bluuebunny/crossref_metadata_2025 huggingface dataset:
Host-Driven Selection, Revealed by Comparative Analysis of Xanthomonas Type III Secretion Effectoromes, Unveils Novel Recognized Effectors
Authors: Xiao Yao , Ray Shatrupa , Burdman Saul , Teper Doron
Published: August 2024

Xanthomonas species are specialized plant pathogens, often exhibiting a narrow host range. They rely on the translocation of effector proteins through the type III secretion system to colonize their respective hosts. The effector arsenal varies among Xanthomonas spp., typically displaying species-specific compositions. This species-specific effector composition, collectively termed the effectorome, is thought to influence host specialization. We determined the plant host-derived effectoromes of more than 300 deposited genomes of Xanthomonas species associated with either Solanaceae or Brassicaceae hosts. Comparative analyses revealed clear species-specific effectorome signatures. However, Solanaceae or Brassicaceae host-associated effectorome signatures were not detected. Nevertheless, host biases in the presence or absence of specific effector classes were observed. To assess whether host-associated effector absence results from selective pressures, we introduced effectors unique to Solanaceae pathogens to X. campestris pv. campestris and effectors unique to Brassicaceae pathogens to X. euvesicatoria pv. euvesicatoria (Xeue) and evaluated if these introductions hindered virulence on their respective hosts. Introducing the effector XopI into X. campestris pv. campestris reduced virulence on white cabbage leaves without affecting localized or systemic colonization. Introducing the XopAC or XopJ5 effectors into Xeue reduced virulence and colonization on tomato but not on pepper. Additionally, XopAC and XopJ5 induced a hypersensitive response on tomato leaves when delivered by Xeue or through Agrobacterium-mediated transient expression, confirming recognition in tomato. This study demonstrates the role of host-derived selection in establishing species-specific effectoromes, identifying XopAC and XopJ5 as recognized effectors in tomato.
Readmissions Among Patients With Surgically Managed Drug Use Associated-Infective Endocarditis Before and After the Implementation of an Addiction Consult Team: A Retrospective, Observational Analysis
Authors: Marinacci Lucas X. , Li Audrey , Tsay Annie , Benarroch Yoel , Hill Kevin P. , Karchmer Adolf W. , Wadhera Rishi K. , Kentoffio Katherine
Published: August 2024

Background

Patients who undergo cardiac surgery for drug use-associated infective endocarditis (DUA-IE) have high rates of readmissions for recurrent endocarditis, substance use disorder (SUD), and septicemia. Our primary objective was to assess whether exposure to an addiction consult team (ACT) was associated with reduced readmissions in this population.

Methods

This single-center retrospective analysis identified patients who underwent cardiac surgery for DUA-IE between 1/2012–9/2022 using the Society for Thoracic Surgeons database, and compared the cumulative incidence of readmissions at 1, 3, 6, and 12 months among those cared for before and after the implementation of an ACT in 9/2017, accounting for competing risk of mortality and adjusted for measured confounders using inverse probability of treatment weighting.

Results

The 58 patients (35 pre-ACT and 23 post-ACT) were young (36.4 +/− 7.7 years) and predominantly White (53.4%) and male (70.7%). The post-ACT cohort had a significantly lower risk of readmission at 1 month (adjusted risk difference [RD] −23.8% [95% CI −94.4%, −8.3%], P = 0.005) and 3 months (RD −34.1% [−55.1%, −13.1%], P = 0.005), but not at 6 or 12 months. In a sensitivity analysis, the post-ACT cohort also had significantly lower risk of readmissions for SUD complications at 3 months.

Discussion and Conclusion

ACT exposure was associated with a lower risk of short-term readmission among patients with surgically managed DUA-IE, possibly due to a reduction in SUD-related complications. Additional studies are needed to replicate these findings and to identify ways to sustain the potential benefits of ACTs over the longer term.
Reimagining Supportive Approaches at the Intersection of Mandatory Reporting Policies for the Mother–Infant Dyad Affected by Substance Use
Authors: McGlothen-Bell Kelly , Cartagena Diana , Malin Kathryn J. , Vittner Dorothy , McGrath Jacqueline M. , Koerner Rebecca L. , Vance Ashlee J. , Crawford Allison D.
Published: August 2024

Background:

As rates of substance use during pregnancy persist, the health and optimal development of infants with prenatal substance exposure remain a key priority. Nurses are tasked with identifying and reporting suspected cases of child maltreatment, including abuse and neglect, which is often assumed to be synonymous with substance use during pregnancy. While policies aimed at protecting infants from child abuse and neglect are well intentioned, literature regarding the short- and long-term social and legal implications of mandatory reporting policies is emerging.

Purpose:

In this article, we explore the intersections between the condition of substance use in pregnancy and policies related to mandatory reporting.

Methods:

We provide an overview of historical and current trends in mandatory reporting policies for nurses related to substance use in pregnancy and related ethical and social implications for mother–infant dyads.

Results:

Nurses often function at the intersection of healthcare and social services, underscoring the important role they play in advocating for ethical and equitable care for both members of the mother–infant dyad affected by substance use.

Implications for Practice and Research:

We offer recommendations for practice including the integration of respectful care and family-centered support for the mother–infant dyad affected by substance use. Cross-sectoral collaborations, inclusive of the family, are important to the advancement of evidence-based and equity-focused research, advocacy, and policy initiatives to support familial preservation and reduce mother–infant separation.
Is a Plantarflexed First Ray the Primary Deformity In Children With Cavovarus Feet Secondary to Charcot-Marie-Tooth Disease? A Pedobarographic Analysis
Authors: Ferguson Stuart , Do Patrick , Feng Jing , Bauer Jeremy
Published: August 2024

Background:

Charcot-Marie-Tooth disease (CMT) is a common cause of cavovarus foot deformity in children. This deformity is often quoted as being forefoot driven, with a primary deformity of first ray plantarflexion driving the hindfoot into varus by virtue of the tripod effect of the foot, which was hypothesized by Coleman and is commonly assessed clinically using his eponymous block test. The primary goal of this study was to objectively investigate this hypothesis using dynamic pedobarography.

Methods:

A review of the gait lab archives at a large tertiary referral center was carried out to identify children with CMT who had foot photos and dynamic pedobarographic data. Two orthopaedic surgeons then determined the weight-bearing hindfoot alignment of these children using clinical photography. The order of contact during gait of the first metatarsal relative to the fifth metatarsal was then obtained from the dynamic pedobarographic data.

Results:

One hundred eighteen feet from 60 children with CMT met the study inclusion criteria. Sixty-eight varus feet were compared with 50 nonvarus feet. First ray contact occurred before fifth ray contact in only 39.7% of the varus feet compared with 34.0% of the nonvarus feet, which did not meet statistical significance (P=0.526).

Conclusions:

In this cohort, dynamic pedobarography did not consistently demonstrate the first metatarsal contact occurring before the fifth metatarsal contact in children with varus feet secondary to CMT. While nearly 40% of the feet did make initial contact on the first ray, 60% of the feet landed in varus before the first ray made contact, leading us to believe that the foot is prepositioned in varus. This may be in part due to the progressive muscle imbalance and secondary deformity that has occurred. Surgical management of these children should take this possibility into consideration and focus on rebalancing the forces causing this varus positioning as well as correcting the resultant bony deformity.
Machine Learning Tools for Acute Respiratory Distress Syndrome Detection and Prediction
Authors: Rubulotta Francesca , Bahrami Sahar , Marshall Dominic C. , Komorowski Matthieu
Published: August 2024

Machine learning (ML) tools for acute respiratory distress syndrome (ARDS) detection and prediction are increasingly used. Therefore, understanding risks and benefits of such algorithms is relevant at the bedside. ARDS is a complex and severe lung condition that can be challenging to define precisely due to its multifactorial nature. It often arises as a response to various underlying medical conditions, such as pneumonia, sepsis, or trauma, leading to widespread inflammation in the lungs. ML has shown promising potential in supporting the recognition of ARDS in ICU patients. By analyzing a variety of clinical data, including vital signs, laboratory results, and imaging findings, ML models can identify patterns and risk factors associated with the development of ARDS. This detection and prediction could be crucial for timely interventions, diagnosis and treatment. In summary, leveraging ML for the early prediction and detection of ARDS in ICU patients holds great potential to enhance patient care, improve outcomes, and contribute to the evolving landscape of precision medicine in critical care settings. This article is a concise definitive review on artificial intelligence and ML tools for the prediction and detection of ARDS in critically ill patients.
High-frequency electrical stimulation increases cortical excitability and mechanical sensitivity in a chronic large animal model
Authors: Meijs Suzan , Andreis Felipe Rettore , Janjua Taha Al Muhammadee , Graven-Nielsen Thomas , Jensen Winnie
Published: August 2024

Translational models of the sensitized pain system are needed to progress the understanding of involved mechanisms. In this study, long-term potentiation was used to develop a mechanism-based large-animal pain model. Event-related potentials to electrical stimulation of the ulnar nerve were recorded by intracranial recordings in pigs, 3 weeks before, immediately before and after, and 3 weeks after peripheral high-frequency stimulation (HFS) applied to the ulnar nerve in the right forelimb (7 pigs) or in control animals (5 pigs). Event-related potential recordings and peripheral HFS were done during anesthesia. Two weeks before and after the HFS, behavioral responses reflecting mechanical and thermal sensitivity were collected using brush, noxious limb-mounted pressure algometer, and noxious laser stimuli. The HFS intervention limb was progressively sensitized to noxious mechanical stimulation in week 1 and 2 compared with baseline (P = 0.045) and the control group (P < 0.034) but not significantly to laser or brush stimulation. The first negative (N1) peak of the event-related potential was increased 30 minutes after HFS compared with before (P < 0.05). The N1 peak was also larger compared with control pigs 20 to 40 minutes after HFS (P < 0.031) but not significantly increased 3 weeks after. The relative increase in N1 30 minutes after HFS and the degree of mechanical hyperalgesia 2 weeks post-HFS was correlated (P < 0.033). These results show for the first time that the pig HFS model resembles the human HFS model closely where the profile of sensitization is comparable. Interestingly, the degree of sensitization was associated with the cortical signs of hyperexcitability at HFS induction.
Advanced neuroimaging of the trigeminal nerve and the whole brain in trigeminal neuralgia: a systematic review
Authors: Watanabe Memi , Shrivastava Raj K. , Balchandani Priti
Published: August 2024

For trigeminal neuralgia (TN), a major role of imaging is to identify the causes, but recent studies demonstrated structural and microstructural changes in the affected nerve. Moreover, an increasing number of studies have reported central nervous system involvement in TN. In this systematic review, recent quantitative magnetic resonance imaging (MRI) studies of the trigeminal nerve and the brain in patients with TN were compiled, organized, and discussed, particularly emphasizing the possible background mechanisms and the interpretation of the results. A systematic search of quantitative MRI studies of the trigeminal nerve and the brain in patients with TN was conducted using PubMed. We included the studies of the primary TN published during 2013 to 2023, conducted for the assessment of the structural and microstructural analysis of the trigeminal nerve, and the structural, diffusion, and functional MRI analysis of the brain. Quantitative MRI studies of the affected trigeminal nerves and the trigeminal pathway demonstrated structural/microstructural alterations and treatment-related changes, which differentiated responders from nonresponders. Quantitative analysis of the brain revealed changes in the brain areas associated with pain processing/modulation and emotional networks. Studies of the affected nerve demonstrated evidence of demyelination and axonal damage, compatible with pathological findings, and have shown its potential value as a tool to assess treatment outcomes. Quantitative MRI has also revealed the possibility of dynamic microstructural, structural, and functional neuronal plasticity of the brain. Further studies are needed to understand these complex mechanisms of neuronal plasticity and to achieve a consensus on the clinical use of quantitative MRI in TN.
Psychosocial Correlates and Behavioral Response to a Carbon Fiber Orthosis and Intensive Rehabilitation Program
Authors: Williamson Jared N. , Grunst Megan M. , Williamson Gary A. , Lynn Jeffrey , Blanck Ryan V. , Wilken Jason M.
Published: August 2024

Introduction

Carbon fiber custom dynamic orthoses (CDOs), a type of ankle-foot orthosis (AFO), have been shown to improve function and mobility. Psychosocial aspects of disability can influence outcomes in prosthetic and orthotic users, but their association with outcomes in CDO users is unknown.

Objective

The aim of this study was to examine the relationships between physical and psychosocial outcomes following an intensive rehabilitative program including a carbon fiber ankle-foot orthosis, and identify factors related to continued orthosis use.

Study Design

Retrospective cohort with long-term follow-up.

Methods

An online survey including questions about device behaviors, self-reported function, pain, global health, self-efficacy, pain interference, resilience, and kinesiophobia was completed by participants who received a custom carbon fiber ankle-foot orthosis and intensive training because of chronic neuromusculoskeletal lower-limb disability.

Results

The mean follow-up was 4.0 (±1.0) years. Sixty-three adult participants responded to the survey (21 women, 42 men; mean age, 41 ± 12 years). All psychosocial outcomes at follow-up were within “good” or “normal” limits (<1 SD from reference population mean) on average. Strong correlations were observed between self-reported physical function and psychosocial outcomes, and moderate correlations were observed among psychosocial outcomes, between baseline physical outcomes and psychosocial outcomes, and between long-term outcomes and psychosocial outcomes. Device continuation at long-term follow-up was 68%.

Conclusions

Four years after the intervention, respondents with chronic lower-limb disabilities reported scores that were comparable to normative values for kinesiophobia, health-related quality of life, self-efficacy for managing their condition, pain interference, and psychological resilience.

Clinical Relevance

Psychosocial variables can affect the outcomes with, and perception of, orthotic devices in individuals with lower-limb neuromusculoskeletal deficits. A goal-oriented care program with emphasis on technique training, postdelivery follow-up, and psychosocial status may help explain long-term outcomes with CDOs and continued device use.
Validation of the AViTA upper-arm blood pressure monitor BP636 with multiple cuff sizes in the general population according to the ANSI/AAMI/ISO 81060-2:2018/Amd1:2020
Authors: Lin Chung-Yu , Huang I-Chih
Published: August 2024

Objective

To determine the accuracy of the AViTA BP636 upper-arm home blood pressure (BP) monitor in general populations with small to extra-large arms according to the ANSI/AAMI/ISO Universal Standard (ISO 81060-2 : 2018/Amd1 : 2020).

Methods

The AViTA BPM636 was utilized on 85 adult participants with upper-arm circumferences ranging from 15 to 52 cm, and four cuffs of different sizes (small: 15–22 cm, normal: 22–33 cm, large: 33–42 cm, and extra large: 42–52 cm) were used in this study. The recruitment fulfills the criteria of the ANSI/AAMI/ISO Universal Standard 81060-2 : 2018/Amd1 : 2020 in the general population using the same arm sequential BP measurement method.

Results

For validation criterion 1, the mean ± SD of the differences between the test device and reference blood pressure readings was −0.35 ± 4.68/0.56 ± 3.93 mmHg (systolic/diastolic) for adults. The mean difference of SBP between the test device and the reference device was −0.35 mmHg with a SD of 3.50 mmHg, which was within the acceptable range for criterion 2 (i.e. less than 6.93 mmHg) Similarly, the mean difference in DBP was 0.56 mmHg with a SD of 3.38 mmHg, which also met the criterion 2 (i.e. within 6.91 mmHg).

Conclusion

AViTA BPM636 passed the criteria of the ANSI/AAMI/ISO 81060-2 : 2018/Amd 1 : 2020 protocol. It can be recommended for home-based BP measurements in the general population and people with extra-large arms ranging from 42 to 52 cm.
Resection of Tumors at the Root of the Tongue and Free Flap Reconstruction: Midline Split With Bilateral Lingual Artery Preservation
Authors: Chen Lei , Liu Xing-Chi , Jia Jun , Yu Zi-Li
Published: August 2024

The removal of tumors at the root of the tongue can be challenging due to anatomic constraints (deep location of the root of the tongue, obstruction by the mandible), leading to poor surgical visibility. Clear visibility of the surgical field is crucial for complete excision to reduce recurrence, hence the need to choose an appropriate surgical approach based on the tumor’s location and size. In this report, the authors describe a case where a midline mandibulotomy and temporary midline glossectomy were utilized to expose and resect a tumor at the root of the tongue. This approach allowed for the complete removal of the tumor while preserving the anterior tongue tissue and bilateral lingual arteries. The defect was then reconstructed using an anterolateral thigh flap. The patient showed good postoperative recovery with significant improvement in swallowing and speech functions. The authors emphasize that the surgical treatment of squamous cell carcinoma (SCC) at the root of the tongue should strive to ensure radical tumor removal while preserving surrounding healthy tissues and critical anatomic structures, particularly the lingual arteries, to facilitate better postoperative recovery for patients.
On the role of geometric phase in the dynamics of elastic waveguides
Authors: Kumar Mohit , Semperlotti Fabio
Published: August 2024

The geometric phase provides important mathematical insights to understand the fundamental nature and evolution of the dynamic response in a wide spectrum of systems ranging from quantum to classical mechanics. While the concept of geometric phase, which is an additional phase factor occurring in dynamical systems, holds the same meaning across different fields of application, its use and interpretation can acquire important nuances specific to the system of interest. In recent years, the development of quantum topological materials and its extension to classical mechanical systems have renewed the interest in the concept of geometric phase. This review revisits the concept of geometric phase and discusses, by means of either established or original results, its critical role in the design and dynamic behaviour of elastic waveguides. Concepts of differential geometry and topology are put forward to provide a theoretical understanding of the geometric phase and its connection to the physical properties of the system. Then, the concept of geometric phase is applied to different types of elastic waveguides to explain how either topologically trivial or non-trivial behaviour can emerge based on the geometric features of the waveguide.

This article is part of the theme issue ‘Current developments in elastic and acoustic metamaterials science (Part 2)’.
Investigating and exploiting the impact of variability in resonator parameters on the vibration attenuation in locally resonant metamaterials
Authors: Van Belle L. , Deckers E. , Cicirello A.
Published: August 2024

Locally resonant metamaterials (LRMs) have recently emerged in the search for lightweight noise and vibration solutions. These materials have the ability to create stop bands, which arise from the sub-wavelength addition of identical resonators to a host structure and result in strong vibration attenuation. However, their manufacturing inevitably introduces variability such that the system
as-manufacture
d often deviates significantly from the original
as-designed
. This can reduce attenuation performance, but may also broaden the attenuation band. This work focuses on the impact of variability within tolerance ranges in resonator properties on the vibration attenuation in metamaterial beams. Following a qualitative pre-study, two non-intrusive uncertainty propagation approaches are applied to find the upper and lower bounds of three performance metrics, by evaluating deterministic metamaterial models with uncertain parameters defined as interval variables. A global search approach is used and compared with a machine learning (ML)-based uncertainty propagation approach which significantly reduces the required number of simulations. Variability in resonator stiffnesses and masses is found to have the highest impact. Variability in the resonator positions only has a comparable impact for less deep sub-wavelength designs. The broadening potential of varying resonator properties is exploited in broadband optimization and the robustness of the optimized metamaterial is assessed.

This article is part of the theme issue ‘Current developments in elastic and acoustic metamaterials science (Part 2)’.
An efficient multiscale method for subwavelength transient analysis of acoustic metamaterials
Authors: Liupekevicius R. , van Dommelen J. A. W. , Geers M. G. D. , Kouznetsova V. G.
Published: August 2024

A reduced-order homogenization framework is proposed, providing a macro-scale-enriched continuum model for locally resonant acoustic metamaterials operating in the subwavelength regime, for both time and frequency domain analyses. The homogenized continuum has a non-standard constitutive model, capturing a metamaterial behaviour such as negative effective bulk modulus, negative effective density and Willis coupling. A suitable reduced space is constructed based on the unit cell response in a steady-state regime and the local resonance regime. A frequency domain numerical example demonstrates the efficiency and suitability of the proposed framework.

This article is part of the theme issue ‘Current developments in elastic and acoustic metamaterials science (Part 2)’.
Mapping the oral resistome: a systematic review
Authors: Sukumar Smitha , Rahmanyar Zalmay , El Jurf Hagaar Q. , Akil William S. , Hussain Jafar , Martin F. Elizabeth , Ekanayake Kanchana , Martinez Elena
Published: August 2024

Studying individual ecological niches within the oral cavity is a logical first step to understanding the distribution of antimicrobial resistance genes (ARGs); however, it is not representative of the whole oral resistome. The aim of our systematic review was to provide a map of the oral resistome by reviewing the composition of individual niches. A total of 580 papers were retrieved from a search of all English language publications investigating the presence of oral ARGs in five electronic databases between January 2015 and August 2023. Fifteen studies [10 PCR and 5 next-generation sequencing (NGS)] were included in this review. The heterogeneity of methods precluded meta-analysis. ARGs are present throughout the oral cavity with 158 unique ARGs identified across 6 locations – supra and sub-gingival biofilm, mucosa, oropharynx, root canal system (RCS) and saliva. The supragingival biofilm had the highest resistome richness, while the RCS had the least. Tetracycline was the dominant antimicrobial resistance (AMR) class found. Three core genes were identified – tet(M), tet(O) and ermB.This review highlights the necessity of NGS studies to comprehensively characterize the oral resistome in its entirety. This is the logical foundation for future ‘omics studies to truly understand the scope of the resistome and its contribution to AMR.
Stimulus encoding shapes tactile perception and underlies alterations in autism
Authors: Semelidou Ourania , Gauvrit Théo , Vandromme Célien , Cornier Alexandre , Saint-Jean Anna , Le Feuvre Yves , Ginger Melanie , Frick Andreas
Published: August 2024

Touch is fundamental for our interaction with the world, and atypical tactile experience is one of the core characteristics of autism, significantly affecting daily life. However, we do not know the neural underpinnings of low-level tactile perception and how they change in autism. Using a translational perceptual task, we reveal that concomitant neuronal activation and inhibition in the primary somatosensory cortex encode tactile stimuli and determine their detection. We recapitulate the multifaceted tactile features of autistic individuals in theFmr1-/ymouse model of autism, showing tactile hyposensitivity, interindividual variability, and unreliable responses. Weak stimulus encoding inFmr1-/y-hyposensitive mice renders perception vulnerable to the ongoing network state and impedes reliable response decoding. Strengthening stimulus encoding by decreasing neuronal hyperexcitability inFmr1-/y-hyposensitive mice improves tactile perception. Our work shows an evolutionarily conserved role for the primary somatosensory cortex in tactile detection and presents a highly translational approach for probing neuronal-perceptual changes in neurodevelopmental conditions.
BrainAgeNeXt: Advancing Brain Age Modeling for Individuals with Multiple Sclerosis
Authors: La Rosa Francesco , Dos Santos Silva Jonadab , Dereskewicz Emma , Invernizzi Azzurra , Cahan Noa , Galasso Julia , Garcia Nadia , Graney Robin , Levy Sarah , Verma Gaurav , Balchandani Priti , Reich Daniel S , Horton Megan , Greenspan Hayit , Sumowski James , Cuadra Merixtell Bach , Beck Erin S
Published: August 2024

Aging is associated with structural brain changes, cognitive decline, and neurodegenerative diseases. Brain age, an imaging biomarker sensitive to deviations from healthy aging, offers insights into structural aging variations and is a potential prognostic biomarker in neurodegenerative conditions. This study introduces BrainAgeNeXt, a novel convolutional neural network inspired by the MedNeXt framework, designed to predict brain age from T1-weighted magnetic resonance imaging (MRI) scans. BrainAgeNeXt was trained and validated on 11,574 MRI scans from 33 private and publicly available datasets of healthy volunteers, aged 5 to 95 years, imaged with 3T and 7T MRI. Performance was compared against three state-of-the-art brain age prediction methods. BrainAgeNeXt achieved a mean absolute error (MAE) of 2.78 ± 3.64 years, lower than the compared methods (MAE = 3.55, 3.59, and 4.16 years, respectively). We tested all methods also across different levels of image quality, and BrainAgeNeXt performed well even with motion artifacts and less common 7T MRI data. In three longitudinal multiple sclerosis (MS) cohorts (273 individuals), brain age was, on average, 4.21 ± 6.51 years greater than chronological age. Longitudinal analysis indicated that brain age increased by 1.15 years per chronological year in individuals with MS (95% CI = [1.05, 1.26]). Moreover, in early MS, individuals with worsening disability had a higher annual increase in brain age compared to those with stable clinical assessments (1.24 vs. 0.75, p < 0.01). These findings suggest that brain age is a promising prognostic biomarker for MS progression and potentially a valuable endpoint for clinical trials.
CO-INFECTS: A Highly Affordable, Portable, Nucleic-Acid-Based Rapid Detector of Active Respiratory Co-Infections via “Swab-to-Result” Integration
Authors: Nag Sudip , Banerjee Saptarshi , Bandopadhyay Aditya , Banerjee Indranath , Jana Subhasis , Mondal Arindam , Chakraborty Suman
Published: August 2024

Early diagnosis of active viral co-infections of similar symptomatic pattern is critical for preventing life-threatening respiratory complications. While facilities for the same are currently available, those are either over-expensive or not amenable for deployment in resource-limited settings. We report a first of its kind isothermal colorimetric nucleic acid-based test integrated in a user-friendly, portable device, that can differentially diagnose respiratory viral infections having similar symptomatic pattern, and illustrate its performance by detecting co-infections of SARS-CoV-2 with seasonal influenza A virus from unprocessed swab sample in an extraction-free analysis mode within 45 minutes without intermediate manual steps. The test obviates the need of any complex disposable cartridge in preference to common laboratory utilities. Further, it harnesses machine learning empowered and smartphone interfaced colorimetric analysis without needing any specialized optical detector. The efficacy of the test is validated via community-adapted randomized field trials at underserved rural settings by frontline health workers, reporting sensitivity >96% and specificity > 98% in 1500 cohorts. The method in the form of three test genes with one internal control assay evidences to facilitate viral surveillance and enables diagnosing complex respiratory infections early enough in a plethora of settings ranging from general hospitals to the community centres, overcoming barriers to access of high-end facilities. Such adaptation of scientifically supreme multiplex nucleic acid based diagnostics in the framework of a simple and user friendly rapid test appears to be the future of infectious disease management in a democratized framework, eradicating the disparities in affordability and accessibility in resource-limited settings.
Educational attainment and mental health conditions: a within-sibship Mendelian randomization study
Authors: Vinueza Veloz María Fernanda , Bhatta Laxmi , Jones Paul Remy , Tesli Martin , Smith George Davey , Davies Neil Martin , Brumpton Ben M. , Næss Øyvind Erik
Published: August 2024

Importance

Observational studies have demonstrated consistent protective effects of higher educational attainment (EA) on the risk of suffering mental health conditions (MHC). Determining whether these beneficial effects are causal is challenging given the potential role of dynastic effects and demographic factors (assortative mating and population structure) in this association.

Objective

To evaluate to what extent the relationship between EA and various MHC is independent from dynastic effects and demographic factors.

Design

Within-sibship Mendelian randomization (MR) study.

Setting

One-sample MR analyses included participants’ data from the Trøndelag Health Study (HUNT, Norway) and UK Biobank (United Kingdom). For two-sample MR analyses we used summary statistics from publicly available genome-wide-association-studies.

Participants

61 880 siblings (27 507 sibships).

Exposure

Years of education.

Main outcomes

Scores for symptoms of anxiety, depression and neuroticism using the Hospital Anxiety Depression Scale (HADS), the 7-item Generalized Anxiety Disorder Scale (GAD-7), the 9-item Patient Health Questionnaire (PHQ-9), and the Eysenck Personality Questionnaire, as well as self-reported consumption of psychotropic medication.

Results

One standard deviation (SD) unit increase in years of education was associated with a lower symptom score of anxiety (−0.20 SD [95%CI: −0.26, −0.14]), depression (−0.11 SD [−0.43, 0.22]), neuroticism (−0.30 SD [−0.53, −0.06]), and lower odds of psychotropic medication consumption (OR: 0.60 [0.52, 0.69]). Estimates from the within-sibship MR analyses showed some attenuation, which however were suggestive of a causal association (anxiety: −0.17 SD [−0.33, −0.00]; depression: −0.18 SD [-1.26, 0.89]; neuroticism: −0.29 SD [−0.43, −0.15]); psychotropic medication consumption: OR, 0.52 [0.34, 0.82]).

Conclusions and Relevance

Associations between EA and MHC in adulthood, although to some extend explained by dynastic effects and demographic factors, overall remain robust, indicative of a causal effect. However, larger studies are warranted to improve statistical power and further validate our conclusions.

Key points

Question

Are the protective effects of higher educational attainment on the risk of suffering mental health conditions independent from familial (i.e.,dynastic effects) and demographic factors (i.e., assortative mating and population structure)?

Findings

Although to some extend explained by familial and demographic factors, overall the protective effects of higher educational attainment remain robust.

Meaning

Our findings are consistent with those of previous observational studies, which suggests that higher educational attainment may causally reduce the risk of suffering a mental health condition.
LORE: A Literature Semantics Framework for Evidenced Disease-Gene Pathogenicity Prediction at Scale
Authors: Li Peng-Hsuan , Sun Yih-Yun , Juan Hsueh-Fen , Chen Chien-Yu , Tsai Huai-Kuang , Huang Jia-Hsin
Published: August 2024

Effective utilization of academic literature is crucial for Machine Reading Comprehension to generate actionable scientific knowledge for wide real-world applications. Recently, Large Language Models (LLMs) have emerged as a powerful tool for distilling knowledge from scientific articles, but they struggle with the issues of reliability and verifiability. Here, we propose LORE, a novel unsupervised two-stage reading methodology with LLM that models literature as a knowledge graph of verifiable factual statements and, in turn, as semantic embeddings in Euclidean space. Applied to PubMed abstracts for large-scale understanding of disease-gene relationships, LORE captures essential information of gene pathogenicity. Furthermore, we demonstrate that modeling a latent pathogenic flow in the semantic embedding with supervision from the ClinVar database leads to a 90% mean average precision in identifying relevant genes across 2,097 diseases. Finally, we have created a disease-gene relation knowledge graph with predicted pathogenicity scores, 200 times larger than the ClinVar database.
Directionality of neural activity in and out of the seizure onset zone in focal epilepsy
Authors: Karimi-Rouzbahani Hamid , McGonigal Aileen
Published: August 2024

Epilepsy affects over 50 million people worldwide, with approximately 30% experiencing drug- resistant forms that may require surgical intervention. Accurate localisation of the epileptogenic zone (EZ) is crucial for effective treatment, but how best to use intracranial EEG data to delineate the EZ remains unclear. Previous studies have used the directionality of neural activities across the brain to investigate seizure dynamics and localise the EZ. However, the different connectivity measures used across studies have often provided inconsistent insights about the direction and the localisation power of signal flow as a biomarker for EZ localisation. In a data-driven approach, this study employs a large set of 13 distinct directed connectivity measures to evaluate neural activity flow in and out the seizure onset zone (SOZ) during interictal and ictal periods. These measures test the hypotheses of “sink SOZ” (SOZ dominantly receiving neural activities during interictal periods) and “source SOZ” (SOZ dominantly transmitting activities during ictal periods). While the results were different across connectivity measures, several measures consistently supported higher connectivity directed towards the SOZ in interictal periods and higher connectivity directed away during ictal period. Comparing six distinct metrics of node behaviour in the network, we found that SOZ separates itself from the rest of the network allowing for the metric of “eccentricity”to localise the SOZ more accurately than any other metrics including “in strength”and “out strength”. This introduced a novel biomarker for localising the SOZ, leveraging the discriminative power of directed connectivity measures in an explainable machine learning pipeline. By using a comprehensive, objective and data-driven approach, this study addresses previously unresolved questions on the direction of neural activities in seizure organisation, and sheds light on dynamics of interictal and ictal activity in focal epilepsy.
Faster amylin aggregation on fibrillar collagen hastens diabetic progression through β cell death and loss of function
Authors: Hazari Md Asrafuddoza , Kannan Gautam , Jha Akash Kumar , Pavan Musale Krushna , Dasgupta Subrata , Sultana Farhin , Pujahari Soumya Ranjan , Singh Simran , Dutta Sarbajeet , Pydi Sai Prasad , Dutta Sankhadeep , Bhaumik Prasenjit , Zafar Hamim , Kumar Ashutosh , Sen Shamik
Published: August 2024

Amyloid deposition of the neuroendocrine peptide amylin in islet tissues is a hallmark of type 2 diabetes (T2DM), leading to β-cell toxicity through nutrient deprivation, membrane rupture and apoptosis. Though accumulation of toxic amylin aggregates in islet matrices is well documented, the role of the islet extracellular matrix in mediating amylin aggregation and its pathological consequences remains elusive. Here, we address this question by probing amylin interaction with collagen I (Col I)—whose expression in the islet tissue increases during diabetes progression. By combining multiple biophysical techniques, we show that hydrophobic, hydrophilic & cation-π interactions regulate amylin binding to Col I, with fibrillar collagen driving faster amylin aggregation. Amylin-entangled Col I matrices containing high amounts of amylin induce death and loss of function of INS1E β-cells. Together, our results illustrate how amylin incorporation in islet matrices through amylin-Col interactions drives T2DM progression by impacting β-cell viability and insulin secretion.
PPARγ activation by lipolysis-generated ligands is required for cAMP dependentUCP1induction in human thermogenic adipocytes
Authors: Desai Anand , Yang Loureiro Zinger , DeSouza Tiffany , Yang Qin , Solivan-Rivera Javier , Corvera Silvia
Published: August 2024

Objective

The uncoupling protein 1 (UCP1) is induced in brown or “beige” adipocytes through catecholamine-induced cAMP signaling, which activates diverse transcription factors. UCP1 expression can also be enhanced by PPARγ agonists such as rosiglitazone (Rsg). However, it is unclear whether this upregulation results from de-novo differentiation of beige adipocytes from progenitor cells, or from the induction of UCP1 in pre-existing adipocytes. To explore this, we employed human adipocytes differentiated from progenitor cells and examined their acute response to Rsg, to the adenylate-cyclase activator forskolin (Fsk), or to both simultaneously.

Methods

Adipocytes generated from primary human progenitor cells were differentiated without exposure to PPARγ agonists, and treated for 3, 6 or 78 hours to Fsk, to Rsg, or to both simultaneously. Bulk RNASeq, RNAScope, RT-PCR, CRISPR-Cas9 mediated knockout, oxygen consumption and western blotting were used to assess cellular responses.

Results

UCP1mRNA expression was induced within 3 hours of exposure to either Rsg or Fsk, indicating that Rsg’s effect is independent on additional adipocyte differentiation. Although Rsg and Fsk induced distinct overall transcriptional responses, both induced genes associated with calcium metabolism, lipid droplet assembly, and mitochondrial remodeling, denoting core features of human adipocyte beiging. Unexpectedly, we found that Fsk-inducedUCP1expression was reduced by approximately 80% following CRISPR-Cas9-mediated knockout ofPNPLA2, the gene encoding the triglyceride lipase ATGL. As anticipated, ATGL knockout suppressed lipolysis; however, the associated suppression of UCP1 induction indicates that maximal cAMP-mediatedUCP1induction requires products of ATGL-catalyzed lipolysis. Supporting this, we observed that the reduction in Fsk-stimulated UCP1 induction caused by ATGL knockout was reversed by Rsg, implying that the role of lipolysis in this process is to generate natural PPARγ agonists.

Conclusion

UCP1transcription is known to be stimulated by transcription factors activated downstream of cAMP-dependent protein kinases. Here we demonstrate thatUCP1transcription can also be acutely induced through PPARγ-activation. Moreover, both pathways are activated in human adipocytes in response to cAMP, synergistically inducing UCP1 expression. The stimulation of PPARγ in response to cAMP occurs as a result of the production of natural PPARγ activating ligands through ATGL-mediated lipolysis.

GRAPHICAL ABSTRACT
3D printed microtissue cassettes enabling high throughput proton radiobiological assays
Authors: Yang Chih-Tsung , Cho I-Chun , Yu Ching-Fang , Cheah Edward , Liu Tesi , Lin Yi-Ping , Hu Sing-Yu , Jheng Jyun-Wei , Kempson Ivan , Chao Tsi-Chian , Lee Sen-Hao , Bezak Eva , Thierry Benjamin
Published: August 2024

Uncertainties on proton relative biological effectiveness (RBE) across the spread out of Bragg peak (SOBP) (typically assumed to be 1.1) may lead to suboptimal treatment plan and unwarranted toxicity to organs-at-risk. Herein, we report a reliable analytical method to determine the proton RBE along the SOBP and distal fall-off region. The 3D microtissue cassette enables the high throughput assessment of biological assays including clonogenic assay and γ-H2AX assay following a single proton irradiation. Clonogenic assay shows the RBE of 1.6 (10% cellular survival) which is consistent with the deter-mined RBE of 1.58 using the γ-H2AX assay. Besides, we also show that the high spatial resolution of the cassette can distinguish the minute but significant foci changes (number, area) in response to small proton radiation dose fraction. The results validate the reliability of our setup in addressing critical proton radiobiological questions.
Use of Biochemical Biomarkers to Evaluate the Role of Oxidative Stress in the Progression of COVID-19 Severity
Authors: Marcano-Marcano Luis , Salazar-Lugo Raquel
Published: August 2024

The role of oxidative stress and the use of biochemical biomarkers in the severity of COVID-19 was evaluated through a literature review (2020–2021) using scientific search engines such as PubMed, Science Direct, and Google Scholar. The search was limited to articles published in Spanish or English that reported on COVID-19 and its relationship with oxidative stress, following PRISMA-2020 guidelines. The search terms included oxidative stress, COVID-19, SARS-CoV-2, oxidative biomarkers, and oxidative damage. 93.5% of the selected studies were from the year 2021. These studies evaluated both oxidative stress biomarkers and oxidative damage biomarkers in COVID-19 patients. The reviewed studies reinforce the strong association of SARS-CoV-2 with oxidative stress and demonstrate how SARS-CoV-2-induced ROS production and disruption of the antioxidant defense system trigger a pro-inflammatory environment and cause severe tissue damage. In 64.7% of the studies, a combination of oxidative stress biomarkers (antioxidant and oxidative damage biomarkers) was used to assess COVID-19 severity. The most commonly used antioxidant biomarkers were thiols and total antioxidant capacity, followed by glutathione. The most commonly used oxidative damage biomarkers were malondialdehyde and peroxides, followed by advanced oxidation protein products. COVID-19 leads to a decrease in the antioxidant defense system, reflected by a decrease in antioxidant biomarkers and an increase in oxidative damage biomarkers.
Mapping Epigenetic Gene Variant Dynamics: Comparative Analysis of Frequency, Functional Impact and Trait Associations in African and European Populations
Authors: Sinkala Musalula , Retshabile Gaone , Mpangase Phelelani T , Bamba Salia , Goita Modibo K , Nembaware Victoria , Elsheikh Samar S. M , Heckmann Jeannine , Esoh Kevin , Matshaba Mogomotsi , Adebamowo Clement A. , Adebamowo Sally N. , Amih Ofon E , Wonkam Ambroise , Ramsay Michele , Mulder Nicola
Published: August 2024

Epigenetic modifications influence gene expression levels, impact organismal traits, and play a role in the development of diseases. Therefore, variants in genes involved in epigenetic processes are likely to be important in disease susceptibility, and the frequency of variants may vary between populations with African and European ancestries. Here, we analyse an integrated dataset to define the frequencies, associated traits, and functional impact of epigenetic gene variants among individuals of African and European ancestry represented in the UK Biobank. We find that the frequencies of 88.4% of epigenetic gene variants significantly differ between these groups. Furthermore, we find that the variants are associated with many traits and diseases, and some of these associations may be population-specific owing to allele frequency differences. Additionally, we observe that variants associated with traits are significantly enriched for quantitative trait loci that affect DNA methylation, chromatin accessibility, and gene expression. We find that methylation quantitative trait loci account for 71.2% of the variants influencing gene expression. Moreover, variants linked to biomarker traits exhibit high correlation. We therefore conclude that epigenetic gene variants associated with traits tend to differ in their allele frequencies among African and European populations and are enriched for QTLs.