coding genes across coronary artery, whole blood, and lung tissues. Genes involved in epigenetic processes (egPAXBPandKIAA0232) causally associated with CAD. Moreover, we identified genes related to the ubiquitin-proteasome system in the coronary artery and kinase signalling in the lung, as being causally related to CAD. The integration of protein interaction networks identified causal connections between CAD and HDL cholesterol levels, providing novel insights into CAD mechanisms, and potential actionable targets for people with this risk profile. The results also provide intriguing insights into the link between SARS-CoV-2 and CAD, unveiling mechanisms that may underlie the increased risk of cardiovascular disease following SARS-CoV-2 infection. The causal mechanisms we identified emphasise the tissue-agnostic and ancestrally unique pathways that underscore the complex interplay between CAD development, metabolic disturbances, and the immune system. Collectively, our results provide valuable insights into CAD pathogenesis and potential therapeutic targets.
Distinct neural alterations in schizophrenia and autism: A meta-analysis of social cognition and emotion processing
Authors: Boisvert Mélanie , Pilon Florence , Mottron Laurent , Potvin Stéphane
Published: October 2024

Objective

Two conditions alter socio-communicative behaviors in humans: autism and schizophrenia. However, it is not well-known if these disorders share the same neural alterations during socio-emotional tasks. The main objective was to examine neural alterations in autism and schizophrenia during emotional and social cognition tasks. Our second objective was to determine if these alterations were common or distinct between disorders.

Methods

Functional neuroimaging studies using an emotional or a social cognition paradigm in schizophrenia or autism were queried from three databases. We selected articles if they reported whole brain coordinates of different activations between autism/schizophrenia participants and non-clinical controls. Using SDM, we analyzed the coordinates of brain activity differences between case and control groups, categorized by diagnosis and paradigm.

Results

The meta-analysis aggregated 104 studies in schizophrenia and 80 studies in autism spectrum disorder. During emotional tasks, individuals with autism showed reduced activity in the left amygdala, while those with schizophrenia showed reduced activity in the right inferior frontal gyrus and the median cingulate gyrus. During social cognition tasks, alterations in both conditions did not survive corrected statistical thresholds. No spatial conjunction was observed between the alterations seen in each disorder during both emotional/social cognition tasks at both corrected and uncorrected thresholds.

Conclusions

These results suggest that the emotional processing in autism and schizophrenia in adulthood are characterized by alterations of bottom-up and top-down mechanisms of the emotional network, respectively. It should encourage the pursuit of functional neuroimaging studies on emotion processing using machine learning to differentiate these two conditions.
Privacy Fact Sheets mitigate Disease-related Privacy Concerns and Facilitate Equal Access to the Electronic Health Record: Randomized Controlled Trial
Authors: von Kalckreuth Niklas , Feufel Markus A.
Published: October 2024

Background

The German electronic health record (EHR) aims to enhance patient care and reduce costs, but users often worry about data security. To mitigate disease-related privacy concerns, for instance, surrounding stigmatized diseases, we test the effect of privacy fact sheets (PFS) - a concise but comprehensive transparency feature - on increasing EHR usage.

Objective

We investigate whether displaying a PFS shortly before upload decisions must be made mitigates disease-related privacy concerns and makes uploads more likely.

Methods

In an online user study, 393 German participants interacted with a randomly assigned medical report that varied systematically in terms of disease-related stigma (high vs. low) and time course (acute vs. chronic). They were then asked to decide whether to upload the report to the EHR, while we systematically varied the presentation of privacy information (PFS vs. no PFS).

Results

The results show that, in general, upload behavior is negatively influenced by disease-related stigma (OR 0.130, p<.001) and positively influenced when a PFS is given (OR 4.527, p<.001). This increase was particularly pronounced for stigmatized diseases (OR 5.952, p=.006). Time course of diseases had no effect.

Conclusions

Our results demonstrate that PFSs help to increase EHR uploads by mitigating privacy concerns related to stigmatized diseases. This indicates that a PFS is mainly relevant and effective for users with increased privacy risk perceptions, while they do not hurt other users. Thus, implementing PFSs can increase the likelihood that more patients, even those with increased privacy concerns due to stigmatized diseases, upload their data to the EHR, ultimately increasing health equity. That is, PFS may help to realize EHR benefits such as more efficient healthcare processes, improved treatment outcomes, and reduced costs for more users.

Trial Registration

Deutsches Register Klinischer Studien DRKS00033652,https://drks.de/search/de/trial/DRKS00033652
The Hydrocephalus Association Patient-Powered Interactive Engagement Registry (HAPPIER): Design and Initial Baseline Report
Authors: Jakopin Noriana E. , Lanjewar Samantha N. , Garzon Amanda , Gross Paul , Holubkov Richard , Moghekar Abhay , Preston Jason , Romanoski Margaret , Shannon Chevis N. , Tamber Mandeep S. , van der Willigen Tessa , Sloan Melissa , Chau Monica J. , Koschnitzky Jenna E.
Published: October 2024

Objective

Hydrocephalus is a neurological condition characterized by an accumulation of cerebrospinal fluid with no cure and limited treatments. There is a significant gap in hydrocephalus research where patients lack opportunities to voice their perspectives on their condition. The Hydrocephalus Association Patient-Powered Interactive Engagement Registry (HAPPIER) database was created to highlight the quality-of-life outcomes in hydrocephalus from a longitudinal perspective. HAPPIER ensures that the lived experiences of those affected by hydrocephalus are highlighted, and provides a platform for researchers to access this data or distribute their own surveys, ultimately aiming to improve patient-centered care and outcomes. This publication introduces the registry to the medical and scientific community by highlighting demographics, etiology, treatments, symptom profiles, and diagnosed comorbidities of the participants.

Methods

HAPPIER was developed by the Hydrocephalus Association and a 10-member steering committee. Development of its surveys was informed by other registries with similar goals, existing surveys and assessments, and input from University of Utah Data Center faculty. The study population was recruited using social and traditional media, referrals from medical professionals, and advertisement at Hydrocephalus Association-sponsored events.

Results

Of the 691 survey participants (referring to those with hydrocephalus), 451 (65.3%) were individuals responding for themselves. 380 (55.0%) of the registry population was female, 594 (86.0%) was white, and 606 (87.7%) was from the United States and territories. The most common age reported for diagnosis was between 0 and 11 months (46.2%), and the most common hydrocephalus etiology reported was congenital hydrocephalus (43.8%). The most prevalent treatment reported was a shunt(s) (71.2%). The most commonly-reported symptom was headaches (60.3%), and 69.9% of participants reported being diagnosed with movement impairments and 70.8% with other health conditions.

Conclusion

HAPPIER is a novel database developed to address the gaps in data in non-clinical outcomes of hydrocephalus, which are critical to clinical care and understanding hydrocephalus in its totality. Patient perspectives and outcomes have been historically underrepresented. By directly engaging individuals living with hydrocephalus and their caregivers, HAPPIER is designed to incorporate essential patient perspectives through planned longitudinal data collection and patient surveys. These data are open to investigators interested in analyzing the collected data.
Misfolded alpha synuclein co-occurrence with Alzheimer’s disease proteinopathy
Authors: Jonaitis Erin M. , MacLeod Karen , Lamoureux Jennifer , Jeffers Beckie , Studer Rachel L. , Middleton John , Wilson Rachael E. , Chin Nathaniel A. , Okonkwo Ozioma C. , Bendlin Barbara B. , Asthana Sanjay , Carlsson Cynthia M. , Gallagher Catherine L. , Hermann Bruce , McEvoy Sean , Kollmorgen Gwendlyn , Zetterberg Henrik , Concha-Marambio Luis , Johnson Sterling C. , Lebovitz Russ M. , Langhough Rebecca E.
Published: October 2024

INTRODUCTION

Multi-etiology dementia necessitates in-vivo markers of copathologies including misfoldedα-synuclein (syn). We measured misfolded syn aggregates (syn-seeds) via qualitative seed amplifcation assays (synSAA) and examined relationships with markers of Alzheimer’s disease (AD).

METHODS

Cerebrospinal fluid (CSF) was obtained from 420 participants in two Wisconsin AD risk cohorts (35% male; 91% cognitively unimpaired; mean (SD) age, 65.42 (7.78) years; education, 16.17 (2.23) years). synSAA results were compared to phosphorylated tau (T), beta amyloid (A), and clinical outcomes. Longitudinal cognition was modeled with mixed effects.

RESULTS

Syn positivity (synSAA+) co-occurred with T (in synSAA+ vs synSAA-, 36% vs 20% T+; p=0.011) and with cognitive impairment (10% vs 7% MCI; 10% vs 0% dementia; p=0.00050). synSAA+ participants’ cognitive performance declined ∼40% faster than synSAA-for Digit Symbol, but not other tests.

DISCUSSION

Findings support prevalent syn copathology in a mostly-unimpaired AD risk cohort. Future work will explore relationships with disease progression.