bluuebunny/crossref_metadata_2025 huggingface dataset:
HM-chromanone alleviates hyperglycemia and inflammation in mice with endotoxin-induced insulin resistance
Authors: Lim Ha J , Park Jae E , Han Ji S
Published: July 2023

This study was designed to investigate whether (E)-5-hydroxy-7-methoxy-3-(2′-hydroxybenzyl)-4-chromanone alleviates inflammation and hyperglycemia in mice with endotoxin-induced insulin resistance. (E)-5-hydroxy-7-methoxy-3-(2′-hydroxybenzyl)-4-chromanone (10, 30, and 50 mg/kg bodyweight) was orally pre-administered to C57BL/6 J mice. An hour later, lipopolysaccharides (20 mg/kg bodyweight) was administered intraperitoneally to induce endotoxins. Blood samples were collected from the tail vein of the mice every 0, 30, and 90 min. The results indicated that (E)-5-hydroxy-7-methoxy-3-(2′-hydroxybenzyl)-4-chromanone effectively regulated blood glucose levels in mice with endotoxin-induced insulin resistance. Furthermore, (E)-5-hydroxy-7-methoxy-3-(2′-hydroxybenzyl)-4-chromanone significantly reduced the phosphorylation of mammalian target of rapamycin, ribosomal protein S6 kinase 1, and protein kinase C θ. Additionally, (E)-5-hydroxy-7-methoxy-3-(2′-hydroxybenzyl)-4-chromanone suppressed the phosphorylation of c-Jun-NH2-terminal kinase and IkB kinase β, thereby decreasing the phosphorylation of inhibitor of nuclear factor kappa-B α and activating the nuclear factor-κB and activator protein-1 in the liver. Therefore, the expression of tumor necrosis factor-α, interleukin-6, and interleukin-1β was significantly reduced by suppressing the nuclear factor-κB and activator protein 1 activity. Suppression of mammalian target of rapamycin, S6 kinase 1, protein kinase C θ, c-Jun-NH2-terminal kinase, and IkB kinase β also ameliorated insulin resistance by reducing the phosphorylation of insulin receptor substrate-1 serine 307, thereby decreasing hyperglycemia. These findings suggest that (E)-5-hydroxy-7-methoxy-3-(2′-hydroxybenzyl)-4-chromanone can alleviate hyperglycemia and inflammation in mice with endotoxin-induced insulin resistance.
‘Through and Through’ History: The Management of Gunshot Wounds From the 14th Century to the Present
Authors: Barr Justin , Schalick Walton O. , Horn Christopher B. , Marble W. Sanders , Devine Shauna , Smith Dale C.
Published: July 2023

Gun violence killed over 46,000 Americans in 2021; almost 120,000 suffered gunshot wounds. This epidemic has attracted national attention and increasing concern from medical and surgical organizations, as evident in this special issue. ‘Through and Through History’ explores the surgical management of gunshot wounds from their earliest appearance in 14th-century Europe to the present. Interweaving the civilian and military experience, it details not only the evolution of care directly applied to patients but also the social, political, and scientific milieu that shaped decisions made and actions performed both in and out of the operating room. The article describes how surgeons have pushed the boundaries of medicine and science in each era, developing new therapies for their patients, a historical trend that persists today when such care has the potential to save tens of thousands of lives each year.
Pathophysiologic Spine Adaptations and Countermeasures for Prolonged Spaceflight
Authors: Schlaff Cody D. , Helgeson Melvin D. , Wagner Scott C.
Published: July 2023

Low back pain due to spaceflight is a common complaint of returning astronauts. Alterations in musculoskeletal anatomy during spaceflight and the effects of microgravity (μg) have been well-studied; however, the mechanisms behind these changes remain unclear. The National Aeronautics and Space Administration has released the Human Research Roadmap to guide investigators in developing effective countermeasure strategies for the Artemis Program, as well as commercial low-orbit spaceflight. Based on the Human Research Roadmap, the existing literature was examined to determine the current understanding of the effects of microgravity on the musculoskeletal components of the spinal column. In addition, countermeasure strategies will be required to mitigate these effects for long-duration spaceflight. Current pharmacologic and nonpharmacologic countermeasure strategies are suboptimal, as evidenced by continued muscle and bone loss, alterations in muscle phenotype, and bone metabolism. However, studies incorporating the use of ultrasound, beta-blockers, and other pharmacologic agents have shown some promise. Understanding these mechanisms will not only benefit space technology but likely lead to a return on investment for the management of Earth-bound diseases.
Asynchrony Injures Lung and Diaphragm in Acute Respiratory Distress Syndrome*
Authors: Hashimoto Haruka , Yoshida Takeshi , Firstiogusran Andi Muhammad Fadlillah , Taenaka Hiroki , Nukiwa Ryota , Koyama Yukiko , Uchiyama Akinori , Fujino Yuji
Published: July 2023

OBJECTIVES:

Patient-ventilator asynchrony is often observed during mechanical ventilation and is associated with higher mortality. We hypothesized that patient-ventilator asynchrony causes lung and diaphragm injury and dysfunction.

DESIGN:

Prospective randomized animal study.

SETTING:

University research laboratory.

SUBJECTS:

Eighteen New Zealand White rabbits.

INTERVENTIONS:

Acute respiratory distress syndrome (ARDS) model was established by depleting surfactants. Each group (assist control, breath stacking, and reverse triggering) was simulated by phrenic nerve stimulation. The effects of each group on lung function, lung injury (wet-to-dry lung weight ratio, total protein, and interleukin-6 in bronchoalveolar lavage), diaphragm function (diaphragm force generation curve), and diaphragm injury (cross-sectional area of diaphragm muscle fibers, histology) were measured. Diaphragm RNA sequencing was performed using breath stacking and assist control (n = 2 each).

MEASUREMENTS AND MAIN RESULTS:

Inspiratory effort generated by phrenic nerve stimulation was small and similar among groups (esophageal pressure swing ≈ –2.5 cm H2O). Breath stacking resulted in the largest tidal volume (>10 mL/kg) and highest inspiratory transpulmonary pressure, leading to worse oxygenation, worse lung compliance, and lung injury. Reverse triggering did not cause lung injury. No asynchrony events were observed in assist control, whereas eccentric contractions occurred in breath stacking and reverse triggering, but more frequently in breath stacking. Breath stacking and reverse triggering significantly reduced diaphragm force generation. Diaphragmatic histology revealed that the area fraction of abnormal muscle was ×2.5 higher in breath stacking (vs assist control) and ×2.1 higher in reverse triggering (vs assist control). Diaphragm RNA sequencing analysis revealed that genes associated with muscle differentiation and contraction were suppressed, whereas cytokine- and chemokine-mediated proinflammatory responses were activated in breath stacking versus assist control.

CONCLUSIONS:

Breath stacking caused lung and diaphragm injury, whereas reverse triggering caused diaphragm injury. Thus, careful monitoring and management of patient-ventilator asynchrony may be important to minimize lung and diaphragm injury from spontaneous breathing in ARDS.
Post-tuberculosis lung disease and chronic obstructive pulmonary disease
Authors: Gai Xiaoyan , Allwood Brian , Sun Yongchang
Published: July 2023

The burden of chronic airway diseases, including chronic obstructive pulmonary disease (COPD), continues to increase, especially in low- and middle-income countries. Post-tuberculosis lung disease (PTLD) is characterized by chronic lung changes after the "cure" of pulmonary tuberculosis (TB), which may be associated with the pathogenesis of COPD. However, data on its prevalence, clinical manifestations, computed tomography features, patterns of lung function impairment, and influencing factors are limited. The pathogenic mechanisms underlying PTLD remain to be elucidated. This review summarizes the recent advances in PTLD and TB-associated COPD. Research is urgently needed both for the prevention and management of PTLD.
Gaps and future of human-centered artificial intelligence in ophthalmology: Future Vision Forum consensus statement
Authors: Ting Daniel Shu Wei , Humayun Mark S. , Huang Suber S.
Published: July 2023

Purpose of review

The Future Vision Forum discussed the current state of Human Centered Computing and the future of data collection, curation, and collation in ophthalmology. Although the uptake of electronic health record (EHR) systems and the digitization of healthcare data is encouraging, there are still barriers to implementing a specialty-wide clinical trial database. The article identifies several critical opportunities, including the need for standardization of image metadata and data, the establishment of a centralized trial database, incentives for clinicians and trial sponsors to participate, and resolving ethical concerns surrounding data ownership.

Findings

Recommendations to overcome these challenges include the standardization of image metadata using the Digital Imaging and Communications in Medicine (DICOM) guidelines, the establishment of a centralized trial database that uses federated learning (FL), and the use of FL to facilitate cross-institutional collaboration for rare diseases. Forum faculty suggests incentives will accelerate artificial intelligence, digital innovation projects, and data sharing agreements to empower patients to release their data.

A specialty-wide clinical trial database could provide invaluable insights into the natural history of disease, pathophysiology, why trials fail, and improve future clinical trial design. However, overcoming the barriers to implementation will require continued discussion, collaboration, and collective action from stakeholders across the ophthalmology community.
Toward safer ophthalmic artificial intelligence via distributed validation on real-world data
Authors: Nath Siddharth , Rahimy Ehsan , Kras Ashley , Korot Edward
Published: July 2023

Purpose of review

The current article provides an overview of the present approaches to algorithm validation, which are variable and largely self-determined, as well as solutions to address inadequacies.

Recent findings

In the last decade alone, numerous machine learning applications have been proposed for ophthalmic diagnosis or disease monitoring. Remarkably, of these, less than 15 have received regulatory approval for implementation into clinical practice. Although there exists a vast pool of structured and relatively clean datasets from which to develop and test algorithms in the computational ‘laboratory’, real-world validation remains key to allow for safe, equitable, and clinically reliable implementation. Bottlenecks in the validation process stem from a striking paucity of regulatory guidance surrounding safety and performance thresholds, lack of oversight on critical postdeployment monitoring and context-specific recalibration, and inherent complexities of heterogeneous disease states and clinical environments. Implementation of secure, third-party, unbiased, pre and postdeployment validation offers the potential to address existing shortfalls in the validation process.

Given the criticality of validation to the algorithm pipeline, there is an urgent need for developers, machine learning researchers, and end-user clinicians to devise a consensus approach, allowing for the rapid introduction of safe, equitable, and clinically valid machine learning implementations.
Platelet mitochondria: the mighty few
Authors: Ajanel Abigail , Campbell Robert A. , Denorme Frederik
Published: July 2023

Purpose of review

Platelet mitochondrial dysfunction is both caused by, as well as a source of oxidative stress. Oxidative stress is a key hallmark of metabolic disorders such as dyslipidemia and diabetes, which are known to have higher risks for thrombotic complications.

Recent findings

Increasing evidence supports a critical role for platelet mitochondria beyond energy production and apoptosis. Mitochondria are key regulators of reactive oxygen species and procoagulant platelets, which both contribute to pathological thrombosis. Studies targeting platelet mitochondrial pathways have reported promising results suggesting antithrombotic effects with limited impact on hemostasis in animal models.

Targeting platelet mitochondria holds promise for the reduction of thrombotic complications in patients with metabolic disorders. Future studies should aim at validating these preclinical findings and translate them to the clinic.
Critical Care Unit Characteristics and Extracorporeal Cardiopulmonary Resuscitation Survival in the Pediatric Cardiac Population: Retrospective Analysis of the Virtual Pediatric System Database
Authors: Lasa Javier J. , Guffey Danielle , Bhalala Utpal , Thiagarajan Ravi R.
Published: July 2023

OBJECTIVES:

Existing literature provides limited data about ICU characteristics and pediatric extracorporeal cardiopulmonary resuscitation (E-CPR) outcomes. We aimed to evaluate the associations between patient and ICU characteristics, and outcomes after E-CPR in the pediatric cardiac population.

DESIGN:

Retrospective analysis of the Virtual Pediatric System database (VPS, LLC, Los Angeles, CA).

SETTING:

PICUs categorized as either cardiac-only versus mixed ICU cohort type.

PATIENTS:

Consecutive cardiac patients less than 18 years old experiencing cardiac arrest in the ICU and resuscitated using E-CPR.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Event and time-stamp filtering identified E-CPR events. Patient, hospital, and event-related variables were aggregated for independent and multivariable mixed effects logistic regression to assess the association between ICU cohort type and survival. Among ICU admissions in the VPS database, 2010–2018, the prevalence of E-CPR was 0.07%. A total of 671 E-CPR events (650 patients) comprised the final cohort; congenital heart disease (84%) was the most common diagnosis versus acquired heart diseases. The majority of E-CPR events occurred in mixed ICUs (67%, n = 449) and in ICUs with greater than 20 licensed bed capacity (65%, n = 436). Survival to hospital discharge was 51% for the overall cohort. Independent logistic regression failed to reveal any association between survival to hospital discharge and ICU type (ICU type: cardiac ICU, odds ratio [OR], 1.01; 95% CI, 0.71–1.44; p = 0.95). However, multivariable logistic regression revealed an association between cardiac surgical patients and greater odds for survival (OR, 2.03; 95% CI, 1.40–2.95; p < 0.001). Also, there was an association between ICUs with capacity greater than 20 (vs not) and lower survival odds (OR, 0.65; 95% CI, 0.43–0.96).

CONCLUSIONS:

The overall prevalence of E-CPR among critically ill children with cardiac disease observed in the VPS database is low. We failed to identify an association between ICU cohort type and survival. Further investigation into organizational factors is warranted.
Resolution of Pruritus in a Child With Alagille Syndrome Treated With Maralixibat for Seven Years: Durable Response and Discontinuation of Other Medications
Authors: Garcia Amy , Hsu Evelyn , Lin Henry C.
Published: July 2023

Intractable pruritus is one of the most prominent and debilitating features of Alagille syndrome. Maralixibat is the first US Food and Drug Administration-approved drug for the treatment of cholestatic pruritus in children with Alagille syndrome aged 3 months and older. Clinical trials of maralixibat have reported follow-up to 4 years and reported a ≥1-pt reduction using the Itch-Reported Outcome (Observer) (ItchRO[Obs]) instrument (0–4 scale), as this decrease was previously defined as a clinically meaningful improvement in pruritus; participants in clinical trials were expected to be maintained on stable doses of antipruritic agents. We report on a patient with 3 notable features: (1) complete resolution of her pruritus; (2) durability of this response for over 7 years; and (3) ability to discontinue all other antipruritic medications.
Don’t Look Back and Spray! Risk of Endoscope Adhesion with Hemospray Application in Retroflexion in a Pediatric Patient
Authors: Edwards Sarah T. , Lerner Diana G. , Alatorre Jimenez Moises , Attard Thomas M.
Published: July 2023

Although the vast majority of recognized pediatric upper gastrointestinal bleeding (GIB) resolves spontaneously, gastrointestinal hemorrhage is the most common indication for urgent or emergent therapeutic endoscopy in pediatric practice. The application of hemostatic powders, including TC-325 (Hemospray, Cook Medical, Winston-Salem, NC, USA), has shown considerable impact on the control of acute bleeding, with the advantage of potentially covering an extensive area and requiring less technical expertise. We report a case of transient adherence of an esophagogastroduodenoscopy following Hemospray application in a 22-month-old with upper GIB. Our experience does not detract from the significant gains in the management of pediatric GIB from Hemospray; however, it does raise a cautionary note toward the application technique utilized.
Reboxetine Combination Therapy With Fluoxetine in Moderate to Severe Obsessive-Compulsive Disorder: A Placebo-Controlled, Double-Blind, Randomized Trial
Authors: Tilaki Erfaneh Hajian , Hasanzadeh Alireza , Shalbafan Mohammadreza , Moghaddam Hossein Sanjari , Shamabadi Ahmad , Boroon Mahsa , Akhondzadeh Shahin
Published: July 2023

Objectives

Reboxetine is a potent and selective norepinephrine reuptake inhibitor that was effective in combination with citalopram for resistant obsessive-compulsive disorder (OCD). This study aims to assess its effectiveness and tolerability in combination with fluoxetine in treating OCD.

Methods

In this 2-center, placebo-controlled, and double-blind, randomized clinical trial, 76 patients with OCD were assigned into 2 parallel groups to receive fluoxetine (up to 80 mg/d) plus placebo (F + P) or fluoxetine (up to 80 mg/d) plus reboxetine (F + R) (10 mg twice daily) for 10 weeks. Participants were assessed with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at baseline and weeks 5 and 10.

Results

A total of 76 patients completed the trial. There was no significant difference between the 2 groups in baseline Y-BOCS scores. General linear model repeated-measures showed significant effects on time-treatment interaction on total Y-BOCS (F = 6.33, df = 1.42, P = 0.006) and obsession subscale scores (F = 10.39, df = 1.48, P < 0.001), and insignificance on compulsion subscale scores (F = 1.86, df = 1.24, P = 0.173). Reboxetine combination therapy demonstrated a higher partial and complete treatment response rate (P < 0.01) according to the Y-BOCS total scores. There was no significant difference between the 2 groups in the frequency of adverse effects.

Conclusions

Reboxetine combination therapy with fluoxetine can effectively improve symptoms in patients with OCD in a short period of treatment. However, further studies with larger sample sizes and longer follow-up periods are needed to confirm these findings.

This trial was registered with the Iranian Registry of Clinical Trials (www.irct.ir; No IRCT20090117001556N129).
Impaired Retinal Capillary Function in Patients With Alzheimer Disease
Authors: Cipolla Jack A. , Jiang Hong , Simms Ava-Gaye Y. , Baumel Bernard , Rundek Tatjana , Wang Jianhua
Published: July 2023

Background:

Extensive evidence indicates that vasculopathy, especially the level of microcirculation, contributes to neurodegeneration in Alzheimer disease (AD). However, it is not easy to directly monitor cerebral microcirculation. The retinal microvasculature has been proposed as a surrogate measure to study cerebral vascular changes. Indeed, decreased retinal microvascular network densities were reported in patients with AD. We sought to determine the retinal capillary function (RCF, the efficiency of blood flow transferring in the capillary network) in patients with AD.

Methods:

Twenty patients (age 60–84 years, mean ± SD: 72.8 ± 7.7 years) with AD and 14 age-matched cognitively normal controls (CN, age 62–81 years, mean ± SD: 68.6 ± 6.7 years.) were recruited. There were no differences in vascular risk factors, including smoking, hypertension, hyperlipidemia, Type 2 diabetes, and cardiovascular disease, between the groups. One eye of each subject in both groups was imaged. Retinal blood flow (RBF) was measured using a retinal function imager, and retinal capillary density (RCD, expressed as fractal dimension Dbox) was measured using optical coherence tomography angiography. RCF was defined as the ratio of RBF to RCD.

Results:

RCF was 1.62 ± 0.56 nl/s/Dbox (mean ± SD) in the AD group, which was significantly lower than that (2.56 ± 0.25 nl/s/Dbox,P< 0.01) in the CN group. The change of RCF in the AD group represented 28% lower than in the CN group. RCF was significantly and positively correlated with RBF in the AD group (r = 0.98,P< 0.05) and in the CN group (r = 0.65,P< 0.05).

Conclusions:

Our study is the first to demonstrate impaired retinal capillary function in patients with AD. The alteration of RCF was mainly due to decreased retinal blood flow, which is transferred by the capillary network. The RCF may be developed as a biomarker of impaired cerebral microcirculation in patients with AD.
Pavement crack detection based on point cloud data and data fusion
Authors: Dong Qiao , Wang Sike , Chen Xueqin , Jiang Wanqi , Li Ruiqi , Gu Xingyu
Published: July 2023

The three-dimensional detection in point cloud data for pavement cracks has drawn the attention of many researchers recently. In the field of pavement surface point cloud detection, the key tasks include the identification of pavement cracks and the extraction of the location and size information of pavement cracks. Based on the point cloud data of pavement surface, we developed two methods to directly extract and detect cracks, respectively. The first method is based on the improved sliding window algorithm by combining the random sample consensus (RANSAC) technique to directly extract the crack information from point clouds. The second method is developed based on YOLOv5 to process the two-dimensional images transformed from point cloud data for automatic pavement crack detection. We also attempted to fuse the point cloud images with greyscale images as input for the YOLOv5. Analysis results show that the improved sliding window algorithm efficiently extracts pavement cracks with less noise, and the YOLOv5-based method obtains a good detection of pavement cracks.

This article is part of the theme issue ‘Artificial intelligence in failure analysis of transportation infrastructure and materials’.
Falling weight deflectometer dispersion curve method for pavement modulus calculation
Authors: Wang Xue , Huang Hai , Zhang Kun , Shen Shihui
Published: July 2023

The falling weight deflectometer (FWD) test is a common non-destructive testing method for evaluating the structural capacity of pavements. At present, data processing of the FWD test mainly focuses on the deflection data, while paying less attention to the deflection-time history. Because a FWD is equipped with impulse loads and geophones, which allow for the generation and capture of surface wave signal propagation, it is hypothesized that Rayleigh wave dispersion theory can be applied to calculate the modulus profile along the pavement depth by analysing the dispersive properties of the deflection signal measured during FWD tests. To test this hypothesis, we develop a new methodology for the FWD test and data analysis, referred to as the FWD dispersion curve method. We first introduce the concept of the new method, followed by an illustration of the procedure and the experimental set-up. Case studies on three concrete pavement segments are then presented to evaluate the effectiveness of the FWD dispersion curve method. Modifications to the existing FWD device are further recommended for the impact loading sources and signal collection process so that the modulus of a much shallower layer, such as the concrete slab and upper asphalt layers, can be obtained.

This article is part of the theme issue 'Artificial intelligence in failure analysis of transportation infrastructure and materials'.
Machine learning-based identification of segment joint failure in underground tunnels
Authors: Jin Zhisheng , Yan Zihai , Fu Haoran , Bian Xuecheng
Published: July 2023

Shield tunnels that reside deep within soft soil are subject to longitudinal differential settlement and structural deformation during long-term operation. Longitudinal deformation can be classified into two modes: bending and dislocation deformation. The failure of bolts and engineering treatment techniques differ between these two modes. Therefore, it is imperative to accurately identify the tunnel's longitudinal deformation mode to determine the validity of the segment joint and implement appropriate engineering treatment. Traditional methods for detecting dislocation or opening suffer from high labour costs. To address this issue, this study presents an innovative identification method using a back-propagation neural network (BPNN) to detect segment joint failure in underground tunnels. First, this study collects the tunnel settlement curves of various subways located in the East China soft soil area, and it calculates tunnel settlement-dislocation and settlement-opening datasets using the equivalent axial stiffness model. A corresponding BPNN regression model is subsequently established, and the new settlement curve is the input to this regression model to predict the dislocation and opening, thereby determining the validity of the segment joint. The efficiency of this method is demonstrated through its successful application to the Hangzhou Metro Tunnel.

This article is part of the theme issue 'Artificial intelligence in failure analysis of transportation infrastructure and materials'.
Machine learning-based rail corrugation recognition: a metro vehicle response and noise perspective
Authors: Cai Xiaopei , Tang Xueyang , Chang Wenhao , Wang Tao , Lau Albert , Chen Zhipei , Qie Luchao
Published: July 2023

Rail corrugation is a common problem in metro lines, and its efficient recognition is always an issue worth studying. To recognize the wavelength and amplitude of rail corrugation, a particle probabilistic neural network (PPNN) algorithm is developed. The PPNN is incorporated with the particle swarm optimization algorithm and the probabilistic neural network. On the basis of the above, the in-vehicle noise characteristics measured in the field are used to recognize normal rail wavelengths of 30 and 50 mm. A stepwise moving window search algorithm suitable for selecting features with a fixed order was developed to select in-vehicle noise features. Sound pressure levels at 400, 500, 630 and 800 Hz of in-vehicle noise are fed into the PPNN, and the average accuracy can reach 96.43%. The bogie acceleration characteristics calculated by the multi-body dynamics simulation model are used to recognize normal rail amplitudes of 0.1 and 0.2 mm. The bogie acceleration is decomposed by the complete ensemble empirical mode decomposition with adaptive noise, and a reconstructional signal is obtained. The energy entropy of the reconstructional signal is fed into the PPNN, and the average accuracy can reach 95.40%.

This article is part of the theme issue 'Artificial intelligence in failure analysis of transportation infrastructure and materials'.
Influence of insertion sequences on population structure of phytopathogenic bacteria in the Ralstonia solanacearum species complex
Authors: Greenrod Samuel T. E. , Stoycheva Martina , Elphinstone John , Friman Ville-Petri
Published: July 2023

Ralstonia solanacearum

species complex (RSSC) is a destructive group of plant pathogenic bacteria and the causative agent of bacterial wilt disease. Experimental studies have attributed RSSC virulence to insertion sequences (IS), transposable genetic elements which can both disrupt and activate host genes. Yet, the global diversity and distribution of RSSC IS are unknown. In this study, IS were bioinformatically identified in a diverse collection of 356 RSSC isolates representing five phylogenetic lineages and their diversity investigated based on genetic distance measures and comparisons with the ISFinder database. IS phylogenetic associations were determined based on their distribution across the RSSC phylogeny. Moreover, IS positions within genomes were characterised and their potential gene disruptions determined based on IS proximity to coding sequences. In total, we found 24732 IS belonging to eleven IS families and 26 IS subgroups with over half of the IS found in the megaplasmid. While IS families were generally widespread across the RSSC phylogeny, IS subgroups showed strong lineage-specific distributions and genetically similar bacterial isolates had similar IS contents. Similar associations with bacterial host genetic background were also observed with IS insertion positions which were highly conserved in closely related bacterial isolates. Finally, IS were found to disrupt genes with predicted functions in virulence, stress tolerance, and metabolism suggesting that they might be adaptive. This study highlights that RSSC insertion sequences track the evolution of their bacterial hosts potentially contributing to both intra- and inter-lineage genetic diversity.
Deep Mutational Scanning in Disease-related Genes with Saturation Mutagenesis-Reinforced Functional Assays (SMuRF)
Authors: Ma Kaiyue , Huang Shushu , Ng Kenneth K. , Lake Nicole J. , Joseph Soumya , Xu Jenny , Lek Angela , Ge Lin , Woodman Keryn G. , Koczwara Katherine E. , Cohen Justin , Ho Vincent , O’Connor Christine L. , Brindley Melinda A. , Campbell Kevin P. , Lek Monkol
Published: July 2023

Interpretation of disease-causing genetic variants remains a challenge in human genetics. Current costs and complexity of deep mutational scanning methods hamper crowd-sourcing approaches toward genome-wide resolution of variants in disease-related genes. Our framework, Saturation Mutagenesis-Reinforced Functional assays (SMuRF), addresses these issues by offering simple and cost-effective saturation mutagenesis, as well as streamlining functional assays to enhance the interpretation of unresolved variants. Applying SMuRF to neuromuscular disease genesFKRPandLARGE1, we generated functional scores for all possible coding single nucleotide variants, which aid in resolving clinically reported variants of uncertain significance. SMuRF also demonstrates utility in predicting disease severity, resolving critical structural regions, and providing training datasets for the development of computational predictors. Our approach opens new directions for enabling variant-to-function insights for disease genes in a manner that is broadly useful for crowd-sourcing implementation across standard research laboratories.
Occupational dermatoses in health care personnel using PPE during the COVID pandemic
Authors: Asati Dinesh P , Baheti Kapil , Kaur Maninder , Patra Suman , Singhal Kritika
Published: July 2023

Background

A sudden surge of occupation-associated dermatoses among the healthcare workers (HCWs) serving COVID-19 patients have been witnessed recently due to increased usage of PPE (PPE) kits and increased frequency of hygiene practices, with a significant impact on their quality of life and compromised efficacy at work. Hence, this study was conducted to measure the prevalence of occupational dermatoses among HCWs serving Covid-19 patients using PPE kits and hygiene practices and their impact on quality of life.

Methods

HCWs of all cadres were screened for occupation-associated dermatoses. Cases with occupational dermatosis were further evaluated regarding using a PPE kit, and DLQI was calculated.

Results

19% of HCWs had dermatoses associated with PPE and hygiene practices. Hands were most affected, followed by the face, nasal bridge, and facial skin in contact with goggles. 48% had Mathias score >/= 4. Most cases had reported some impact on their quality of life. A significant association could be established between frequency of hand washing >/= 10 times/day with hand dermatitis (p=0.000).

Conclusion

The use of PPE has significantly raised cases of occupational dermatosis among HCWs. Repeated hand washing and hand sanitizer use has increased the incidence of hand dermatitis.
Clinical manifestations and mortality among hospitalized COVID-19 patients in Tanzania, 2021-2022
Authors: Osati Elisha , Shayo Grace A. , Nagu Tumaini , Sangeda Raphael Z , Moshiro Candida , Adams Naveeda , Ramadhani Athumani , Wanja Bahati , Muniko Albert , Seni Jeremia , Nicholaus Mary A. , Kilonzo Kajiru G , Nyaisonga Gervas , Mbije Christian , Meda John , Rainer Denis , Nkya Martha , Mhame Paulo , Samwel Lucy , Vumilia Liggyle , Shekalaghe Seif , Makubi Abel
Published: July 2023

Background

There have been differential mortality rates from Corona Virus Disease of 2019 (COVID-19) in different parts of the world. It is not clear whether the clinical presentation does also differ, thus the need for this study in a Sub-Saharan African country. The aim of this study was to describe clinical manifestations and outcome of patients diagnosed with COVID-19 in selected tertiary hospitals in Tanzania.

Methods and Findings

A retrospective analysis of archived data from 26thMarch, 2021 to 30thSeptember, 2022 was done for adults aged ≥18 years who were admitted in five tertiary-level hospitals in Tanzania. Information collected included socio-demographic, radiological and clinical characteristics of the patients as well as outcome of the admission (discharge vs death). Categorical variables were presented as frequencies and proportions and compared using Chi square test. Logistic regression was used to assess the relationship between COVID-19 mortality and the collected variables. Out of 1387 COVID-19 patients, approximately 52% were males. The median age was 60 years [(IQR)= (19-102)). The most common symptoms were dyspnea (943,68%), cough (889, 64%), fever (597,43%) and fatigue (570, 41%). In hospital mortality was (476, 34%). Mortality significantly increased with increasing age, being the most in age >90 years [aOR (95% CI) =6.72 (1.94-20.81), P<0.001. Other predictors of death were not possessing a health insurance, [aOR (95% CI) = 2.78 (2.09-3.70), P<0. 001], dyspnea [aOR (95% CI) = 1.40(1.02-2.06), P=0.03]; chest pain, [aOR (95% CI) = 1.78 (1.12-3.21), P=0.03]; HIV positivity, [aOR (95% CI) = 4.62 (2.51-8.73), P<0.001]; neutrophilia, [aOR (95% CI) = 1.02 (1.01 – 1.03), P=0.02]; none use of ivermectin, [aOR (95% CI) = 1.46 (1.09 – 2.22), P=0.02] and non-use of steroid, [aOR (95% CI) = 1.40 (1.2 – 2.5), P=0.04]. Retrospective nature of this study which based on documented patients records, with a large number of patients left out of the analysis due to missed data, this might in a way affect the results of the present study.

Conclusions

The most common presenting symptoms were dyspnea, cough and fever, just as what was common elsewhere in the world. Mortality increased significantly with age, in HIV-infected patients, in those without a health insurance, those presenting with dyspnea, chest pain, or neutrophilia and those who did not use steroid or ivermectin. Clinicians should actively look for the predictors of mortality and take appropriate management to reduce mortality.
Internet-connected cortical organoids for project-based stem cell and neuroscience education
Authors: Elliott Matthew A.T. , Schweiger Hunter E. , Robbins Ash , Vera-Choqqueccota Samira , Ehrlich Drew , Hernandez Sebastian , Voitiuk Kateryna , Geng Jinghui , Sevetson Jess L. , Rosen Yohei M. , Teodorescu Mircea , Wagner Nico O. , Haussler David , Mostajo-Radji Mohammed A.
Published: July 2023

The introduction of internet-connected technologies to the classroom has the potential to revolutionize STEM education by allowing students to perform experiments in complex models that are unattainable in traditional teaching laboratories. By connecting laboratory equipment to the cloud, we introduce students to experimentation in pluripotent stem cell-derived cortical organoids in two different settings: Using microscopy to monitor organoid growth in an introductory tissue culture course, and using high density multielectrode arrays to perform neuronal stimulation and recording in an advanced neuroscience mathematics course. We demonstrate that this approach develops interest in stem cell and neuroscience in the students of both courses. All together, we propose cloud technologies as an effective and scalable approach for complex project-based university training.

HIGHLIGHTS

- Development of cortical organoids as pedagogical tools for undergraduate education.

- Organoids implemented in a tissue culture course through cloud-enabled microscopy.

- Multielectrode arrays allow for live organoid manipulation in a mathematics course.

- Students self-report increased interest in neuroscience and stem cells topics.
Information-theory analysis of mouse string-pulling agrees with Fitts’s Law: Increasing task difficulty engages multiple sensorimotor modalities in a dual oscillator behavior
Authors: Sandhu Pardeepak S. , Agha Behroo Mirza , Inayat Samsoon , Singh Surjeet , Ryait Hardeep S. , Mohajerani Majid H. , Whishaw Ian Q.
Published: July 2023

Mouse string pulling, in which a mouse reels in a string with hand-over-hand movements, can provide insights into skilled motor behavior, neurological status, and cognitive function. The task involves two oscillatory movements connected by the string. The snout tracks the pendulum movement of the string produced by hand-over-hand pulls and so guides the hands to grasp the string. The present study examines the allocation of time required to pull strings of varying diameter. Movement is also described with end-point measures, string-pulling topography with 2D markerless pose estimates based on transfer learning with deep neural networks, and Mat-lab image-segmentation and heuristic algorithms for object tracking. With reduced string diameter, mice took longer to pull 60cm long strings. They also made more pulling cycles, misses, and mouth engagements, and displayed changes in the amplitude and frequency of pull cycles. The time measures agree with Fitts’s law in showing that increased task difficulty slows behavior and engages multiple compensatory sensorimotor modalities. The analysis reveals that time is a valuable resource in skilled motor behavior and information-theory can serve as a measure of its effective use.
Arsenophonussymbiosis with louse flies: multiple origins, coevolutionary dynamics, and metabolic significance
Authors: Říhová Jana , Gupta Shruti , Darby Alistair C , Nováková Eva , Hypša Václav
Published: July 2023

Arsenophonusis a widespread insect symbiont with life strategies that vary from parasitism to obligate mutualism. In insects living exclusively on vertebrate blood, mutualisticArsenophonusstrains are presumed to provide B vitamins missing in the insect host diet. Hippoboscidae, obligate blood-feeders related to tsetse flies, were previously suggested to have acquiredArsenophonussymbionts in several independent events. Based on comparative genomic analyzes of eleven Hippoboscidae-associated strains, nine of them newly assembled, we reveal a wide range of their genomic characteristics and phylogenetic affiliations. Phylogenetic patterns and genomic traits split the strains into two different types. Seven strains display characteristics of obligate mutualists with significantly reduced genomes and long phylogenetic branches. The remaining four genomes cluster on short branches, and their genomes resemble those of free-living bacteria or facultative symbionts. Both phylogenetic positions and genomic traits indicate that evolutionary history of the Hippoboscidae-Arsenophonusassociations is a mixture of short-term coevolutions with at least four independent origins. The comparative approach to a reconstruction of B vitamin pathways across the availableArsenophonusgenomes produced two kinds of patterns. On one hand, it indicated the different importance of individual B vitamins in the host-symbiont interaction. While some (riboflavin, pantothenate, folate) seem to be synthesized by all Hippoboscidae-associated obligate symbionts, pathways for others (thiamine, nicotinamide, cobalamin) are mostly missing. On the other hand, the broad comparison produced patterns which can serve as bases for further assessments of the pathways’ completeness and functionality.

Importance

Insects that live exclusively on vertebrate blood utilize symbiotic bacteria as a source of essential compounds, e.g. B vitamins. In louse flies, the most frequent symbiont originated in genusArsenophonus, known from a wide range of insects. Here, we analyze genomic traits, phylogenetic origins, and metabolic capacities of elevenArsenophonusstrains associated with louse flies. We show that in louse fliesArsenophonusestablished symbiosis in at least four independent events, reaching different stages of symbiogenesis. This allowed for comparative genomic analysis, including convergence of metabolic capacities. The significance of the results is two-fold. First, based on a comparison of independently originatedArsenophonussymbioses, it determines the importance of individual B vitamins for the insect host. This expands our theoretical insight into insect-bacteria symbiosis. The second outcome is of methodological significance. We show that the comparative approach reveals artifacts that would be difficult to identify based on a single-genome analysis.
On the variability of dynamic functional connectivity assessment methods
Authors: Torabi Mohammad , Mitsis Georgios D. , Poline Jean-Baptiste
Published: July 2023

Dynamic functional connectivity (dFC) has become an important measure for understanding brain function and as a potential biomarker. However, various methodologies have been developed for assessing dFC, and it is unclear how the choice of method affects the results. In this work, we aimed to study the results variability of commonly-used dFC methods. We implemented seven dFC assessment methods in Python and used them to analyze fMRI data of 395 subjects from the Human Connectome Project. We measured the pairwise similarity of dFC results using several similarity metrics in terms of overall, temporal, spatial, and inter-subject similarity. Our results showed a range of weak to strong similarity between the results of different methods, indicating considerable overall variability. Surprisingly, the observed variability in dFC estimates was comparable to the expected natural variation over time, emphasizing the impact of methodological choices on the results. Our findings revealed three distinct groups of methods with significant inter-group variability, each exhibiting distinct assumptions and advantages. These findings highlight the need for multi-analysis approaches to capture the full range of dFC variation. They also emphasize the importance of distinguishing neural-driven dFC variations from physiological confounds, and developing validation frameworks under a known ground truth. To facilitate such investigations, we provide an open-source Python toolbox that enables multi-analysis dFC assessment. This study sheds light on the impact of dFC assessment analytical flexibility, emphasizing the need for careful method selection and validation, and promoting the use of multi-analysis approaches to enhance reliability and interpretability of dFC studies.
An expression-directed linear mixed model (edLMM) discovering low-effect genetic variants
Authors: Li Qing , Bian Jiayi , Qian Yanzhao , Kossinna Pathum , Gordon Paul MK , Zhou Xiang , Guo Xingyi , Yan Jun , Wu Jingjing , Long Quan
Published: July 2023

Detecting genetic variants with low effect sizes using a moderate sample size is difficult, hindering downstream efforts to learn pathology and estimating heritability. In this work, by utilizing informative weights learned from training genetically predicted gene expression models, we formed an alternative approach to estimate the polygenic term in a linear mixed model (LMM). Our LMM estimates the genetic background by incorporating their relevance to gene expression. Our protocol, expression-directed linear mixed model (edLMM), enables the discovery of subtle signals of low-effect variants using moderate sample size. By applying edLMM to cohorts of around 5,000 individuals with either binary (WTCCC) or quantitative (NFBC1966) traits, we demonstrated its power gain at the low-effect end of the genetic etiology spectrum. In aggregate, the additional low-effect variants detected by edLMM substantially improved estimation of missing heritability. edLMM moves precision medicine forward by accurately detecting the contribution of low-effect genetic variants to human diseases.
A Recurrent Neural Circuit Mechanism of Temporal-scaling Equivariant Representation
Authors: Zuo Junfeng , Liu Xiao , Wu Ying Nian , Wu Si , Zhang Wen-Hao
Published: July 2023

Time perception is fundamental in our daily life. An important feature of time perception is temporal scaling (TS): the ability to generate temporal sequences (e.g., movements) with different speeds. However, it is largely unknown about the mathematical principle underlying TS in the brain. The present theoretical study investigates temporal scaling from the Lie group point of view. We propose a canonical nonlinear recurrent circuit dynamics, modeled as a continuous attractor network, whose neuronal population responses embed a temporal sequence that is TS equivariant. We find the TS group operators can be explicitly represented by a time-invariant control input to the network, whereby the input gain determines the TS factor (group parameter), and the spatial offset between the control input and the network state on the continuous attractor manifold gives rise to the generator of the Lie group. The recurrent circuit’s neuronal responses are consistent with experimental data. The recurrent circuit can drive a feedforward circuit to generate complex sequences with different temporal scales, even in the case of negative temporal scaling (“time reversal”). Our work for the first time analytically links the abstract temporal scaling group and concrete neural circuit dynamics.
Beta-blocker exposure is associated with nonunion in a geriatric cohort of 253,266 extremity fractures
Authors: Steffenson Lillia , Martin Brook , Kantor Adam , O’Neill Dillon , Myhre Luke , Thorne Tyler , Rothberg David , Higgins Thomas , Haller Justin , Marchand Lucas
Published: July 2023

Previously published animal studies have shown positive skeletal effects with local or systemic administration of beta blockers (BBs). However, population studies have shown mixed effects on bone mineral density (BMD) and fracture risk with BB use. The goal of this study was to evaluate whether exposure to BB is associated with fracture nonunion. Fee-for-service Medicare beneficiaries with an extremity fracture were identified by International Classification of Diseases (ICD)-10 and current procedural terminology (CPT) codes from 2016-2019. Charlson Comorbidity Index (CCI) was assigned using diagnoses prior to index fracture and nonunion identified by ICD-10 or CPT codes within one year from index fracture diagnosis. Patients were classified by BB exposure based on Part D (Pharmacy) claims between 90 days prior to and one year following index fracture. Chi square and Student’s T-tests were performed on categorical and continuous variables, respectively. Logistic regression was performed to evaluate the association between BB use and nonunion, controlling for age, sex, race, and comorbidity. Total number of fractures meeting inclusion criteria was 253,266 with 45% of patients having used a BB during the study period. The incidence of nonunion was 3.9% overall. BBs were associated with a 13% increase in non-union for all fracture types, after controlling for age, sex, fracture location, and CCI (OR 1.13 [CI 1.06-1.20], p<.001). Results of this study suggest a negative influence of BB on bone healing, contrary to results of previously published animal models and epidemiologic observations, and demonstrate that BB use during fracture care is associated with significant increase in incidence of nonunion.