bluuebunny/crossref_metadata_2025 huggingface dataset:
Interdisciplinary perspectives on multimorbidity in Africa: developing an expanded conceptual model
Authors: Dixon Justin , Morton Ben , Nkhata Misheck J. , Silman Alan , Simiyu Ibrahim G. , Spencer Stephen A. , Van Pinxteren Myrna , Bunn Christopher , Calderwood Claire , Chandler Clare I.R. , Chikumbu Edith , Crampin Amelia C. , Hurst John R. , Jobe Modou , Kengne Andre Pascal , Levitt Naomi S. , Moshabela Mosa , Owolabi Mayowa , Peer Nasheeta , Phiri Nozgechi , Singh Sally J. , Tamuhla Tsaone , Tembo Mandikudza , Tiffin Nicki , Worrall Eve , Yongolo Nateiya M. , Banda Gift T. , Bickton Fanuel , Bilungula Abbi-Monique Mamani , Bosire Edna , Chawani Marlen Stacy , Chinoko Beatrice , Chisala Mphatso , Chiwanda Jonathan , Drew Sarah , Farrant Lindsay , Ferrand Rashida A. , Gondwe Mtisunge , Gregson Celia L. , Harding Richard , Kajungu Dan , Kasenda Stephen , Katagira Winceslaus , Kwaitana Duncan , Mendenhall Emily , Mensah Adwoa Bemah Boamah , Mnenula Modai , Mupaza Lovemore , Mwakasungula Maud , Nakanga Wisdom , Ndhlovu Chiratidzo , Nkhoma Kennedy , Nkoka Owen , Opare-Lokko Edwina Addo , Phulusa Jacob , Price Alison , Rylance Jamie , Salima Charity , Salimu Sangwani , Sturmberg Joachim , Vale Elizabeth , Limbani Felix
Published: September 2023

Multimorbidity is an emerging challenge for healthcare systems globally. It is commonly defined as the co-occurrence of two or more chronic conditions in one person, but the suitability and utility of this concept beyond high-income settings is uncertain. This article presents the findings from an interdisciplinary research initiative that drew together 60 academic and applied partners working in 10 African countries to critically consider existing concepts and definitions of multimorbidity, to evaluate their utility and limitations, and to co-develop an context-sensitive, interdisciplinary conceptual framing. This iterative process was guided by the principles of grounded theory and involved focus- and whole-group discussions during a three-day concept-building workshop, thematic coding of workshop discussions, and further post-workshop iterative development and refinement. The three main thematic domains that emerged from workshop discussions were: the disease-centricity of current concepts and definitions; the need to foreground what matters to people living with multimorbidity (PLWMM), families, and other stakeholders; and the need for conceptual breadth and flexibility to accommodate the contributions of multiple disciplinary perspectives and heterogeneity within and between different African countries. These themes fed into the development of an expanded conceptual model that centres the catastrophic impacts multimorbidity often has for PLWMM, their families and support structures, for service providers, and for resource-constrained healthcare systems.
What Loss Functions Do Humans Optimize When They Perform Regression and Classification
Authors: Ryu Hansol X. , Srinivasan Manoj
Published: September 2023

Studying how humans perceive patterns in visually presented data is useful for understanding data-based decision-making and potentially understanding visually mediated sensorimotor control. We conducted experiments to examine how human subjects perform the simplest machine learning or statistical estimation tasks: linear regression and binary classification on 2D scatter plots. We used inverse optimization to infer the loss function humans optimize when they perform these tasks. Minimizing the sum of regression error raised to the power of 1.7 best-described human performing regression on sparse data. Loss functions with lower exponents, which are less sensitive to outliers, were better descriptors for regression tasks performed on less sparse data consisting of more data points. For the classification task, minimizing a logistic loss function was on average a better descriptor of human choices than an exponential loss function applied to only misclassified data. People changed their strategies as data density increased. These results represent overall trends across subjects and trials but there was large inter- and intra-subject variability in human choices. Future work may examine other loss function families and other tasks. Such understanding of human loss functions may inform the design of applications that interact with humans better and imitate humans more effectively.
An accurate probabilistic step finder for time-series analysis
Authors: Rojewski Alex , Schweiger Maxwell , Sgouralis Ioannis , Comstock Matthew , Pressé Steve
Published: September 2023

Noisy time-series data is commonly collected from sources including Förster Resonance Energy Transfer experiments, patch clamp and force spectroscopy setups, among many others. Two of the most common paradigms for the detection of discrete transitions in such time-series data include: hidden Markov models (HMMs) and step-finding algorithms. HMMs, including their extensions to infinite state-spaces, inherently assume in analysis that holding times in discrete states visited are geometrically–or, loosely speaking in common language, exponentially–distributed. Thus the determination of step locations, especially in sparse and noisy data, is biased by HMMs toward identifying steps resulting in geometric holding times. In contrast, existing step-finding algorithms, while free of this restraint, often rely onad hocmetrics to penalize steps recovered in time traces (by using various information criteria) and otherwise rely on approximate greedy algorithms to identify putative global optima. Here, instead, we devise a robust and general probabilistic (Bayesian) step-finding tool that neither relies onad hocmetrics to penalize step numbers nor assumes geometric holding times in each state. As the number of steps themselves in a time-series are,a prioriunknown, we treat these within a Bayesian nonparametric (BNP) paradigm. We find that the method developed, Bayesian Nonparametric Step (BNP-Step), accurately determines the number and location of transitions between discrete states without any assumed kinetic model and learns the emission distribution characteristic of each state. In doing so, we verify that BNP-Step can analyze sparser data sets containing higher noise and more closely-spaced states than otherwise resolved by current state-of-the-art methods. What is more, BNP-Step rigorously propagates measurement uncertainty into uncertainty over state transition locations, numbers, and emission levels as characterized by the posterior. We demonstrate the performance of BNP-Step on both synthetic data as well as data drawn from force spectroscopy experiments.

SIGNIFICANCE

Many time-series data sets exist which are challenging to analyze with current state-of-the-art methods, either because they contain excessive noise or because they violate one or more assumptions inherent to the chosen analysis method. To our knowledge, BNP-Step is the first time-series analysis algorithm which leverages Bayesian nonparametrics to learn the number and location of transitions between states and the emission levels associated to each state, while providing rigorous estimates of uncertainty for the learned quantities. We anticipate our algorithm will allow analysis of data sets at levels of noise or sparsity beyond what current state-of-the-art methods allow, and could potentially reveal previously unknown features in data sets analyzed using existing methods.
TwinsMX: Exploring the Genetic and Environmental Influences on Health Traits in the Mexican Population
Authors: García-Vilchis B. , Román-López T.V. , Ramírez-González D. , López-Camaño X. , Murillo-Lechuga V. , Díaz X. , Sánchez-Moncada I.C. , Espinosa-Méndez I.M. , Zenteno-Morales D. , Espinosa-Valdes Z.X. , Pradel-Jiménez S. , Tapia-Atilano A. , Zanabria-Pérez A.V. , Livas-Gangas F. , Aldana-Assad O. , Caballero-Sánchez U. , Dominguez-Frausto C.A. , Rentería M.E. , Medina-Rivera A. , Alcauter S. , Ruiz-Contreras A.E.
Published: September 2023

TwinsMX registry is a national research initiative in Mexico that aims to understand the complex interplay between genetics and environment in shaping physical and mental health traits among the country’s population. With a multidisciplinary approach, TwinsMX aims to advance our knowledge of the genetic and environmental mechanisms underlying ethnic variations in complex traits and diseases, including behavioral, psychometric, anthropometric, metabolic, cardiovascular, and mental disorders. With information gathered from over 2800 twins, this article updates the prevalence of several complex traits; and describes the advances and novel ideas we have implemented such as magnetic resonance imaging. The future expansion of the TwinsMX registry will enhance our comprehension of the intricate interplay between genetics and environment in shaping health and disease in the Mexican population. Overall, this report describes the progress in the building of a solid database which shall allow to study complex traits in the Mexican population, valuable not only for our consortium but for the worldwide scientific community by providing new insights of understudied genetically admixed populations.
Pre-Diagnosis Dietary Patterns and Risk of Multiple Myeloma in the NIH-AARP Diet and Health Study
Authors: Castro Francesca , Parikh Richa , Eustaquio Jelyn C. , Derkach Andriy , Joseph Janine M. , Lesokhin Alexander M. , Usmani Saad Z. , Shah Urvi A.
Published: September 2023

Background

Despite patient interest in knowing whether diet is linked to multiple myeloma (MM), there is limited research on dietary patterns and MM risk. Two studies have assessed this risk, albeit with a small number of MM cases. The EPIC-Oxford cohort and Oxford Vegetarian study (65 MM cases) showed that fish eaters, vegetarians and vegans had significantly reduced MM risk compared to meat eaters. The Nurses’ Health Study and Health Professionals Follow-up Study (478 MM cases) showed a significantly increased MM risk in men with Empirical Dietary Inflammatory Pattern.

Methods

The NIH-AARP Diet and Health study is a prospective cohort of 567,169 persons who completed a food frequency questionnaire in 1995-1996 and were followed until December 2011. Healthy Eating Index-2015 (HEI-2015), Healthy Diet Score (HDS), alternate Mediterranean Diet (aMED) and healthful Plant-based Diet Index (hPDI) scores were calculated usinga prioridefined methods and grouped into quartiles, with higher scores reflecting healthier eating patterns. We prospectively evaluated the association between pre-diagnosis dietary patterns and MM incidence in this cohort. Hazard ratios (HR) and 95% confidence intervals (95%CI) were estimated using multivariate Cox proportional hazards models adjusted for age at study entry, sex, race, body mass index, education, and total energy intake (by residual method). Sensitivity analysis was conducted to assess reverse causality by excluding MM cases diagnosed within one year of follow-up.

Results

Among 392,589 participants (after exclusions), a total of 1,366 MM cases (59% males; 92% non-Hispanic whites) were identified during the follow-up period. Analysis revealed a significant association between hPDI scores and reduced MM risk (highest vs lowest quartile, HR 0.85; 95%CI 0.73-1.0; p=0.043) (Table). In sensitivity analysis (1,302 MM cases), the association was no longer significant (HR 0.87; 95%CI 0.74-1.03; p 0.09) but trended in the same direction. This may be due to small sample size, given MM is a rare disease. HEI-2015, HDS and aMED scores were not associated with MM risk.

Conclusions

A healthful plant-based diet was associated with reduced MM risk in the NIH-AARP cohort. These results will help oncologists and patients make informed choices about their diet. To our knowledge, this is the largest epidemiologic study to date assessing pre-diagnosis dietary patterns and MM risk.
Estimating changes in antibiotic consumption with the introduction of doxycycline post-exposure prophylaxis in the United States
Authors: Roster Kirstin I. Oliveira , Grad Yonatan H.
Published: September 2023

Doxycycline as post-exposure prophylaxis (doxy-PEP) reduces the risk of gonorrhea, chlamydia, and syphilis in studies of men who have sex with men (MSM) and transgender women (TGW) on HIV Pre-exposure Prophylaxis (PrEP) and people living with HIV (PLWH)). Doxy-PEP is an important tool to address the increasing burden of sexually transmitted infections (STIs), but there is concern that increased consumption of doxycycline may drive antimicrobial resistance. We estimated the expected increase in antibiotic use in the US under several doxy-PEP prescribing scenarios. We accounted for doses of antibiotics that may be averted due to the prevention of chlamydia, gonorrhea, and syphilis infections by doxy-PEP. Under a scenario of 75% adoption among the eligible population, with rates of consumption similar to the DoxyPEP trial population, monthly antibiotic consumption would increase by around 2.52 million doses, driven by doxy-PEP consumption of 2.58 million doses and less 62.1 thousand antibiotic doses that would otherwise have been used for chlamydia, gonorrhea, and syphilis treatment.
Lack of genetic evidence for NLRP3-inflammasome involvement in Parkinson’s disease pathogenesis
Authors: Senkevich Konstantin , Liu Lang , Alvarado Chelsea X. , Leonard Hampton L. , Nalls Mike A. ,   Global Parkinson’s Genetics Program (GP2), Gan-Or Ziv
Published: September 2023

Activation of the NLRP3-inflammasome has been implicated in Parkinson’s disease based onin vitroandin vivostudies. Clinical trials targeting the NLRP3-inflammasome in Parkinson’s disease are ongoing. However, the evidence supporting NLRP3’s involvement in Parkinson’s disease from human genetics data is limited. In this study, we conducted analyses of common and rare variants in NLRP3-inflammasome related genes in Parkinson’s disease cohorts. We performed pathway-specific analyses using polygenic risk scores and studied potential causal associations using Mendelian randomization with the NLRP3 components and the cytokines IL-1β and IL-18. Our findings showed no associations of common or rare variants, nor of the pathway polygenic risk score with Parkinson’s disease. Mendelian randomization suggests that altering the expression of the NLRP3-inflammasome, IL-1β or IL-18, does not affect Parkinson’s disease risk or progression. Therefore, our results do not support a role for the NLRP3-inflammasome in Parkinson’s disease pathogenesis or as a target for drug development.
Driving Under the Influence of Alcohol in People with Major Depressive Episodes and Alcohol Use Disorder
Authors: Park Ji-Yeun , Peterson Brent M. , Kim Jinsil , Galbadage Thushara
Published: September 2023

Objectives

Alcohol use disorder (AUD) and depression are the most commonly reported psychiatric comorbid conditions. We examined trends in the past-year prevalence of driving under the influence of alcohol (DUIA) among people with major depressive episodes (MDE), AUD, or both in the United States.

Methods

We analyzed 543,573 individuals aged 18 years or older from the 2005-2019 National Surveys on Drug Use and Health (NSDUH). Multivariate logistic regression models were applied to examine the adjusted past-year prevalence of DUIA. To assess trends in DUIA over time, annual average percent change (AAPC) was calculated.

Results

From 2005 to 2019, DUIA prevalence among US adults with MDE declined significantly from 18.1% to 9.4% (AAPC = -4.9). Decreasing trends in DUIA were also observed among those with AUD (from 55.4% to 37.8%, AAPC = -3.0) and among those with co-occurring MDE and AUD (from 58.3% to 38.8%, AAPC = -3.1). Compared to those with no AUD or MDE (from 8.42% to 3.99%, AAPC = -5.6), individuals with AUD and those with co-occurring MDE and AUD had significantly lower AAPCs. There was no significant AAPC difference between those with MDE and those with no AUD or MDE. Regarding sociodemographic characteristics, younger adults aged 18-34 exhibited the lowest AAPC among all diagnostic groups.

Conclusions

From 2005 to 2019, DUIA prevalence declined significantly with varying rates of decrease across different diagnostic groups. Focused public health efforts are needed to engage high-risk groups that have shown a tendency toward less expedient reductions in DUIA.
Altered placental phenotype and increased risk of placental pathology in fetal spina bifida: a matched case-control study
Authors: White Marina , Grynspan David , Arif-Pardy Jayden , Van Mieghem Tim , Connor Kristin L
Published: September 2023

Open spina bifida (SB) remains one of the most common congenital anomalies and associates with significant comorbidities in the fetus, which may, in part, be driven by placental maldevelopment. We hypothesised that placental pathologies and maldevelopment would be more prevalent in fetuses with SB compared to fetuses without congenital anomalies. Placental histopathology (H&E-stained slides) and transcriptome (Clariom D™ microarray) were evaluated for fetuses with isolated open SB undergoing either pregnancy terminations or term deliveries (cases; n=12) and control fetuses without congenital anomalies having term or preterm births (n=22). Associations between study group and placental histopathology were adjusted for fetal sex and gestational age [GA] at delivery. Relationships between placental histopathology and select placental gene expression signatures were also evaluated. Case placentae had lower placental weight than controls (median [IQR]: 263g [175, 370] vs. 455 [378, 560], p=0.001). Placental villi structural phenotype was different in cases, who had a higher proportion of immature intermediate villi than controls (32.5% [6.3, 56.3] vs. 10% [5, 13.8], p=0.01), but similar proportions of mature intermediate (10% [5, 10] vs. 10% [8.75, 11.25]) and terminal villi (22.5% [11.3, 43.8] vs. 30 [20, 36.3]), and similar odds of having many syncytial knots (adjusted odds ratio [aOR]=6 [0.2, 369]) as full-term born controls. Cellular phenotypic differences in case placentae included higher odds of having many Hofbauer cells (aOR=16.2 [1.4, 580], p=0.02) and a thick syncytial membrane (aOR=146 [3, 3.46e5], p=0.007). Expression in gene pathways related to immune/inflammatory processes, spinal cord injury, and Hedgehog and Wnt signaling were associated with placental maturity in cases. This study is the first to characterize placental histopathology in a contemporary cohort of fetuses with SB. Improved knowledge on placental histopathological and genetic phenotypes in spina bifida increases our understanding of mechanisms that may drive comorbidities to ultimately reduce offspring morbidity and mortality.
CD8 T cell hyperfunction and reduced tumour control in models of advanced liver fibrosis
Authors: Madani Jood , Li Jiafeng , Vranjkovic Agatha , Jorritsma Katrina , Hasim Mohamed S , Daneshmand Manijeh , Cheung Angela C , E Ching Angela M , Bruin Jennifer E , Ardolino Michele , Crawley Angela M
Published: September 2023

Immune dysfunction, both depression and hyperactivation, in liver disease contributes to significant morbidities and mortalities, depending on liver damage severity and etiology. The underlying causes of immune dysfunction in advanced liver disease, whether pathogen or host-mediated, remain unclear. We reported lasting generalized CD8+T cell hyperfunction in individuals with advanced liver fibrosis in chronic HCV infection. The separation of viral and fibrosis-driven effects or the association of this phenomenon with clinical outcomes of advanced liver fibrosis remains to be determined. Here, a hepatotoxic murine model of liver fibrosis was used to decouple liver fibrosis from viral infection. Carbon tetrachloride (CCl4)-treated mice presented progressive liver fibrosis within ≈12 weeks, resulting in severe diffuse fibrosis, focal necrosis and surrounding mixed inflammation; pathology similar to that of chronic HCV infection. Taking advantage of this model, we investigated if liver fibrosis caused systemic CD8+T cell hyperfunction and evaluated its impact on host immune response. At peak liver fibrosis, circulating CD8+T cells presented increased expression of IFN-γ and granzyme B (GrzB) in comparison to control animals. CD8+T cell hyperfunction arose by 8 weeks of CCl4treatment and was sustained with continued liver insult. As a result, fibrotic mice were unable to resist an ectopic tumour challenge and were less responsive to immunotherapy. Furthermore, CD8+T cell dysfunction was observed in other contexts of chronic liver insult such as high fat diet-induced liver steatosis, even in the absence of significant fibrosis. Collectively, this study shows the impact of chronic liver insult on systemic CD8+T cell function and its association with impaired immune response, such as tumour surveillance.
Mapping Structural Distribution and Gating-Property Impacts of Disease-Associated Missense Mutations in Voltage-Gated Sodium Channels
Authors: Ahangar Amin Akbari , Elhanafy Eslam , Blanton Hayden , Li Jing
Published: September 2023

Thousands of voltage-gated sodium (Nav) channel variants contribute to a variety of disorders, including epilepsy, autism, cardiac arrhythmia, and pain disorders. Yet variant effects of more mutations remain unclear. The conventional gain-of-function (GoF) or loss-of-function (LoF) classifications is frequently employed to interpret of variant effects on function and guide precision therapy for sodium channelopathies. Our study challenges this binary classification by analyzing 525 mutations associated with 34 diseases across 366 electrophysiology studies, revealing that diseases with similar phenotypic effects can stem from unique molecular mechanisms. Our results show a high biophysical agreement (86%) between homologous disease-associated variants in different Navgenes, significantly surpassing the 60% phenotype (GoFo/LoFo) agreement among homologous mutants, suggesting the need for more nuanced disease categorization and treatment based on specific gating-property changes. Using UniProt data, we mapped over 2,400 disease-associated missense variants across nine human Nav channels and identified three clusters of mutation hotspots. Our findings indicate that mutations near the selectivity filter generally diminish the maximal current amplitude, while those in the fast inactivation region lean towards a depolarizing shift in half-inactivation voltage in steady-state activation, and mutations in the activation gate commonly enhance persistent current. In contrast to mutations in the PD, those within the VSD exhibit diverse impacts and subtle preferences on channel activity. This study shows great potential to enhance prediction accuracy for variant effects based on the structural context, laying the groundwork for targeted drug design in precision medicine.
Genome related features of introns and exons reveal new properties and pareto fronts
Authors: Adiguzel Yekbun
Published: September 2023

Genome annotations reveal vast amount information, as well as genome related features. We looked at the genome related features of eukaryotes, grouped as primates, rodents, birds, fishes, insects, and plants. Features related to introns and exons reveal distinct assets. Genes’ mean lengths are positively correlated with the collective data of counts of exons in coding transcripts and both the mean lengths and counts of introns in coding transcripts. Mean lengths of introns in non-coding transcripts are also positively correlated and correlations with the counts-data are excluding the data of plants and fishes. These are valid for the median lengths as well. In addition, certain feature comparisons reveal separation of primates, rodents, birds, fishes, insects, and plants. We also observed pareto fronts in the cumulative data with the max length values of genes and introns in coding transcripts, as well as introns in coding and non-coding transcripts.
Stochastic Force Generation in an Isometric Binary Mechanical System: A Thermodynamic Model of Muscle Force Generation
Authors: Murthy Vidya , Baker Josh E.
Published: September 2023

With implications for both clean energy technologies and human health, models of muscle contraction provide insights into the inner workings of one of the most energy-efficient engines on the planet and into the modifications to that engine that lead to human diseases. However, only scientific methods can provide these insights. A binary mechanical model is a recently developed thermodynamic model of muscle contraction that implies a novel entropic kinetic formalism, provides a solution to a paradox that has perplexed scientists for over a century, and accounts for many mechanical and energetic aspects of muscle contraction. Here we use this model to perform discrete state chemical simulations of isometric force generation under different conditions and show explicitly that force generating kinetics are bounded by thermodynamic equations, that four phases of force generation occur as four separate thermodynamic processes, and that periodic force generation emerges with amplitudes and periodicities that bifurcate between constant and stochastic values through mechanisms easily understood relative to ideal thermodynamic processes. We discuss these results relative to experimental observations of spontaneous oscillatory contractions (SPOCs) in muscle and periodic force generation in small myosin ensembles.

Significance Statement

Most models of muscle contraction to date are based on the obsolete 17th century scientific philosophy that the force of the system is determined by the force of the molecules in that system. A new thermodynamic model of muscle provides a completely different interpretation of muscle mechanics and chemistry, implies a novel thermodynamic kinetic formalism, and has solved a paradigm that has intrigued scientists for over a century. Here, we use this model to simulate muscle force generation and show that force generating kinetics are constrained by thermodynamic equations that provide a clear mechanism for the periodic force generation that emerges from these stochastic simulations.
Four Phases of a Force Transient Emerge from a Binary Mechanical System
Authors: Baker Josh E.
Published: September 2023

Models of muscle contraction are important for guiding drug discovery, drug validation, and clinical decision-making with the goal of improving human health. Models of muscle contraction are also key to discovering clean energy technologies from one of the most efficient and clean-burning machines on the planet. However, these important goals can only be met through muscle models that are based on science. Most every model and mechanism (e.g., a molecular power stroke) of muscle contraction described in the literature to date is based on a corpuscular mechanic philosophy that has been challenged by science for over two decades. A thermodynamic model and mechanisms (e.g., a molecular switch) of muscle contraction is supported by science but has not yet been tested against experimental data. Here, I show that following a rapid perturbation to the free energy of a thermodynamic muscle system, a transient force response emerges with four phases, each corresponding to a different clearly-defined thermodynamic (not molecular) process. I compare these four phases to those observed in two classic muscle transient experiments. The observed consistency between model and data implies that the simplest possible model of muscle contraction (a binary mechanical system) accurately describes muscle contraction.
Within Thermal Scales: The Kinetic and Energetic Pull of Chemical Entropy
Authors: Baker Josh E.
Published: September 2023

Biological systems are fundamentally containers of thermally fluctuating atoms that through unknown mechanisms are structurally layered across many thermal scales from atoms to amino acids to primary, secondary, and tertiary structures to functional proteins to functional macromolecular assemblies and up. Understanding how the irreversible kinetics (i.e., the arrow of time) of biological systems emerge from the equilibrium kinetics of constituent structures defined on smaller thermal scales is central to describing biological function. Muscle’s irreversible power stroke – with its mechanochemistry defined on both the thermal scale of muscle and the thermal scale of myosin motors – provides a clear solution to this problem.

Individual myosin motors function as reversible force-generating switches induced by actin binding and gated by the release of inorganic phosphate, Pi. As shown in a companion article, whenNindividual switches thermally scale up to an ensemble ofNswitches in muscle, the entropy of a binary system of switches is created. We have shown in muscle that a change in state of this binary system of switches entropically drives actin-myosin binding (the switch) and muscle’s irreversible power stroke, and that this simple two-state model accurately accounts for most key aspects of muscle contraction. Extending this observation beyond muscle, here I show that the chemical kinetics of an ensemble ofNmolecules differs fundamentally from a conventional chemical analysis ofNindividual molecules, describing irreversible chemical reactions as being pulled into the future by the a priori defined entropy of a binary system rather than being pushed forward by the physical occupancy of chemical states (e.g., mass action).
GIA: A genome interval arithmetic toolkit for high performance interval set operations
Authors: Teyssier Noam , Kampmann Martin , Goodarzi Hani
Published: September 2023

Motivation

This study addresses the pressing need for efficient interval techniques in processing vast genomic datasets, such as those generated by ChIP-seq, RNA-seq, and whole-genome sequencing. Intervals are critical in characterizing biological features, necessitating streamlined interval manipulation for meaningful insights. Existing tools often struggle with memory and runtime requirements when managing extensive genomic region arithmetic.

Results

The study introduces GIA (Genomic Interval Arithmetic) and BEDRS, a novel command-line tool and a rust library that significantly enhance the performance of genomic interval analysis. GIA outperforms existing tools like BEDOPS, BEDTools, and GenomicRanges by a factor of 2x to 20x across a range of operations. These advances enable researchers to perform genomic interval operations more efficiently, drastically reducing computational time and resource requirements in high-throughput genomic sequencing analysis.

Availability and Implementation

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https://github.com/noamteyssier/gia

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https://github.com/noamteyssier/bedrs
Reference Sequence Browser: An R application with a user-friendly GUI to rapidly query sequence databases
Authors: Ramesh Sriram , Rapp Samuel , Tapias Gomez Jorge , Levine Benjamin , Tapias-Gomez Daniel , Chung Dickson , Truong Zia
Published: September 2023

Land managers, researchers, and regulators increasingly utilize environmental DNA (eDNA) techniques to monitor species richness, presence, and absence. In order to properly develop a biological assay for eDNA metabarcoding or quantitative PCR, scientists must be able to find not only reference sequences (previously identified sequences in a genomics database) that match their target taxa but also reference sequences that match non-target taxa. Determining which taxa have publicly available sequences in a time-efficient and accurate manner currently requires computational skills to search, manipulate, and parse multiple unconnected DNA sequence databases.

Our team iteratively designed a Graphic User Interface (GUI) Shiny application called the Reference Sequence Browser (RSB) that provides users efficient and intuitive access to multiple genetic databases regardless of computer programming expertise. The application returns the number of publicly accessible barcode markers per organism in the NCBI Nucleotide, BOLD, or CALeDNA CRUX Metabarcoding Reference Databases. Depending on the database, we offer various search filters such as min and max sequence length or country of origin. Users can then download the FASTA/GenBank files from the RSB web tool, view statistics about the data, and explore results to determine details about the availability or absence of reference sequences.
Short-term statin treatment reduces, and long-term statin treatment abolishes chronic vascular injury by radiation therapy
Authors: Ait-Aissa Karima , Guo Xutong , Klemmensen Madelyn , Leng Linette N. , Koval Olha M. , Grumbach Isabella M.
Published: September 2023

Background

The incidental use of statins during radiation therapy has been associated with a reduced long-term risk of developing atherosclerotic cardiovascular disease.

Objectives

Determine if irradiation causes chronic vascular injury and whether short-term administration of statins during and after irradiation is sufficient to prevent chronic injury compared to long-term administration.

Methods

C57Bl/6 mice were pretreated with pravastatin for 72 hours and then exposed to 12 Gy x-ray head-and-neck irradiation. Subsequently, they received pravastatin either for one additional day or for one year. Carotid arteries were tested for vascular reactivity and altered gene expression one year after irradiation.

Results

Treatment with pravastatin for 24 hours reduced the loss of endothelium-dependent vasorelaxation and protected against enhanced vasoconstriction after IR. It reduced the expression of some markers associated with inflammation and oxidative stress and modulated that of subunits of the voltage and Ca2+activated K+(BK) channel in the carotid artery one year after irradiation. Treatment with pravastatin for one year completely reversed the changes caused by irradiation.

Conclusions

In mice, short-term administration of pravastatin is sufficient to reduce chronic vascular injury after irradiation. Long-term administration eliminates the effects of irradiation. These findings suggest that a prospective treatment strategy involving statins could be effective in patients undergoing radiation therapy. The optimal duration of treatment in humans has yet to be determined.
Genetic networks suggest Asperger’s Syndrome as a distinct subtype of Autism Spectrum Conditions
Authors: Dmytriw Adam A. , Naveed Sadiq , Ghozy Sherief , Morsy Sara
Published: September 2023

Background

The Diagnostic and Statistical Manual of Mental Disorders (DSM-V) issued new diagnostic criteria for autism spectrum conditions (ASC) which excluded cases of Asperger’s syndrome (AS) and pervasive developmental disorder not otherwise specified (PDD-NOS). This negatively affected the support received by those affected. In this study, we explored if AS can be considered a subtype of autism.

Methods

We explored if AS is considered a subtype of autism through gene network analysis. We analysed the GEO microarray data of 170 autism patients, then, used a weighted gene co-expression network (WGCNA) pipeline. We explored whether these modules share the same expression patterns across autism subtypes. The study had 170 patients grouped into three groups: AS, autism, and PDD-NOS.

Results

Twenty-one genetic modules were constructed for autism spectrum conditions. However, only AS had a significant downregulation in one of the modules. The module genes were significantly involved in the regulation of proteolysis, catabolic process, and NF-kappaB signalling. Pathway analysis showed the association of these genes with RIPK1-mediated necrosis and regulation of necroptotic cell death. Brain enrichment analysis showed a spatiotemporal distribution. There was significant gene enrichment in the prefrontal cortex during infancy and childhood then it changes in adulthood to be more abundant in the cingulum bundle, and corpus callosum.

Conclusions

Our results suggest AS can be a distinct subtype of ASD, showing a similar gene expression pattern. Spatiotemporal distribution of the module genes in different brain regions explains the high functionality in individuals with AS.
Association between upper and lower respiratory disease among patients with primary ciliary dyskinesia: an international study
Authors: Lam Yin Ting , Papon Jean-François , Alexandru Mihaela , Anagiotos Andreas , Armengot Miguel , Boon Mieke , Burgess Andrea , Calmes Doriane , Crowley Suzanne , Dheyauldeen Sinan Ahmed. D. , Emiralioglu Nagehan , Erdem Eralp Ela , van Gogh Christine , Gokdemir Yasemin , Haarman Eric G. , Harris Amanda , Hayn Isolde , Ismail-Koch Hasnaa , Karadag Bülent , Kempeneers Céline , Kieninger Elisabeth , Kim Sookyung , Lorent Natalie , Ozcelik Ugur , Pioch Charlotte , Raidt Johanna , Reula Ana , Roehmel Jobst , Sperstad Kennelly Synne , Yiallouros Panayiotis , Goutaki Myrofora
Published: September 2023

Introduction

Nearly all patients with primary ciliary dyskinesia (PCD) report ear-nose-throat (ENT) symptoms. However, scarce evidence exists about how ENT symptoms relate to pulmonary disease in PCD. We explored possible associations between upper and lower respiratory disease among patients with PCD in a multicentre study.

Methods

We included patients from the ENT Prospective International Cohort (EPIC-PCD). We studied associations of several reported ENT symptoms and chronic rhinosinusitis (CRS)—defined using patient-reported information and examination findings—with reported sputum production and shortness of breath—using ordinal logistic regression. In a subgroup with available lung function results, we used linear regression to study associations of CRS and FEV1, accounting for relevant factors.

Results

We included 457 patients [median age: 15; interquartile range (IQR) 10–24; 54% males]. Shortness of breath associated with reported nasal symptoms and ear pain of any frequency, often or daily hearing problems, headache when bending down [odds ratio (OR) 2.1; 95% confidence interval (CI) 1.29–3.54], and CRS (OR 2.3; 95% CI 1.57–3.38) regardless of polyp presence. Sputum production associated with daily reported nasal (OR 2.2; 95% CI 1.20–4.09) and hearing (OR 2.0; 95% CI 1.10–3.64) problems and CRS (OR 2.1; 95% CI 1.48–3.07). We did not find any association between CRS and FEV1.

Conclusion

Reported upper airway symptoms and signs of CRS associated with reported pulmonary symptoms; however, not with lung function. Our results emphasise assessing and managing upper and lower respiratory disease as a common, interdependent entity among patients with PCD.
Liver abnormalities following SARS-CoV-2 infection in children under 10 years of age
Authors: Terebuh Pauline , Olaker Veronica R. , Kendall Ellen K. , Kaelber David C. , Xu Rong , Davis Pamela B.
Published: September 2023

Objective

Beginning in October 2021 in the US and elsewhere, cases of severe pediatric hepatitis of unknown etiology were identified in young children. While the adenovirus and adenovirus-associated virus have emerged as leading etiologic suspects, we attempted to investigate a potential role for SARS-CoV-2 in the development of subsequent liver abnormalities.

Design

We conducted a study utilizing retrospective cohorts of de-identified, aggregated data from the electronic health records of over 100 million patients contributed by US health care organizations.

Results

Compared to propensity-score-matched children with other respiratory infections, children aged 1-10 years with COVID-19 had a higher risk of elevated transaminases (Hazard ratio (HR) (95% Confidence interval (CI)) 2.16 (1.74-2.69)) or total bilirubin (HR (CI) 3.02 (1.91-4.78)), or new diagnoses of liver diseases (HR (CI) 1.67 (1.21-2.30)) from one to six months after infection. Patients with pre-existing liver abnormalities, liver abnormalities surrounding acute infection, younger age (1-4 years), or illness requiring hospitalization all had similarly elevated risk. Children who developed liver abnormalities following COVID-19 had more pre-existing conditions than those who developed abnormalities following other infections.

Conclusion

These results indicate that SARS-CoV-2 may prime the patient for subsequent development of liver infections or non-infectious liver diseases. While rare (∼1 in 1,000), SARS-CoV-2 is a risk for subsequent abnormalities in liver function or the diagnosis of diseases of the liver.

What is already known on this topic

Clusters of severe hepatitis in children in 2022 coincident with the increase in COVID-19 infections in children raised the question of the contribution of SARS-CoV-2 to the hepatitis outbreak, though it was soon determined that SARS-CoV-2 was not the primary etiologic agent.

What this study adds

SARS-CoV-2 may prime the patient for subsequent development of liver infections or non-infectious liver diseases.

How this study might affect research, practice or policy

Despite the mild initial disease in children, there may be longer term consequences of COVID-19, such as liver abnormalities, that warrants further investigation.
The impact of motor, non-motor, and social aspects on the sexual health of men living with Parkinson’s disease
Authors: Antunes Souza Bruno Rafael , Costa Nóbrega Kátia Cirilo , de Almeida da Silva Bruno Eron , Gonçalves Raissa Amorim , Martins Thalyta Silva , Santos Geovanna Ferreira , Frazão Andre Helene , Roque Antonio Carlos , da Silva Nascimento Isaíra Almeida Pereira , Pimentel Piemonte Maria Elisa
Published: September 2023

Background

Sexual health (SH) is influenced by several biological, mental, and social factors which may be negatively impacted by PD. Despite its prevalence and relevance for quality of life, the factors that affect the SH in men with Parkinson’s disease (MwPD) are still poorly understood, and research in this area is scarce.

Aim

To investigate the impact of motor, non-motor, and social aspects on the SH in MwPD.

Method

We conducted a cross-sectional study of 80 men (mean age 53.55±10.8) in stages 1-3 of disease progression according to Hoehn and Yahr classification (H&Y), who reported to have sexual activity. The following data were collected for each person (used tests/scales indicated within parentheses and defined in glossary): (1) demographic information and global cognitive capacity (T-MoCA); (2) non-motor aspects of daily life experiences (MDS-UPDRS, part I); (3) motor aspects of daily life experiences (MDS-UPDRS, part II); (4) fatigue (FSS); (5) self-esteem (RSES); (6) sleep disorder (PDSS); (7) couple relationship quality (DAS); (8) depressive signals (BDI); (8) short-term sexual health by International Index of Erectile Function (IIFE); and (9) long-term sexual health by Sexual Quotient-Male (SQ-M).

Results

Our results suggest that the quality of marital relationships predicts short-term SH, motor disability level predicts erectile dysfunction, and depression predicts long-term SH in MwPD. Age, disease onset, disease duration, Levodopa dosage, and non-motor symptoms, excluding depression, were not correlated with SH.

Conclusion

Our findings confirm that multidimensional factors can affect the SH of MwPD and emphasize that only a multi-professional team can offer proper care to improve SH in MwPD.
Anti-SARS-CoV-2 Antibody Levels Associated with COVID-19 Protection in Outpatients Tested for SARS-CoV-2, US Flu VE Network, October 2021–June 2022
Authors: Sumner Kelsey M. , Yadav Ruchi , Noble Emma K. , Sandford Ryan , Joshi Devyani , Tartof Sara Y. , Wernli Karen J. , Martin Emily T. , Gaglani Manjusha , Zimmerman Richard K. , Talbot H. Keipp , Grijalva Carlos G. , Chung Jessie R. , Rogier Eric , Coughlin Melissa M. , Flannery Brendan
Published: September 2023

Background

We assessed the association between antibody concentration ≤5 days of symptom onset and COVID-19 illness among patients enrolled in a test-negative study

Methods

From October 2021─June 2022, study sites in seven states enrolled and tested respiratory specimens from patients of all ages presenting with acute respiratory illness for SARS-CoV-2 infection using rRT-PCR. In blood specimens, we measured concentration of anti- SARS-CoV-2 antibodies against the ancestral strain spike protein receptor binding domain (RBD) and nucleocapsid (N) antigens in standardized binding antibody units (BAU/mL). Percent reduction in odds of symptomatic COVID-19 by anti-RBD antibody was estimated using logistic regression modeled as (1–adjusted odds ratio of COVID-19)x100, adjusting for COVID-19 vaccination status, age, site, and high-risk exposure.

Results

A total of 662 (33%) of 2,018 symptomatic patients tested positive for acute SARS- CoV-2 infection. During the Omicron-predominant period, geometric mean anti-RBD binding antibody concentrations measured 823 BAU/mL (95%CI:690─981) among COVID-19 case- patients versus 1,189 BAU/mL (95%CI:1,050─1,347) among SARS-CoV-2 test-negative patients. In the adjusted logistic regression, increasing levels of anti-RBD antibodies were associated with reduced odds of COVID-19 for both Delta and Omicron infections.

Conclusion

Higher anti-RBD antibodies in patients were associated with protection against symptomatic COVID-19 during emergence of SARS-CoV-2 Delta and Omicron variants.
Associations between depression symptom burden and delirium risk: a prospective cohort study
Authors: Gaba Arlen , Li Peng , Zheng Xi , Gao Chenlu , Ruixue Cai , Hu Kun , Gao Lei
Published: September 2023

BACKGROUND AND OBJECTIVES

Delirium and depression are increasingly common in aging. There is considerable clinical overlap, including shared symptoms and comorbid conditions, including Alzheimer’s disease (AD), functional decline, and mortality. Despite this, the long-term relationship between depression and delirium remains unclear. This study assessed the associations of depression symptom burden and its trajectory with delirium risk in a 12-year prospective study of older individuals during hospitalization.

RESEARCH DESIGN AND METHODS

319,141 UK biobank participants between 2006-2010 (mean 58y [range 37-74, SD=8], 54% female) reported frequency (0-3) of four depressive symptoms (mood, disinterest, tenseness, or lethargy) in the preceding 2 weeks, and aggregated into a depressive symptom burden score (0-12). New-onset delirium was obtained from hospitalization records during 12y median follow-up. 40,451 (mean age 57±8; range 40-74y) had repeat assessment on average 8y after their first. Cox proportional hazard models examined whether depression symptom burden and trajectory predicted incident delirium during hospitalization.

RESULTS

5,753 (15 per 1000) newly developed delirium during follow-up. Increased risk for delirium was seen for mild (aggregated scores 1-2, hazards ratio, HR=1.16, [95% confidence interval 1.08–1.25],p<0.001), modest (scores 3-5, 1.30 [1.19–1.43],p<0.001) and severe (scores ≥ 5, 1.38 [1.24–1.55],p<0.001) depressive symptoms, versus none in the fully adjusted model. These findings were independent of the number of hospitalizations and consistent across hospitalization settings (e.g., surgical, medical, or critical care) and specialty (e.g., neuropsychiatric, cardiorespiratory or other). Worsening depression symptoms (≥1 point increase), compared to no change/improved score, were associated with an additional 39% increased risk (1.39 [1.03–1.88],p=0.03) independent of baseline depression burden. The association was strongest in those over 65y at baseline (pfor interaction <0.001).

DISCUSSION AND IMPLICATIONS

Depression symptom burden and worsening trajectory predicted delirium risk during hospitalization. Increased awareness of subclinical depression symptoms may be warranted for delirium prevention.