bluuebunny/crossref_metadata_2025 huggingface dataset:
Reliability, Validity, and Responsiveness of the Patient-Specific Functional Scale for Measuring Mobility-Related Goals in People With Multiple Sclerosis
Authors: Mañago Mark M. , Cohen Evan T. , Cameron Michelle H. , Christiansen Cory L. , Bade Michael
Published: March 2023

Background and Purpose:

This study's purpose was to investigate the reliability, validity, and responsiveness of the Patient-Specific Functional Scale (PSFS) for measuring mobility-related goals in people with multiple sclerosis (MS).

Methods:

Data from 32 participants with MS who underwent 8 to 10 weeks of rehabilitation were analyzed (Expanded Disability Status Scale scores 1.0-7.0). For the PSFS, participants identified 3 mobility-related areas where they had difficulty and rated them at baseline, 10 to 14 days later (before starting intervention), and immediately after intervention. Test-retest reliability and response stability of the PSFS were calculated using the intraclass correlation coefficient (ICC2,1) and minimal detectable change (MDC95), respectively. Concurrent validity of the PSFS was determined with the 12-item Multiple Sclerosis Walking Scale (MSWS-12) and the Timed 25-Foot Walk Test (T25FW). PSFS responsiveness was determined using Cohen's d, and minimal clinically important difference (MCID) was calculated based on patient-reported improvements on a Global Rating of Change (GRoC) scale.

Results:

The PSFS total score demonstrated moderate reliability (ICC2,1 = 0.70, 95% CI: 0.46 to 0.84) and the MDC was 2.1 points. At baseline, the PSFS was fairly and significantly correlated with the MSWS-12 (r = −0.46, P = 0.008) but not with the T25FW. Changes in the PSFS were moderately and significantly correlated with the GRoC scale (ρ = 0.63, P < 0.001), but not with MSWS-12 or T25FW changes. The PSFS was responsive (d = 1.7), and the MCID was 2.5 points or more to identify patient-perceived improvements based on the GRoC scale (sensitivity = 0.85, specificity = 0.76).

Discussion and Conclusions:

This study supports the use of the PSFS as an outcome measure in people with MS to assess mobility-related goals.

Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A423).
Child Opportunity Index and Emergent PICU Readmissions: A Retrospective, Cross-Sectional Study of 43 U.S. Hospitals
Authors: Akande Manzilat Y. , Ramgopal Sriram , Graham Robert J. , Goodman Denise M. , Heneghan Julia A.
Published: March 2023

OBJECTIVES:

To examine the association between a validated composite measure of neighborhood factors, the Child Opportunity Index (COI), and emergent PICU readmission during the year following discharge for survivors of pediatric critical illness.

DESIGN:

Retrospective cross-sectional study.

SETTING:

Forty-three U.S. children’s hospitals contributing to the Pediatric Health Information System administrative dataset.

PATIENTS:

Children (< 18 yr) with at least one emergent PICU admission in 2018–2019 who survived an index admission.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Of 78,839 patients, 26% resided in very low COI neighborhoods, 21% in low COI, 19% in moderate COI, 17% in high COI, and 17% in very high COI neighborhoods, and 12.6% had an emergent PICU readmission within 1 year. After adjusting for patient-level demographic and clinical factors, residence in neighborhoods with moderate, low, and very low COI was associated with increased odds of emergent 1-year PICU readmission relative to patients in very high COI neighborhoods. Lower COI levels were associated with readmission in diabetic ketoacidosis and asthma. We failed to find an association between COI and emergent PICU readmission in patients with an index PICU admission diagnosis of respiratory conditions, sepsis, or trauma.

CONCLUSIONS:

Children living in neighborhoods with lower child opportunity had an increased risk of emergent 1-year readmission to the PICU, particularly children with chronic conditions such as asthma and diabetes. Assessing the neighborhood context to which children return following critical illness may inform community-level initiatives to foster recovery and reduce the risk of adverse outcomes.
Parental Perspectives on Life-Altering News in Emergency Settings
Authors: Visclosky Timothy , Kadri Adam , Sedig Laura , Reynolds Lyndsey , Wolff Margaret
Published: March 2023

Introduction

Delivering life-altering news is a difficult task that is frequently the responsibility of emergency physicians. However, the existing frameworks for guiding such interactions fail to address the physician-parent-patient dynamic of pediatric emergency encounters. To date, no study has investigated the parental perspective, limiting the ability to provide evidence-based recommendations. This study describes how parents experience receiving life-altering news about their child in emergency settings.

Methods

This qualitative study used virtual asynchronous focus groups. Through purposeful sampling of virtual support and advocacy groups, we recruited parents of children diagnosed with either malignancy or type 1 diabetes in an emergency department. Participants were then assigned to private Facebook groups established solely for this study. Questions were posted to these groups over the course of 5 days. At their convenience, participants could post responses, replies, or new questions. Three members of the research team performed thematic analysis and used team consensus to ensure validity.

Results

Four focus groups were conducted with a total of 28 participants. Parents described their experiences receiving life-altering news as a process with 4 primary emergent themes: lens through which they view the experience, the ED encounter, the immediate response, and the long-term impact. Each parent entered into the ED encounter with a unique collection of personal experiences, circumstances, and knowledge. These factors shaped the lens through which they perceived the events of the ED encounter. Ultimately, this determined participants' response to the life-altering news, leading to many long-term impacts on the various dynamics within each parent's life.

Conclusions

The words used to disclose life-altering news are only a small piece of the experience for parents. Personal lenses changed how encounters were perceived, resulting in variable and long-lasting implications. We recommend the following framework for providers: understand the lens, control encounters, manage responses, and respect long-term impacts.
The Safety and Strategies for Reinitiating Electroconvulsive Therapy After ECT-Induced Takotsubo Cardiomyopathy
Authors: Kinoshita Michiko , Kinoshita Makoto , Takahashi Rikako , Mutoh Sarara , Kakuta Nami , Tanaka Katsuya
Published: March 2023

Objectives

Takotsubo cardiomyopathy (TCM) is a life-threatening complication of electroconvulsive therapy (ECT). We report the case of a 66-year-old woman who was rechallenged with ECT after ECT-induced TCM. Moreover, we have made a systematic review to assess the safety of and strategies for reinitiating ECT after TCM.

Methods

We searched for published reports on ECT-induced TCM since 1990 in MEDLINE (PubMed), Scopus, Cochrane Library, ICHUSHI, and CiNii Research.

Results

A total of 24 ECT-induced TCM cases were identified. Patients who developed ECT-induced TCM were predominantly middle-aged and older women. There was no specific trend in anesthetic agents used. Seventeen (70.8%) cases developed TCM by the third session in the acute ECT course. Eight (33.3%) cases developed ECT-induced TCM despite the use of β-blockers. Ten (41.7%) cases developed cardiogenic shock or abnormal vital signs related to cardiogenic shock. All cases recovered from TCM. Eight (33.3%) cases tried to receive ECT retrial. The duration until ECT retrial was between 3 weeks and 9 months. The most common preventive measures during ECT retrial were related to β-blockers; however, the type, dose, and route of administration of β-blockers varied. In all cases, ECT could be reperformed without TCM recurrence.

Conclusions

Electroconvulsive therapy–induced TCM is more likely to cause cardiogenic shock than nonperioperative cases; nevertheless, it has good prognosis. Cautious reinitiation of ECT after TCM recovery is possible. Further studies are required to determine preventive measures for ECT-induced TCM.
A Multi-layer Perceptron Neural Network for Predicting the Osteoporosis in Women Using Physical Activity Factors
Authors: Kim Jun-hee
Published: March 2023

Introduction

Osteoporosis (OP) is a bone disease caused by a decrease in bone mineral density (BMD). OP is common in women because BMD gradually decreases after age 35. OP due to decreased BMD is highly likely to cause fatal traumatic injuries such as hip fracture. The purpose of this study was developed and evaluated a multi-layer perceptron neural network model that predicts OP using physical characteristics and activity factors of adult women over the age of 35 whose BMD begins to decline.

Materials and Methods

Data from KNHANES were used to develop a multi-layer perceptron model for predicting OP. Data preprocessing included variable selection and sample balancing, and LASSO was used for feature selection. The model used 5 hidden layers, dropout and batch normalization and was evaluated using evaluation scores such as accuracy and recall score calculated from a confusion matrix.

Results

Models were trained and evaluated to predict OP using selected features including age, quality of life index, weight, grip strength and average working hours per week. The model achieved 76.8% accuracy, 74.5% precision, 80.5% recall, 77.4% F1 score, and 74.8% ROC AUC.

Conclusion

A multi-layer perceptron neural network for predicting OP diagnosis using physical characteristics and activity factors in women aged 35 years or older showed relatively good performance. Since the selected variables can be easily measured through surveys, assessment tool, and digital hand dynamometer, this model will be useful for screening elderly women with OP or not in areas with poor medical facilities or difficult access.
Characterisation of the retinal phenotype using multimodal imaging in novel compound heterozygote variants ofCYP2U1
Authors: Sallo Ferenc B , Dysli Chantal , Holzer Franz Josef , Ranza Emmanuelle , Guipponi Michel , Antonarakis Stylianos E , Munier Francis L , Bird Alan C , Schorderet Daniel F , Rossillion Beatrice , Vaclavik Veronika
Published: March 2023

Purpose

To report the retinal phenotype in two patients simulating type 2 macular telangiectasis with new variants inCYP2U1implicated in Hereditary Spastic Paraplegia type 56 (HSP 56).

Methods

Five members of a non-consanguineous family (parents and three male children) were investigated. All family members underwent a full ophthalmological evaluation and multimodal retinal imaging. Two family members demonstrating retinal anomalies underwent additional OCT angiography, dual wavelength autofluorescence and fluorescence lifetime imaging ophthalmoscopy, kinetic perimetry, fundus-correlated microperimetry, electroretinography and electro-oculography. Whole exome sequencing was performed in all five family members.

Results

The two siblings with compound heterozygous novel variants c.452C>T; p.(Pro151Leu), c.943C>T; p.(Gln315Ter) inCYP2U1demonstrated parafoveal loss of retinal transparency and hyperreflectivity to blue light, redistribution of luteal pigment to the parafoveal edge, photoreceptor loss, FLIO anomalies: a pattern compatible with that seen in macular telangiectasia type 2 (MacTel). One had manifest neurological abnormalities since early childhood, the second had no neurological abnormalities. Each parent and the third sibling were heterozygous for one variant and were neurologically and ophthalmologically normal.

Conclusion

TheseCYP2U1variants are associated with a retinal phenotype very similar to that otherwise specific for MacTel, suggestive of possible links in the aetiology/pathogenesis of these diseases.
Preterm Prelabour Rupture Of Membranes (PPROM) before 23 weeks gestation: A prospective observational study
Authors: Goodfellow L , Care A , Curran C , Roberts D , Turner M.A. , Knight M , Alfirevic Z
Published: March 2023

Objectives

Describe infant and maternal outcomes of a national cohort of women with preterm prelabour rupture of membranes (PPROM) under 23 weeks gestation.

Design

Prospective national population-based cohort study using the UK Obstetric Surveillance System (UKOSS).

Setting

All 194 obstetric units in the UK.

Participants

330 women with singleton and 38 with multiple pregnancies and PPROM between 16+0and 22+6weeks gestation 1/9/19-28/2/21.

Main outcome measures

Infant outcomes: livebirth, survival to hospital discharge and severe morbidity, defined as intraventricular haemorrhage grade 3 or 4 and/or supplemental oxygen requirement at 36 weeks postmenstrual age.

Maternal outcomes: surgery for placental removal; sepsis; admission to intensive treatment unit (ITU) and death.

Methods

All data including rates of termination of pregnancy for medical reasons (TFMR) were reported. Three rates were calculated for infant outcomes: i) all TFMR excluded; ii) assuming that all TFMR and those with missing data would have died; iii) assuming that all TFMR and those with missing data would be liveborn. Rates are presented as i (ii to iii).

Results

For singleton pregnancies the livebirth rate was 44% (30 to 62%), infant survival to discharge was 26% (16 to 54%) and 18% (12 to 49%) of infants survived without severe morbidity. Maternal sepsis rate was 12% for singleton and 26% for twin pregnancies. Surgery for placental removal was 20% and 14%, respectively.

Five women became severely unwell with sepsis, 2 died and a further 3 required ITU care.

Conclusions

Although significant numbers of pregnancies with very early PPROM have favourable outcomes, morbidity and mortality rates in this cohort are high for mothers and infants.

These data can be used in counselling families facing PPROM prior to 23 weeks gestation and to underpin research into the complex pathologies, including sepsis, related to this condition. Currently available guidelines should be updated accordingly.

What is already known on this topic

PPROM under 23 weeks gestation is a serious pregnancy complication with high rates of morbidity for mothers and infants

Women are often advised to consider termination for medical reasons (TFMR)

Contemporary, population based, pregnancy outcomes are not available, making counselling even more difficult

What this study adds

This study identified significant maternal morbidity; 12% of women developed sepsis and 2 women (0.6%, 95%CI 0.17-2.2%) died

Conversely infant outcomes were relatively favourable; 26% of expectantly managed infants survived to hospital discharge and the potential worst-best case survival range including those that had termination for medical reasons (TFMR) was 16-54%

Understanding of these results are imperative to appropriate counselling and management of women facing this difficult complication
Deeplasia: prior-free deep learning for pediatric bone age assessment robust to skeletal dysplasias
Authors: Rassmann Sebastian , Keller Alexandra , Skaf Kyra , Hustinx Alexander , Gausche Ruth , Ibarra-Arrelano Miguel A. , Hsieh Tzung-Chien , Madajieu Yolande E. D. , Nöthen Markus M. , Pfäffle Roland , Attenberger Ulrike I. , Born Mark , Mohnike Klaus , Krawitz Peter M. , Javanmardi Behnam
Published: March 2023

Background

Skeletal dysplasias collectively affect a large number of patients worldwide. The majority of these disorders cause growth anomalies. Hence, assessing skeletal maturity via determining the bone age (BA) is one of the most valuable tools for their diagnoses. Moreover, consecutive BA assessments are crucial for monitoring the pediatric growth of patients with such disorders, especially for timing hormone treatments or orthopedic interventions. However, manual BA assessment is time-consuming and suffers from high intra-and inter-rater variability. This is further exacerbated by genetic disorders causing severe skeletal malformations. While numerous approaches to automatize BA assessment were proposed, few were validated for BA assessment on children with abnormal development.

Objective

We design and present Deeplasia, an open-source prior-free deep-learning approach for pediatric bone age assessment specifically validated on patients with skeletal dysplasias.

Materials and methods

We extensively experiment with training multiple convolutional neural network models under various conditions and select three to build a precise model ensemble. We utilize the public RSNA BA dataset consisting of training, validation, and test subsets each containing 12,611, 1,425, and 200 hand X-rays, respectively. For testing the performance of our model ensemble on dysplastic hands, we retrospectively collected 568 X-ray images from 189 patients with molecularly confirmed diagnoses of seven different genetic bone disorders including Achondroplasia and Hypochondroplasia.

Results

On the public RSNA test set, we achieve state-of-the-art performance with a mean absolute difference (MAD) of 3.87 months based on the average of six different reference ratings. We demonstrate the generalizability of Deeplasia to the dysplastic hands (unseen by the models) achieving a MAD of 5.84 months w.r.t. to the average of two reference ratings. Further, using longitudinal data from a subset of the dysplastic cohort (149 images), we estimate the test-retest precision of our model ensemble to be at least at the human expert level (2.74 months).

Conclusion

We conclude that Deeplasia suits assessing and monitoring the BA in patients with skeletal dysplasia.
How has the municipal availability of theGeneXpert®MTB/RIFsystem affected the detection of drug-resistant tuberculosis in Brazil?
Authors: Aguilar-Jiménez Jhancy Rocío , Pelissari Daniele Maria , Diaz-Quijano Fredi Alexander
Published: March 2023

Objective

To evaluate the association between the availability ofGeneXpert®MTB/RIFin municipalities and the proportion of people who have access to this diagnostic technology for tuberculosis (TB), as well as the resistance detected by the surveillance system in Brazil.

Methods

We analyzed 4,998 Brazilian municipalities that reported 432,937 new TB cases between 2015 and 2020. We compared municipalities with and without the availability ofGeneXpert®MTB/RIFregarding the prevalence of effective access toGeneXpert®MTB/RIFdiagnosis and that of detected resistance.

Results

Municipalities with at least oneGeneXpert®MTB/RIFsystem had three times (95%CI 2.9-3.0) the access to diagnostic tests and 80.4% (95%CI 70.6%-90.2%) higher detection of resistance, compared to municipalities without this technology. We estimate that there have been 2,110 cases of undetected resistance during this period in the country.

Conclusions

The availability ofGeneXpert®MTB/RIFsystem in the municipality increased the sensitivity of the surveillance for detecting TB resistance.

Public Health implications

It is a priority to strengthen laboratory networks and narrow the gap in access to rapid diagnosis in remote areas to improve the detection and control of drug-resistant tuberculosis.
SEX DIFFERENCES IN THE MANAGEMENT OF SUSPECTED STROKE IN A TELESTROKE NETWORK
Authors: Pérez-Sánchez Soledad , Barragán-Prieto Ana , Loscertales Juan Bautista , Cabezas Rodríguez Juan Antonio , Zapata-Arriaza Elena , Amaya Laura , Gómez Andrés Hermosín , Gamero García Miguel Ángel , Galeano Benito , Fernández Javier , Galiana Blanca Pardo , Mayoral Ana Domínguez , Gómez Leire Ainz , Navarro Jose Fernández , del Toro Cristina , Medina Manuel , de Torres Reyes , Baena Pablo , Moniche Francisco , Moyano Roberto Valverde , Martínez Patricia , González Alejandro , Montaner Joan
Published: March 2023

BACKGROUND

The evolution of ischemic stroke is different according to sex and is one of the main causes of death in women. In the literature, it is not clear if this is due to biological differences or to disparities in medical care. Previous studies have shown that women are less likely to receive acute treatment, and stroke center type is an important predictor of door-to-needle times. We investigated whether women are attended in a similar way to men in the telestroke network with specialized stroke physicians.

METHODS

A prospective registry of ischemic strokes recorded in the centralized Andalusian telestroke network (CATI) was analyzed, focusing on sex differences. Demographic data, clinical characteristics (risk factors), neuroimaging data, treatment intervals, and clinical results (the modified Rankin Scale [mRS] score) were collected. Functional outcomes were evaluated using the mRS at 90 days.

RESULTS

A total of 3009 suspected stroke patients were attended to in the telestroke network in the last three years, of which 42.74% were women. A total of 69.54% of the men and 63.85% of the women were diagnosed with ischemic stroke (p=0.002). Women were older (p>0.001) and less independent upon arrival (p=0.006) than men. There was no difference in the treatment received or in the treatment intervals between the groups. Importantly, there was no difference in mRS scores at 3 months between sexes. However, at follow-up, women had fewer imaging tests (p = 0.018) and fewer outpatient visits (p<0.001) than men.

CONCLUSIONS

No significant difference between men and women has been found in the acute treatment of stroke in a large telestroke network. However, the same is not true for the follow-up and management of patients after the acute phase. This fact supports that strict adherence to protocols, training, and specialization of care and providing equal attention prevents sex differences in stroke treatment and functional outcomes.
signifinder enables the identification of tumor cell states and cancer expression signatures in bulk, single-cell and spatial transcriptomic data
Authors: Pirrotta Stefania , Masatti Laura , Corrà Anna , Pedrini Fabiola , Esposito Giovanni , Martini Paolo , Risso Davide , Romualdi Chiara , Calura Enrica
Published: March 2023

Over the last decade, many studies and some clinical trials have proposed gene expression signatures as a valuable tool for understanding cancer mechanisms, defining subtypes, monitoring patient prognosis, and therapy efficacy. However, technical and biological concerns about reproducibility have been raised. Technical reproducibility is a major concern: we currently lack a computational implementation of the proposed signatures, which would provide detailed signature definition and assure reproducibility, dissemination, and usability of the classifier. Another concern regards intratumor heterogeneity, which has never been addressed when studying these types of biomarkers using bulk transcriptomics.

With the aim of providing a tool able to improve the reproducibility and usability of gene expression signatures, we proposesignifinder, an R package that provides the infrastructure to collect, implement, and compare expression-based signatures from cancer literature. The included signatures cover a wide range of biological processes from metabolism and programmed cell death, to morphological changes, such as quantification of epithelial or mesenchymal-like status. Collected signatures can score tumor cell characteristics, such as the predicted response to therapy or the survival association, and can quantify microenvironmental information, including hypoxia and immune response activity.

signifinderhas been used to characterize tumor samples and to investigate intra-tumor heterogeneity, extending its application to single-cell and spatial transcriptomic data. Through these higher-resolution technologies, it has become increasingly apparent that the single-sample score assessment obtained by transcriptional signatures is conditioned by the phenotypic and genetic intratumor heterogeneity of tumor masses. Since the characteristics of the most abundant cell type or clone might not necessarily predict the properties of mixed populations, signature prediction efficacy is lowered, thus impeding effective clinical diagnostics. Throughsignifinder, we offer general principles for interpreting and comparing transcriptional signatures, as well as suggestions for additional signatures that would allow for more complete and robust data inferences. We considersignifindera useful tool to pave the way for reproducibility and comparison of transcriptional signatures in oncology.
Microglial MHC-I induction with aging and Alzheimer’s is conserved in mouse models and humans
Authors: Kellogg Collyn M. , Pham Kevin , Machalinski Adeline H. , Porter Hunter L. , Blankenship Harris E. , Tooley Kyla , Stout Michael B. , Rice Heather C. , Sharpe Amanda L. , Beckstead Michael J. , Chucair-Elliott Ana J. , Ocañas Sarah R. , Freeman Willard M.
Published: March 2023

Major Histocompatibility Complex I (MHC-I) CNS cellular localization and function is still being determined after previously being thought to be absent from the brain. MHC-I expression has been reported to increase with brain aging in mouse, rat, and human whole tissue analyses but the cellular localization was undetermined. Neuronal MHC-I is proposed to regulate developmental synapse elimination and tau pathology in Alzheimer’s disease (AD). Here we report that across newly generated and publicly available ribosomal profiling, cell sorting, and single-cell data, microglia are the primary source of classical and non-classical MHC-I in mice and humans. Translating Ribosome Affinity Purification-qPCR analysis of 3-6 and 18-22 month old (m.o.) mice revealed significant age-related microglial induction of MHC-I pathway genesB2m,H2-D1,H2-K1,H2-M3,H2-Q6, andTap1but not in astrocytes and neurons. Across a timecourse (12-23 m.o.), microglial MHC-I gradually increased until 21 m.o. and then accelerated. MHC-I protein was enriched in microglia and increased with aging. Microglial expression, and absence in astrocytes and neurons, of MHC-I binding Leukocyte Immunoglobulin-like (Lilrs) and Paired immunoglobin-like type 2 (Pilrs) receptor families could enable cell-autonomous MHC-I signaling and increased with aging in mice and humans. Increased microglial MHC-I, Lilrs, and Pilrs were observed in multiple AD mouse models and human AD data across methods and studies. MHC-I expression correlated withp16INK4A, suggesting an association with cellular senescence. Conserved induction of MHC-I, Lilrs, and Pilrs with aging and AD opens the possibility of cell-autonomous MHC-I signaling to regulate microglial reactivation with aging and neurodegeneration.
High Volume Rate 3-D Ultrasound Imaging Using Fast-Tilting and Redirecting Reflectors
Authors: Dong Zhijie , Li Shuangliang , Duan Xiaoyu , Lowerison Matthew R. , Huang Chengwu , You Qi , Chen Shigao , Zou Jun , Song Pengfei
Published: March 2023

3-D ultrasound imaging has many advantages over 2-D imaging such as more comprehensive tissue evaluation and less operator dependence. Although many 3-D ultrasound imaging techniques have been developed in the last several decades, a low-cost and accessible solution with high imaging volume rate and imaging quality remains elusive. Recently we proposed a new, high volume rate 3-D ultrasound imaging technique: Fast Acoustic Steering via Tilting Electromechanical Reflectors (FASTER), which uses a water-immersible and fast-tilting acoustic reflector to steer ultrafast plane waves in the elevational direction to achieve high volume rate 3-D ultrasound imaging with conventional 1-D array transducers. However, the initial implementation of FASTER imaging only involves a single fast-tilting acoustic reflector, which is inconvenient to use because the probe cannot be held in the regular upright position. Also, conventional FASTER imaging can only be performed inside a water tank because of the necessity of using water for acoustic conduction. To address these limitations of conventional FASTER, here we developed a novel ultrasound probe clip-on device that encloses a fast-tilting reflector, a redirecting reflector, and an acoustic wave conduction medium. The new FASTER 3-D imaging device can be easily attached to or removed from clinical ultrasound transducers, allowing rapid transformation from 2-D to 3-D ultrasound imaging.In vitroB-mode imaging studies demonstrated that the proposed method provided comparable imaging quality (e.g., spatial resolution and contrast-to-noise ratio) to conventional, mechanical-translation-based 3-D imaging while providing a much faster 3-D volume rate (e.g., 300 Hz vs ∼10 Hz). In addition to B-mode imaging, we also demonstrated 3-D power Doppler imaging and 3-D super-resolution ultrasound localization microscopy with the newly developed FASTER device. Anin vivoimaging study showed that the FASTER device could clearly visualize the 3-D anatomy of the basilic vein of a healthy volunteer, and customized beamforming was implemented to accommodate the speed of sound difference between the acoustic medium and the imaging object (e.g., soft tissue). These results suggest that the newly developed redirecting reflector and the clip-on device could overcome key hurdles for future clinical translation of the FASTER 3-D imaging technology.
Data-driven representations using deep network-coherent methylation autoencoders to identify robust disease and risk factor signatures
Authors: Martínez-Enguita David , Dwivedi Sanjiv K. , Jörnsten Rebecka , Gustafsson Mika
Published: March 2023

Data analysis in systems medicine often employs knowledge-driven approaches, which leverage prior biological insights to guide and inform the study of large omic sets. However, the current state of knowledge in biology is still partial and biased. For example, cancer-associated genes are overrepresented in protein interaction networks. As a result, these approaches may fail to capture novel or unexpected phenomena. In this study, we present a data-driven workflow for the functional analysis of large DNA methylation data using deep autoencoders with biologically relevant latent embeddings (network-coherent autoencoders, NCAEs). We observed an increasing gene co-localization gradient, consistent with the human interactome, within the learned representation of a deep methylation autoencoder. We showcased the capacity of this coherent compressed space to discover signatures for classification associated with aging, smoking, and disease. We believe this approach can improve the understanding of complex epigenetic processes and help develop more effective diagnostic and therapeutic strategies.
Combinatorial multimer staining and spectral flow cytometry facilitate quantification and characterization of polysaccharide-specific B cell immunity
Authors: Hoving D. , Marques A.H.C. , Huisman W. , Nosoh B.A. , de Kroon A.C. , van Hengel O.R.J. , Wu B.R. , van Helden P.M. , Urban B.C. , Dhar N. , Ferreira D.M. , Kwatra G. , Hokke C.H. , Jochems S.P.
Published: March 2023

Bacterial capsular polysaccharides are important vaccine immunogens. However, the study of polysaccharide-specific immune responses has been hindered by technical restrictions. Here, we developed and validated a high-throughput method to analyse antigen-specific B cells using combinatorial staining with fluorescently-labelled capsular polysaccharide multimers. Concurrent staining of 25+ cellular markers further enables the in-depth characterization of polysaccharide-specific cells. We used this assay to simultaneously analyse 14Streptococcus pneumoniaeor 5Streptococcus agalactiaeserotype-specific B cell populations. The phenotype of polysaccharide-specific B cells was associated with serotype specificity, vaccination history and donor population. For example, we observed a link between non-class switched (IgM+) memory B cells and vaccine-inefficientS. pneumoniaeserotypes 1 and 3. Moreover, B cells had increased activation in donors from South Africa, which has high-incidence ofS. agalactiaeinvasive disease, compared to European donors. This assay allows for the characterization of heterogeneity in B cell immunity that may underlie immunization efficacy.
Crosstalkr: An open-source R package to facilitate drug target identification
Authors: Weaver Davis T. , Scott Jacob G.
Published: March 2023

In the last few decades, interest in graph-based analysis of biological networks has grown substantially. Protein-protein interaction networks are one of the most common biological networks, and represent the molecular relationships between every known protein and every other known protein. Integration of these interactomic data into bioinformatic pipelines may increase the translational potential of discoveries made through analysis of multi-omic datasets. Crosstalkr provides a unified toolkit for drug target and disease subnetwork identification, two of the most common uses of protein protein interaction networks. First, crosstalkr enables users to download and leverage high-quality protein-protein interaction networks from online repositories. Users can then filter these large networks into manageable subnetworks using a variety of methods. For example, network filtration can be done using random walks with restarts, starting at the user-provided seed proteins. Affinity scores from a given random walk with restarts are compared to a bootstrapped null distribution to assess statistical significance. Random walks are implemented using sparse matrix multiplication to facilitate fast execution. Next, users can perform in-silico repression experiments to assess the relative importance of nodes in their network. At this step, users can supply protein or gene expression data to make node rankings more meaningful. The default behavior evaluates the human interactome. However, users can evaluate more than 1000 non-human protein-protein interaction networks as a result of integration with StringDB. It is a free, open-source R package designed to allow users to integrate functional analysis using the protein-protein interaction network into existing bioinformatic pipelines. A beta version of crosstalkr available on CRAN (https://cran.rstudio.com/web/packages/crosstalkr/index.html).
Elevational and latitudinal range extensions of the puna mouse,Punomys(Cricetidae), with the first record of the genus from Chile
Authors: Quiroga-Carmona Marcial , Storz Jay F. , D’Elía Guillermo
Published: March 2023

We report an elevational record for the Andean sigmodontine puna mousePunomys, which is also the first record of the genus in Chile. The record is based on a mummified specimen that we discovered at an elevation of 5,461 m (17,917’) in the caldera of Volcán Acamarachi, Región de Antofagasta, Chile. Results of a morphological suggest that the specimen can be provisionally referred to the speciesP. lemminus. This new record also extends the known geographic distribution of the genus by 700 km to the south and brings the known Chilean mammal richness to a total of 170 living species and 88 genera. This finding highlights the need for increased survey efforts in more remote, high-elevation regions and demonstrates that there is still much to be learned about the mammal fauna of the Andean Altiplano.
The Voltage-gated sodium channel in Drosophila, Para, localizes to dendrites as well as axons in mechanosensitive chordotonal neurons
Authors: Ravenscroft Thomas A. , Jacobs Ashleigh , Gu Mingxue , Eberl Daniel F. , Bellen Hugo J.
Published: March 2023

The fruit flyDrosophila melanogasterhas provided important insights into how sensory information is transduced by Transient Receptor Potential (TRP) channels in the Peripheral Nervous System (PNS). However, TRP channels alone have not been able to completely model mechanosensitive transduction in mechanoreceptive chordotonal neurons (CN). Here we show that, in addition to TRP channels, the sole voltage-gated sodium channel (NaV) inDrosophila, Para, is localized to the dendrites of CNs. Para is localized to the distal tip of the dendrites in all CNs, from embryos to adults, and is colocalized with the mechanosensitive TRP channels No mechanoreceptor potential C (NompC) and Inactive/Nanchung (Iav/Nan). Para localization also demarcates spike initiation zones (SIZ) in axons and the dendritic localization of Para is indicative of a likely dendritic SIZ in fly CNs. Para is not present in the dendrites of other peripheral sensory neurons. In both multipolar and bipolar neurons in the PNS, Para is present in a proximal region of the axon, comparable to the axonal initial segment in vertebrates, 40-60μm from the soma in multipolar neurons and 20-40μm in bipolar neurons. Whole-cell reduction ofparaexpression using RNAi in CNs of the adult Johnston’s organ severely affects sound-evoked potentials. However, the duality of Para localization in the CN dendrites and axons identifies a need to develop resources to study compartment-specific roles of proteins that will enable us to better understand Para’s role in mechanosensitive transduction.

Significance Statement

Several transient receptor potential (TRP) channels have been shown to localize to dendrites ofDrosophilamechanosensitive chordotonal neurons (CN). Here, we show that the fly voltage-gated sodium channel, Para co-localizes with the TRP channels NompC and iav and a possible dendritic spike initiation zone (SIZ) in CN dendrites. This dendritic localization is unique to CNs, is not seen in other peripheral neurons, and may account for some aspects of mechanotransduction. Para also localizes to a SIZ at an axonal initial segment-like region, which is shared amongst many peripheral neurons.
Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer’s disease
Authors: Ocañas Sarah R. , Pham Kevin D. , Cox Jillian E.J. , Keck Alex W. , Ko Sunghwan , Ampadu Felix A. , Porter Hunter L. , Ansere Victor A. , Kulpa Adam , Kellogg Collyn M. , Machalinski Adeline H. , Chucair-Elliott Ana J. , Freeman Willard M.
Published: March 2023

Background

Microglia, the brain’s principal immune cells, have been implicated in the pathogenesis of Alzheimer’s disease (AD), a condition shown to affect more females than males. Although sex differences in microglial function and transcriptomic programming have been described across development and in disease models of AD, no studies have comprehensively identified the sex divergences that emerge in the aging mouse hippocampus. Further, existing models of AD generally develop pathology (amyloid plaques and tau tangles) early in life and fail to recapitulate the aged brain environment associated with late-onset AD. Here, we examined and compared transcriptomic and translatomic sex effects in young and old murine hippocampal microglia.

Methods

Hippocampal tissue from C57BL6/N and microglial NuTRAP mice of both sexes were collected at young (5-6 month-old [mo]) and old (22-25 mo) ages. Cell sorting and affinity purification techniques were used to isolate the microglial transcriptome and translatome for RNA-sequencing and differential expression analyses. Flow cytometry, qPCR, and imaging approaches were used to confirm the transcriptomic and translatomic findings.

Results

There were marginal sex differences identified in the young hippocampal microglia, with most differentially expressed genes (DEGs) restricted to the sex chromosomes. Both sex chromosomally-and autosomally-encoded sex differences emerged with aging. These sex DEGs identified at old age were primarily female-biased and enriched in senescent and disease-associated microglial signatures. Normalized gene expression values can be accessed through a searchable web interface (https://neuroepigenomics.omrf.org/). Pathway analyses identified upstream regulators induced to a greater extent in females than in males, including inflammatory mediators IFNG, TNF, and IL1B, as well as AD-risk genes TREM2 and APP.

Conclusions

These data suggest that female microglia adopt disease-associated and senescent phenotypes in the aging mouse hippocampus, even in the absence of disease pathology, to a greater extent than males. This sexually divergent microglial phenotype may explain the difference in susceptibility and disease progression in the case of AD pathology. Future studies will need to explore sex differences in microglial heterogeneity in response to AD pathology and determine how sex-specific regulators (i.e., sex chromosomal or hormonal) elicit these sex effects.
An atlas of gene regulatory networks for memory CD4+T cells in youth and old age
Authors: Wayman Joseph A. , Thomas Alyssa , Bejjani Anthony , Katko Alexander , Almanan Maha , Godarova Alzbeta , Korinfskaya Svetlana , Cazares Tareian A. , Yukawa Masashi , Kottyan Leah C. , Barski Artem , Chougnet Claire A. , Hildeman David A. , Miraldi Emily R.
Published: March 2023

Aging profoundly affects immune-system function, promoting susceptibility to pathogens, cancers and chronic inflammation. We previously identified a population of IL-10-producing, T follicular helper-like cells (“Tfh10”), linked to suppressed vaccine responses in aged mice. Here, we integrate single-cell (sc)RNA-seq, scATAC-seq and genome-scale modeling to characterize Tfh10 – and the full CD4+memory T cell (CD4+TM) compartment – in young and old mice. We identified 13 CD4+TM populations, which we validated through cross-comparison to prior scRNA-seq studies. We built gene regulatory networks (GRNs) that predict transcription-factor control of gene expression in each T-cell population and how these circuits change with age. Through integration with pan-cell aging atlases, we identified intercellular-signaling networks driving age-dependent changes in CD4+TM. Our atlas of finely resolved CD4+TM subsets, GRNs and cell-cell communication networks is a comprehensive resource of predicted regulatory mechanisms operative in memory T cells, presenting new opportunities to improve immune responses in the elderly.
CircRNA-disease inference using deep ensemble model based on triple association
Authors: Fu Laiyi , Du Hongkai , Wang Ying , Peng Qinke
Published: March 2023

Accumulating evidence indicates more and more circular RNAs (i.e. circRNAs) have played a vital role in regulating gene expression and are related to diseases through different biological procedures. Predicting circRNA-disease associations helps to conjecture possible disease related circRNA and facilitate human disease diagnosis and downstream treatment. Nevertheless, little effort was made to uncover the interaction between various diseases and circRNAs. In our work, human circRNA-disease association network is first generated using known miRNA-circRNA interactions and disease related miRNA (microRNA) information. Then we further integrated this information to compute similarity scores between human diseases and circRNAs. Here, we proposed one deep ensemble model called DeepInteract, which first used two stacked auto-encoders to explore hidden features utilizing similarity information, and adopted a 3-layer neuron network to predict the final association. Our method is capable of capturing more complex non-linear features comparing to other approaches. Our results indicate the proposed method is superior to other previous competitors. Many prediction results have been validated by some biological experiments using our model.
Microsatellites used in forensics are located in regions unusually rich in trait-associated variants
Authors: Link Vivian , Zavaleta Yuómi Jhony A. , Reyes Rochelle-Jan , Ding Linda , Wang Judy , Rohlfs Rori V. , Edge Michael D.
Published: March 2023

The 20 short tandem repeat (STR) markers of the combined DNA index system (CODIS) are the basis of the vast majority of forensic genetics in the United States. One argument for permissive rules about the collection of CODIS genotypes is that the CODIS markers are thought to contain information relevant to identification only (such as a human fingerprint would), with little information about ancestry or traits. However, in the past 20 years, a quickly growing field has identified hundreds of thousands of genotype-trait associations. Here we conduct a survey of the landscape of such associations surrounding the CODIS loci as compared with non-CODIS STRs. We find that the regions around the CODIS markers are enriched for both known pathogenic variants (>90th percentile) and for SNPs identified as trait-associated in genome-wide association studies (GWAS) (≥95th percentile in 10kb and 100kb flanking regions), compared with other random sets of autosomal tetranucleotide-repeat STRs. Although it is not obvious how much phenotypic information CODIS would need to convey to strain the “DNA fingerprint” analogy, the CODIS markers, considered as a set, are in regions unusually dense with variants with known phenotypic associations.
NDC80 status pinpoints mitotic kinase inhibitors as emerging therapeutic options in clear cell renal cell carcinoma
Authors: Hu Cheng , Lin Weiming , Zhao Kemeng , Tian Guiyou , Kong Xiangquan , Luo Guangcheng , Wolf Dieter A. , Cheng Yabin
Published: March 2023

∼30% of clear cell renal cell carcinoma (ccRCC) patients present with metastatic disease at the time of diagnosis, causing a dire 5-year survival rate of 13%. Whereas anti-PD-1 immunotherapy has improved survival, a strong need remains for new therapeutic options. Using integrated network analysis, we identified the mitotic regulator NDC80 as a predictor of ccRCC progression. Overexpression of NDC80 fosters the malignant phenotype by promoting cell cycle progression through S phase as well as boosting glycolysis and mitochondrial respiration. Despite high levels of immune infiltration, particularly derived from tumor resident CD8+ T cells with an exhausted phenotype, NDC80 defines a class of ccRCCs that poorly respond to immune checkpoint blockade. Instead, bioinformatics identified NDC80-high ccRCCs as sensitive to inhibitors of mitotic kinases, PLK1 and AURK, therapeutic approaches we validated in cell lines and mouse xenograft studies. Thus, NDC80 status pinpoints mitotic kinase inhibitors as promising therapeutic options in difficult-to-treat ccRCCs.
Integrating 4 Measures to Evaluate Physical Function in Patients with Cancer (In4M): Protocol for a prospective study
Authors: Thanarajasingam Gita , Kluetz Paul , Bhatnagar Vishal , Brown Abbie , Cathcart-Rake Elizabeth , Diamond Matthew , Faust Louis , Fiero Mallorie , Huntington Scott , Jeffery Molly Moore , Jones Lee , Noble Brie , Paludo Jonas , Powers Brad , Ross Joseph S. , Ritchie Jessica , Ruddy Kathryn , Schellhorn Sarah , Tarver Michelle , Dueck Amylou , Gross Cary
Published: March 2023

Introduction Accurate, patient-centered evaluation of physical function in patients with cancer can provide important information on the functional impacts experienced by patients both from the disease and its treatment. Increasingly, digital health technology is facilitating and providing new ways to measure symptoms and function. There is a need to characterize the longitudinal measurement characteristics of physical function assessments, including clinician reported physical function (ClinRo), patient-reported physical function (PRO), performance outcome tests (PerfO) and wearable data, to inform regulatory and clinical decision making in cancer clinical trials and oncology practice. Methods and analysis In this prospective study, we are enrolling 200 English- and/or Spanish-speaking patients with breast cancer or lymphoma seen at Mayo Clinic or Yale University who will receive standard of care intravenous cytotoxic chemotherapy. Physical function assessments will be obtained longitudinally using multiple assessment modalities. Participants will be followed for 9 months using a patient-centered health data aggregating platform that consolidates study questionnaires, electronic health record data, and activity and sleep data from a wearable. Data analysis will focus on understanding variability, sensitivity, and meaningful changes across the included physical function assessments and evaluating their relationship to key clinical outcomes. Additionally, the feasibility of multi-modal physical function data collection in real world patients with cancer will be assessed, as will patient impressions of the usability and acceptability of the wearable sensor, data aggregation platform, and PROs. Ethics and dissemination This study has received approval from IRBs at Mayo Clinic, Yale University, and the U.S. Food & Drug Administration. Results will be made available to participants, funders, the research community, and the public.