bluuebunny/crossref_metadata_2025 huggingface dataset:
Trauma Across the Life Span and Multisystem Morbidity in Women With HIV
Authors: Rubin Leah H. , Maki Pauline M. , Dastgheyb Raha M. , Steigman Pamela J. , Burke-Miller Jane , Xu Yanxun , Jin Wei , Sosanya Oluwakemi , Gustafson Deborah , Merenstein Daniel , Milam Joel , Weber Kathleen M. , Springer Gayle , Cook Judith A.
Published: March 2023

Objective

Sexual and physical abuse are highly prevalent among women living with HIV (WLWH) and are risk factors for the development of mental health and substance use disorders (MHDs, SUDs), and cognitive and medical comorbidities. We examined empirically derived patterns of trauma, MHD, and SUD, and associations with later cognitive and health outcomes.

Methods

A total of 1027 WLWH (average age = 48.6 years) in the Women’s Interagency HIV Study completed the World Mental Health Composite International Diagnostic Interview from 2010 to 2013 to identify MHDs, SUDs, and age at onset of sexual and physical abuse. Then, cognitive impairment, cardiovascular/metabolic conditions, and HIV disease outcomes were assessed for up to 8.8 years. Latent class analysis identified patterns of co-occurring trauma, MHDs, and/or SUDs. Generalized estimating equations determined associations between these patterns and midlife cognitive and medical outcomes.

Results

Six distinct profiles emerged: no/negligible sexual/physical trauma, MHD, or SUD (39%); preadolescent/adolescent sexual trauma with anxiety and SUD (22%); SUD only (16%); MHD + SUD only (12%); early childhood sexual/physical trauma only (6%); and early childhood sexual/physical trauma with later MHD + SUD (4%). Profiles including early childhood trauma had the largest number of midlife conditions (i.e., cognitive, cardiovascular, HIV-related). Preadolescent/adolescent sexual trauma with anxiety and SUD predicted both global and domain-specific cognitive declines. Only SUD without trauma predicted lower CD4, whereas childhood trauma with MHD + SUD predicted increased CD8.

Conclusions

WLWH have complex multisystem profiles of abuse, MHD, and/or SUD that predict midlife cognitive, metabolic/cardiovascular, and HIV outcomes. Understanding the interplay between these factors over time can identify risks and personalize preventative and treatment interventions.
Telehealth and Telemedicine in Latin American Rheumatology, a New Era After COVID-19
Authors: Graf Cesar , Fernández-Ávila Daniel G. , Plazzotta Fernando , Soriano Enrique R.
Published: March 2023

Telemedicine is the delivery of health care services by health care professionals using information and communication technologies to exchange valid information for the diagnosis, treatment, and prevention of diseases. Telemedicine was further developed in Latin America during the COVID-19 (coronavirus disease 2019) pandemic, becoming the first line of defense for health professionals to stop the spread of infections and allow them to continue the care of their patients. During the pandemic, 79% of rheumatologists in Latin America reported the use of remote communication, the most frequent being the use of phone calls and WhatsApp voice messages. In contrast, 84% of the patients reported that telemedicine was appropriate for them during the pandemic, but only 54% considered telemedicine to be a valid option for rheumatic health care after the pandemic. Telemedicine and telehealth have advantages such as lower costs, improved access in rural areas, shortage of care providers, and reduction in waiting time for appointments. However, it also has some challenges, such as legal, technological, and organizational barriers. In this review, we explore the current state of telemedicine in Latin America and discuss its future.
Changes in the Long Noncoding RNA Expression Profile in the Development of the Embryonic External Ear After BMP5 Gene Mutation
Authors: Liu Wei , Jin Shengyang , Lin Lin , Yang Qinghua , Jiang Haiyue
Published: March 2023

To understand the role of long noncoding RNA (lncRNA) gene regulation and changes in expression in mouse external ear embryonic development, a BMP5 short ear mouse model was used to measure changes in the lncRNA expression in the outer ear tissues of mouse embryos developed to E15.5 and E17.5 using high-throughput sequencing. The changes in lncRNA expression were identified using find_circ and CIRI2 software, and functional analyses were performed using gene ontology and the Kyoto encyclopedia of genes and genomes annotations of differentially expressed lncRNAs. The results show a correlation between the regulation of lncRNA and some key regulatory lncRNA changes after point mutations in BMP5. This study provides new insights into the mechanism, by which lncRNAs regulate the development of the mouse's external ear. The change in lncRNA expression profiles can also provide clues for the study of the regulatory mechanisms of external ear embryonic development.
Cosmetic Open Rhinoplasty in Acute Nasal Bone Fracture With Pre-Existing Deformity
Authors: Kim Yong-Ha , Lee Won Seob , Kim Jae-Won , Chung Kyu-Jin
Published: March 2023

The simultaneous reduction of nasal bone fracture and cosmetic rhinoplasty is a challenging procedure, because of fracture severity and skeletal instability. Our aim was to investigate the surgical strategy and outcomes of cosmetic rhinoplasty according to the pre-existing nasal deformity when performing simultaneous reduction of nasal bone fracture and cosmetic rhinoplasty. In total, 71 patients who underwent cosmetic rhinoplasty were included. All patients were categorized according to pre-existing deformity, dorsal hump and irregularities, and deviation of the nose, wide nose, and flat nasal dorsum. The authors performed individual maneuvers to correct each deformity. Autologous tissue was used in all maneuvers for graft. Photoanalysis was performed to measure the deviation, nasal length, radix height, dorsal height, tip projection, nasofrontal angle, and nasolabial angle. Subjective evaluation of the functional and esthetic problems was confirmed through rhinoplasty outcome evaluation. In the analysis of the photographs, most patients presented improved scores (P<0.05). The scores of satisfaction were significantly higher in the postoperative state (P<0.05). As a postoperative complication, 2 cases of deviated tip occurred due to septal instability and were successfully revised with septoplasty and columellar strut graft. The authors created a harmonious face by evaluating, categorizing, and treating each deformity of the nose in patients with nasal fractures according to our algorithm.
Gordonia aquimaris sp. nov., a novel marine actinobacterium isolated from seawater in the upper gulf of Thailand
Authors: Pansomsuay Rawirat , Duangupama Thitikorn , Pittayakhajonwut Pattama , Intaraudom Chakapong , Suriyachadkun Chanwit , He Ya-Wen , Tanasupawat Somboon , Thawai Chitti
Published: March 2023

An actinobacterium strain, SW21T, was isolated from seawater collected in the upper Gulf of Thailand. Cells were Gram-stain-positive, aerobic and rod-shaped. Growth was observed from 15 to 37 °C and at pH 6–8. Maximum NaCl for growth was 14 % (w/v).meso-Diaminopimelic acid, arabinose, galactose, glucose, rhamnose and ribose were detected in the whole-cell hydrolysate. Diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol and phosphatidylinositol mannoside were detected as the phospholipids in the cells. The major menaquinones were MK-9(H2) and MK-7(H2). The major cellular fatty acids were C16 : 0, C18 : 1 ω9c, C18 : 0and C18 : 010-methyl (TBSA). The 16S rRNA gene sequence data supported the assignment of strain SW21Tto the genusGordoniaand showed thatGordonia mangroviKCTC 49383T(98.7 %) was the closest relative. Moreover, the average nucleotide identity-blast(85.5 %) and digital DNA–DNA hybridization (30.7 %) values between strain SW21Tand its closest neighbour were below the threshold values for delineation of a novel species. The combination of genotypic and phenotypic data indicated that strain SW21Tis representative of novel species of the genusGordonia. The nameGordonia aquimarissp. nov. is proposed for strain SW21T. The type strain is SW21T(=TBRC 15691T=NBRC 115558T).
Stochastic model for cell population dynamics quantifies homeostasis in colonic crypts and its disruption in early tumorigenesis
Authors: Mamis Konstantinos , Zhang Ruibo , Bozic Ivana
Published: March 2023

The questions of how healthy colonic crypts maintain their size, and how homeostasis is disrupted by driver mutations, are central to understanding colorectal tumorigenesis. We propose a three-type stochastic branching process, which accounts for stem, transit-amplifying (TA) and fully differentiated (FD) cells, to model the dynamics of cell populations residing in colonic crypts. Our model is simple in its formulation, allowing us to estimate all but one of the model parameters from the literature. Fitting the single remaining parameter, we find that model results agree well with data from healthy human colonic crypts, capturing the considerable variance in population sizes observed experimentally. Importantly, our model predicts a steady state population in healthy colonic crypts for relevant parameter values. We show thatAPCandKRASmutations, the most significant early alterations leading to colorectal cancer, result in increased steady-state populations in mutated crypts, in agreement with experimental results. Finally, our model predicts a simple condition for unbounded growth of cells in a crypt, corresponding to colorectal malignancy. This is predicted to occur when the division rate of TA cells exceeds their differentiation rate, with implications for therapeutic cancer prevention strategies.
Pannexin 3deletion in mice results in knee osteoarthritis and intervertebral disc degeneration after forced treadmill running
Authors: Wakefield Brent , Hutchinson Jeffrey Lawrence , Tang Justin , Kanji Rehanna , Brooks Courtney , Séguin Cheryle A , Penuela Silvia , Beier Frank
Published: March 2023

Pannexin 3 (Panx3) is a glycoprotein that forms mechanosensitive channels expressed in chondrocytes and annulus fibrosus cells of the intervertebral disc (IVD). Evidence suggestsPanx3plays contrasting roles in traumatic versus aging osteoarthritis (OA) and intervertebral disc degeneration (IDD). However, whether its deletion influences the response of joint tissue to mechanical stress is unknown. The purpose of this study was to determine ifPanx3deletion in mice causes increased knee joint OA and IDD after forced treadmill running. Male and female wildtype (WT) andPanx3knockout (KO) mice were randomized to either a no exercise group (sedentary; SED) or daily forced treadmill running (forced exercise; FEX) from 24 to 30 weeks of age. Knee cartilage, tibial secondary ossification center and IVD histopathology were evaluated by histology. Both male and femalePanx3KO mice developed larger superficial defects of the tibial cartilage after forced treadmill running compared to SED WT mice. Additionally, both male and femalePanx3KO mice developed greater bone area of the tibial secondary ossification center with running. In the lower lumbar spine, both male and femalePanx3KO mice developed histopathological features of IDD after running compared to SED WT mice. These findings suggest that the combination of deletingPanx3and forced treadmill running induces OA and causes histopathological changes associated with degeneration of the IVDs in mice.
Fabrication and Characterization of Ceramic-Polymer composite 3D scaffolds and Demonstration of Osteoinductive propensity with gingival Mesenchymal Stem Cells
Authors: Bahir Manjushree M , Rajendran Archana , Pattanayak Deepak , Lenka Nibedita
Published: March 2023

Bone tissue engineering involves the usage of metals, polymers, and ceramics as the base constituents in the fabrication of various biomaterial 3D scaffolds. Of late, the composite materials facilitating enhanced osteogenic differentiation/regeneration have been endorsed as the ideally suited bone grafts for addressing critical-sized bone defects. Here, we report the successful fabrication of 3D composite scaffolds with collagen type I (Col-I) in conjunction with three different crystalline phases of calcium-phosphate (CP) nanomaterials [hydroxyapatite (HAp), beta-tricalcium phosphate (βTCP), biphasic hydroxyapatite (βTCP-HAp or BCP)], obtained by altering the pH as the major variable. The fabricated 3D scaffolds consisting of ∼70 wt % CP nanomaterials and ∼ 30 Wt % of Col-I did mimic the ECM of bone tissue. The different Ca/P ratio and the orientation of CP nanomaterials in CP/Col-I composite scaffolds altered the microstructure, surface area, porosity, and mechanical strength of the scaffolds and also influenced the bioactivity, biocompatibility, and osteogenic differentiation of gingival-derived mesenchymal stem cells (gMSCs). The microstructure of CP/Col-I 3D scaffolds assessed by Micro-CT analysis revealed randomly oriented interconnected pores with pore sizes ranging from 80-250, 125-380, and 100-450µm respectively for βTCP/Col-I, BCP/Col-I, and HAp/Col-I scaffolds. Among these, the BCP/Col-I achieved the highest surface area (∼ 42.6 m2/g) and porosity (∼85%), demonstrated improved bioactivity and biocompatibility, and promoted osteogenic differentiation of gMSCs. Interestingly, the Ca2+ions (3 mM) released from scaffolds could also facilitate the osteocyte differentiation of gMSCssansosteoinduction. Collectively, our study has demonstrated the ECM mimicking biphasic CP/Col-I 3D scaffold as an ideally suited tissue-engineered bone graft.
Assessing genotype adaptability and stability in perennial forage breeding trials using random regression models for longitudinal dry matter yield data
Authors: Fernandes Filho Claudio Carlos , Lima Barrios Sanzio Carvalho , Santos Mateus Figueiredo , Rodrigues Nunes Jose Airton , do Valle Cacilda Borges , Jank Liana , Rios Esteban Fernando
Published: March 2023

Genotype selection for dry matter yield (DMY) in perennial forage species is based on repeated measures over time. Repeated measurements in forage breeding trials generate longitudinal datasets that must be properly analyzed giving a useful interpretation in the genotype selection process. In this study, we have presented a random regression (RRM) approach for selecting genotypes based on longitudinal DMY data generated from ten breeding trials and three perennial species, alfalfa (Medicago sativaL.), guineagrass (Megathyrsus maximus), andbrachiaria (Urochloa spp.). We also proposed the estimation of adaptability based on the area under the curve and stability based on the curve coefficient of variation. Our results showed that RRM always approximated the (co)variance structure into an autoregressive pattern. Furthermore, RRM can offer useful information about longitudinal data in forage breeding trials, where the breeder can select genotypes based on their seasonality by interpreting reaction norms. Therefore, we recommend using RRM for longitudinal traits in breeding trials for perennial species.
OverexpressedMalat1Drives Metastasis through Inflammatory Reprogramming of Lung Adenocarcinoma Microenvironment
Authors: Martínez-Terroba Elena , de Miguel Fernando J. , Li Vincent , Robles-Oteiza Camila , Politi Katerina , Zamudio Jesse R. , Dimitrova Nadya
Published: March 2023

Metastasis is the main cause of cancer deaths but the molecular events leading to metastatic dissemination remain incompletely understood. Despite reports linking aberrant expression of long noncoding RNAs (lncRNAs) with increased metastatic incidence, in vivoevidence establishing driver roles for lncRNAs in metastatic progression is lacking. Here, we report that overexpression of the metastasis-associated lncRNAMalat1(metastasis-associated lung adenocarcinoma transcript 1) in the autochthonous K-ras/p53 mouse model of lung adenocarcinoma (LUAD) is sufficient to drive cancer progression and metastatic dissemination. We show that increased expression of endogenousMalat1RNA cooperates with p53 loss to promote widespread LUAD progression to a poorly differentiated, invasive, and metastatic disease. Mechanistically, we observe thatMalat1overexpression leads to the inappropriate transcription and paracrine secretion of the inflammatory cytokine, Ccl2, to augment the mobility of tumor and stromal cellsin vitroand to trigger inflammatory responses in the tumor microenvironmentin vivo. Notably, Ccl2 blockade fully reverses cellular and organismal phenotypes ofMalat1overexpression. We propose thatMalat1overexpression in advanced tumors activates Ccl2 signaling to reprogram the tumor microenvironment to an inflammatory and pro-metastatic state.
A comprehensive map of hotspots of de novo telomere addition inSaccharomyces cerevisiae
Authors: Ngo Katrina , Gittens Tristen H. , Gonzalez David I. , Hatmaker E. Anne , Plotkin Simcha , Engle Mason , Friedman Geofrey A. , Goldin Melissa , Hoerr Remington E. , Eichman Brandt F. , Rokas Antonis , Benton Mary Lauren , Friedman Katherine L.
Published: March 2023

Telomere healing occurs when telomerase, normally restricted to chromosome ends, acts upon a double-strand break to create a new, functional telomere. De novo telomere addition on the centromere-proximal side of a break truncates the chromosome but, by blocking resection, may allow the cell to survive an otherwise lethal event. We previously identified several sequences in the baker’s yeast,Saccharomyces cerevisiae, that act as hotspots of de novo telomere addition (termed Sites of Repair-associated Telomere Addition or SiRTAs), but the distribution and functional relevance of SiRTAs is unclear. Here, we describe a high-throughput sequencing method to measure the frequency and location of telomere addition within sequences of interest. Combining this methodology with a computational algorithm that identifies SiRTA sequence motifs, we generate the first comprehensive map of telomere-addition hotspots in yeast. Putative SiRTAs are strongly enriched in subtelomeric regions where they may facilitate formation of a new telomere following catastrophic telomere loss. In contrast, outside of subtelomeres, the distribution and orientation of SiRTAs appears random. Since truncating the chromosome at most SiRTAs would be lethal, this observation argues against selection for these sequences as sites of telomere addition per se. We find, however, that sequences predicted to function as SiRTAs are significantly more prevalent across the genome than expected by chance. Sequences identified by the algorithm bind the telomeric protein Cdc13, raising the possibility that association of Cdc13 with single-stranded regions generated during the response to DNA damage may facilitate DNA repair more generally.
Multi-layered genetic approaches to identify approved drug targets
Authors: Sadler Marie C. , Auwerx Chiara , Deelen Patrick , Kutalik Zoltán
Published: March 2023

Drugs targeting genes that harbor natural variations associated with the disease the drug is in-dicated for have increased odds to be approved. Various approaches have been proposed to iden-tify likely causal genes for complex diseases, including gene-based genome-wide association stud-ies (GWAS), rare variant burden tests in whole exome sequencing studies (Exome) or integration of GWAS with expression/protein quantitative trait loci (eQTL-GWAS/pQTL-GWAS). Here, we compare gene-prioritization approaches on 30 common clinical traits and benchmarked their ability to recover drug target genes defined using a combination of five drug databases. Across all traits, the top pri-oritized genes were enriched for drug targets with odds ratios (ORs) of 2.17, 2.04, 1.81 and 1.31 for the GWAS, eQTL-GWAS, Exome and pQTL-GWAS methods, respectively. We quantified the perfor-mance of these methods using the area under the receiver operating characteristic curve as metric, and adjusted for differences in testable genes and data origins. GWAS performed significantly better (54.3%) than eQTL (52.8%) and pQTL-GWAS (51.3%), but not significantly so against the Exome ap-proach (51.7%vs52.8% for GWAS restricted to UK Biobank data). Furthermore, our analysis showed increased performance when diffusing gene scores on gene networks. However, substantial improve-ments in the protein-protein interaction network may be due to circularity in the data generation process, leading to the node (gene) degree being the best predictor for drug target genes (OR = 8.7, 95% CI = 7.3-10.4) and warranting caution when applying this strategy. In conclusion, we systematically as-sessed strategies to prioritize drug target genes highlighting promises and potential pitfalls of current approaches.
The SMART Text2FHIR Pipeline
Authors: Miller Timothy A. , McMurry Andrew J. , Jones James , Gottlieb Daniel , Mandl Kenneth D.
Published: March 2023

Objective

To implement an open source, free, and easily deployable high throughput natural language processing module to extract concepts from clinician notes and map them to Fast Healthcare Interoperability Resources (FHIR).

Materials and Methods

Using a popular open-source NLP tool (Apache cTAKES), we create FHIR resources that use modifier extensions to represent negation and NLP sourcing, and another extension to represent provenance of extracted concepts.

Results

The SMART Text2FHIR Pipeline is an open-source tool, released through standard package managers, and publicly available container images that implement the mappings, enabling ready conversion of clinical text to FHIR.

Discussion

With the increased data liquidity because of new interoperability regulations, NLP processes that can output FHIR can enable a common language for transporting structured and unstructured data. This framework can be valuable for critical public health or clinical research use cases.

Conclusion

Future work should include mapping more categories of NLP-extracted information into FHIR resources and mappings from additional open-source NLP tools.
Runx1 regulates critical factors that control uterine angiogenesis and trophoblast differentiation during placental development
Authors: Kannan Athilakshmi , Beal Jacob R. , Neff Alison M. , Bagchi Milan K. , Bagchi Indrani C.
Published: March 2023

During early pregnancy in humans and rodents, uterine stromal cells undergo a remarkable differentiation to form the decidua, a transient maternal tissue that supports the growing fetus. It is important to understand the key decidual pathways that orchestrate the proper development of the placenta, a key structure at the maternal-fetal interface. We discovered that ablation of expression of the transcription factor Runx1 in decidual stromal cells in a conditionalRunx1-null mouse model (Runx1d/d) causes fetal lethality during placentation. Further phenotypic analysis revealed that uteri of pregnantRunx1d/dmice exhibited severely compromised decidual angiogenesis, and a lack of trophoblast differentiation and migration, resulting in impaired spiral artery remodeling. Gene expression profiling using uteri fromRunx1d/dand control mice revealed that Runx1 directly controls the decidual expression of the gap junction protein connexin 43 (also known as GJA1), which was previously shown to be essential for decidual angiogenesis. Our study also revealed a critical role of Runx1 in controlling insulin-like growth factor (IGF) signaling at the maternal-fetal interface. While Runx1-deficiency drastically reduced the production of IGF2 by the decidual cells, we observed concurrent elevated expression of the IGF-binding protein 4 (IGFBP4), which regulates the bioavailability of IGFs thereby controlling trophoblast differentiation. We posit that dysregulated expression of GJA1, IGF2, and IGFBP4 inRunx1d/ddecidua contributes to the observed defects in uterine angiogenesis, trophoblast differentiation, and vascular remodeling. This study therefore provides unique insights into key maternal pathways that control the early phases of maternal-fetal interactions within a critical window during placental development.

Significance

A clear understanding of the maternal pathways that ensure coordination of uterine differentiation and angiogenesis with embryonic growth during the critical early stages of placenta formation still eludes us. The present study reveals that the transcription factor Runx1 controls a set of molecular, cellular, and integrative mechanisms that mediate maternal adaptive responses controlling uterine angiogenesis, trophoblast differentiation, and resultant uterine vascular remodeling, which are essential steps during placenta development.
Foundation model of neural activity predicts response to new stimulus types and anatomy
Authors: Wang Eric Y. , Fahey Paul G. , Ding Zhuokun , Papadopoulos Stelios , Ponder Kayla , Weis Marissa A. , Chang Andersen , Muhammad Taliah , Patel Saumil , Ding Zhiwei , Tran Dat , Fu Jiakun , Schneider-Mizell Casey M. , Reid R. Clay , Collman Forrest , da Costa Nuno Maçarico , Franke Katrin , Ecker Alexander S. , Reimer Jacob , Pitkow Xaq , Sinz Fabian H. , Tolias Andreas S.
Published: March 2023

The complexity of neural circuits makes it challenging to decipher the brain’s algorithms of intelligence. Recent break-throughs in deep learning have produced models that accurately simulate brain activity, enhancing our understanding of the brain’s computational objectives and neural coding. However, these models struggle to generalize beyond their training distribution, limiting their utility. The emergence of foundation models, trained on vast datasets, has introduced a new AI paradigm with remarkable generalization capabilities. We collected large amounts of neural activity from visual cortices of multiple mice and trained a foundation model to accurately predict neuronal responses to arbitrary natural videos. This model generalized to new mice with minimal training and successfully predicted responses across various new stimulus domains, such as coherent motion and noise patterns. It could also be adapted to new tasks beyond neural prediction, accurately predicting anatomical cell types, dendritic features, and neuronal connectivity within the MICrONS functional connectomics dataset. Our work is a crucial step toward building foundation brain models. As neuroscience accumulates larger, multi-modal datasets, foundation models will uncover statistical regularities, enabling rapid adaptation to new tasks and accelerating research.
Retrospective transcriptome analyses identifyLINC01013as an activation marker in human dermal fibroblasts
Authors: Dolivo David M. , Rodrigues Adrian E. , Galiano Robert D. , Mustoe Thomas A. , Hong Seok Jong
Published: March 2023

Study of fibroblast biology, including the process of fibroblast activation, is critical to our understanding of wound healing, tissue fibrosis, and cancer. However, the rapid adoption of next-generation sequencing technologies, particularly single-cell RNA-seq and spatial transcriptomics, has revealed that fibroblast heterogeneity of both healthy and pathological tissues is more complicated than we currently understand. Therefore, a better understanding of molecular players that are not only indicative of but also that contribute to fibroblast activation is critical to piecing together the complete picture and to informing therapeutic strategies to combat associated pathologies. Here we focus on a long-noncoding RNA,LINC01013, recently implicated in pathological activation of cardiac fibroblasts and valvular interstitial cell. We analyze several sets of publicly available human transcriptomic data with the aim of determining whetherLINC01013correlates with fibroblast activation state, and whether compounds that affect fibroblast activation also modulate expression ofLINC01013. We find that, in numerous independent datasets of healthy and diseased human fibroblasts,LINC01013expression is associated with fibroblast activation. We also describe that, even in datasets comprised of small sample sizes, statistically significant correlations exist between expression ofLINC01013and expression of fibroblast activation markersACTA2andCCN2. This finding, while preliminary, suggests that changes inLINC01013expression may be an indicator of changes in fibroblast activation state, and thatLINC01013might functionally contribute to fibroblast activation, lending potential rationale for greater exploration of this lncRNA in the context of tissue fibrosis or tumor stroma.
Effects on wrong-patient errors by limiting access to concurrently open ERH charts: A preliminary systematic mapping and synthesis review
Authors: Myronuk Lonn D. S.
Published: March 2023

Background

Several recent outcome studies have been published looking at the effects of restricting electronic health record (EHR) user interfaces to limit the number of concurrently accessible patient records. Strong recommendations have been in place for several years to have user interfaces constrained to only display one patient chart at a time in order to reduce the risk of data (documentation, orders) being entered on the wrong patient (Joint Commission, 2015; ONC, 2016). This recommendation was made based on expert opinion rather than objective information, raising the question whether the accumulating evidence supports continued implementation of such chart access restrictions.

Objectives

This work reports a systematic mapping and synthesis review addressing research questions, “What is the evidence that restricting the number of concurrently open records reduces errors? (RQ1), “How effective is restriction of concurrently open charts at reducing wrong-patient errors? (RQ2), and “What additional inquiry is needed to make evidence-based policy decisions about restricting concurrent chart access? (RQ3).

Methods

A systematic search of CINAHL, PubMed, and Web of Science databases was performed with full search string specification to retrieve a result set that is the conjunction of result sets for concepts ofEHR, concurrently open charts, andmedical error. Of 407 studies identified and screened, five were eligible for inclusion in the qualitative synthesis review, and three were amenable to data extraction and pooled effect size calculation.

Results

None of the studies included for review found evidence of statistically significant change in wrong-patient error rates associated with implementing restriction in the number of patient records allowed to be open concurrently in the EHR. The combined OR for the pooled studies was 1.02 (95% CI 0.90 – 1.15) with low estimates for inter-study heterogeneity and no indication of publication bias.

Conclusion

There is no evidence that restricting the number of concurrently open records reduces errors (RQ1). It is not possible to definitively answer RQ2, but the magnitude of any yet to be detected beneficial effect that might be lost with lifting of chart access restriction can be no greater than an absolute risk increase of 33 errors per 100,000 ordering sessions. While it has been claimed that restricting the number of concurrently open EHR records is necessary for patient safety, the present review demonstrates that it is insufficient to attain a measurable improvement in error rates. Additional investigation of the usability and human factors aspects of EHR configuration decisions as well as knowledge of the impacts on clinical workflows will be necessary to provide policymakers, operational leaders, and practitioners with insight into the nature of the threats and opportunities with respect to safety, as well as the strengths and weaknesses of potential interventions.
Immune responses and disease biomarker long-term changes following COVID-19 mRNA vaccination in a cohort of rheumatic disease patients
Authors: An Zesheng , Zhou Xian , Li Yanfeng , Jaquith Jane , McCarthy-Fruin Kathleen , Sletten Jennifer , Warrington Kenneth J. , Weyand Cornelia , Crowson Cynthia S. , Chumsri Saranya , Knutson Keith L. , Figueroa-Parra Gabriel , Sanchez-Rodriguez Alain , Thanarajasingam Uma , Duarte-García Alí , Zeng Hu
Published: March 2023

Objective

To evaluate seroreactivity and disease biomarkers after 2 or 3 doses of COVID-19 mRNA vaccines in a cohort of patients with rheumatic diseases.

Methods

We collected biological samples longitudinally before and after 2-3 doses of COVID-19 mRNA vaccines from a cohort of patients with systemic lupus erythematosus (SLE), psoriatic arthritis, Sjogren’s syndrome, ankylosing spondylitis, and inflammatory myositis. Anti-SARS-CoV-2 spike IgG and IgA and anti-dsDNA concentration were measured by ELISA. A surrogate neutralization assay was utilized to measure antibody neutralization ability. Lupus disease activity was measured by Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Expression of type I interferon signature was measured by real-time PCR. The frequency of extrafollicular double negative 2 (DN2) B cells was measured by flow cytometry.

Results

Most of the patients generated high SARS-CoV-2 spike-specific neutralizing antibodies comparable to those in healthy controls after 2 doses of mRNA vaccines. The antibody level declined over time but recovered after the third dose of the vaccine. Rituximab treatment substantially reduced antibody level and neutralization ability. Among SLE patients, no consistent increase in SLEDAI scores was observed post-vaccination. The changes in anti-dsDNA antibody concentration and expression of type I IFN signature genes were highly variable but did not show consistent or significant increases. Frequency of DN2 B cells remained largely stable.

Conclusion

Rheumatic disease patients without rituximab treatment have robust antibody responses toward COVID-19 mRNA vaccination. Disease activity and disease-associated biomarkers remain largely stable over 3 doses of vaccines, suggesting that COVID-19 mRNA vaccines may not exacerbate rheumatic diseases.

KEY MESSAGES

Patients with rheumatic diseases mount robust humoral immunity towards 3 doses of COVID-19 mRNA vaccines.

Disease activity and biomarkers remain stable following 3 doses of COVID-19 mRNA vaccines.
Circulating immune cell populations at rest and in response to acute endurance exercise in young adults with cerebral palsy
Authors: Kruse Annika , Imery Ian , Corell Linnéa , Hjalmarsson Emma , Fernandez-Gonzalo Rodrigo , von Walden Ferdinand , Reitzner Stefan M.
Published: March 2023

Aim

Low physical activity alters immune function and increases the risk of developing chronic inflammation. This cross-sectional study aimed at determining the immune status and function in young adults with cerebral palsy (CP) in comparison to typically developing (TD) individuals.

Method

Blood samples from 12 individuals with CP and 17 TD were collected before, immediately after, and one hour following 45 minutes of Frame Running or running, respectively. Independent t-tests were used to compare heart rate, level of exertion, and baseline cell proportions between groups. Mixed model ANOVA was utilized to investigate immune cell responses to exercise across groups.

Results

Baseline levels of TCRγδ+ T-cells were significantly higher in the individuals with CP. Several cell populations showed significant changes after exercise in both CP and TD groups. CD8+ T-cells were only significantly elevated immediately after exercise in the TD participants. Individuals with CP exhibited significantly lower heart rates, despite similar ratings of perceived exertion.

Interpretation

Elevated baseline TCRγδ+ T-cells may indicate low-grade inflammation in adults with CP. Although most of the cell populations showed typical responses to endurance exercise, the absence of response in CD8+ T-cells in individuals with CP may indicate the need for higher intensity during exercise.

What this paper adds

This is the first study addressing immune cells in adults with CP

TCRγδ+ T-cell baseline levels are elevated in adults with CP

The CD8+ T-cell response to exercise was blunted in adults with CP

Exercise intensity is decisive for CD8+ T-cell responses in individuals with CP
Single-cell transcriptomics reveals that glial cells integrate homeostatic and circadian processes to drive sleep-wake cycles
Authors: Dopp Joana , Ortega Antonio , Davie Kristofer , Poovathingal Suresh , Baz El-Sayed , Liu Sha
Published: March 2023

The sleep-wake cycle is determined by circadian and sleep homeostatic processes. However, the molecular impact of these processes and their interaction in different brain cell populations remain unknown. To fill this gap, we profiled the single-cell transcriptome of adultDrosophilabrains across the sleep-wake cycle and four circadian times. We show cell type-specific transcriptomic changes with glia displaying the largest variation. Glia are also among the few cell types whose gene expression correlates with both sleep homeostat and circadian clock. The sleep-wake cycle and sleep drive level affect expression of clock gene regulators in glia, while diminishing the circadian clock specifically in glia impairs homeostatic sleep rebound after sleep deprivation. These findings reveal a comprehensive view of the effects of sleep homeostatic and circadian processes on distinct cell types in an entire animal brain and reveal glia as an interaction site of these two processes to determine sleep-wake dynamics.
Schrödinger’s Cat in Simulations in Genome-wide Association Studies
Authors: Ozkaraca Mustafa Ismail , Tenesa Albert
Published: March 2023

Simulations are essential components for testing methods or assumptions in genome-wide association studies (GWAS). We show through theory and examples that markers can be both causal and non-causal simultaneously, resulting in a paradox, had simulation not being run properly. We developed a software (ParaPheSim – a paradoxical phenotype simulator) that allows users to create different traits whose genetic correlation is exactly 1 and yet they have no genetic overlap.
Group AStreptococcusstrains causing meningitis without distinct invasive phenotype
Authors: Marquardt Laura , Andreoni Federica , Boumasmoud Mathilde , Schweizer Tiziano A. , Heuberger Dorothea M. , Parietti Elena , Hertegonne Sanne , Epprecht Jana , Mattle Dario , Raez Anna K. , Marques-Maggio Ewerton , Schuepbach Reto A. , Hasse Barbara , Mairpady-Shambat Srikanth , Brugger Silvio D. , Zinkernagel Annelies S.
Published: March 2023

Group A streptococcal (GAS, akaStreptococcus pyogenes) meningitis is a fulminant disease associated with high morbidity and mortality. To elucidate the mechanisms underlying the invasiveness of GAS in meningitis, we compared GAS isolates derived from five cases of meningitis, to otitis and colonizing isolates. We did not observe differences in adherence to and invasion of human brain microvascular endothelial cells, virulence factors activity or barrier disruption. Whole genome sequencing did not reveal particular invasiveness traits. Most patients previously suffered from otitis media suggesting that meningitis likely resulted from a continuous spread of the infection rather than being attributable to changes in pathogen’s virulence.
Re-evaluating the nuclear staining on pathological sections in Alzheimer’s disease
Authors: Fu Hualin , Li Jilong , Zhang Chunlei , Du Peng , Gao Guo , Ge Qiqi , Guan Xinping , Cui Daxiang
Published: March 2023

A paper recently published on Nature Neuroscience, asserting that lysosome leakage induces neuronal cell death and the formation of senile plaques in Alzheimer’s disease. The study believed that flower-like perikaryal rosettes formed by packed autophagic vacuoles around central nuclei, termed “PANTHOS” neurons, are responsible for the senile plaque formation. However, all of the nuclei staining in this paper based on images in the blue fluorescence channel. We did detailed studies on the senile plaque blue autofluorescence and found that senile plaque blue autofluorescence could be easily mistaken as nuclear staining. The blue “nuclear” staining in this paper is probably inaccurate since it was not verified in red or green fluorescence channels and their “nuclei”-related data might be mis-interpreted.
A domain-agnostic MR reconstruction framework using a randomly weighted neural network
Authors: Pal Arghya , Ning Lipeng , Rathi Yogesh
Published: March 2023

Purpose

To design a randomly-weighted neural network that performs domain-agnostic MR image reconstruction from undersampled k-space data without the need for ground truth or extensive in-vivo training datasets. The network performance must be similar to the current state-of-the-art algorithms that require large training datasets.

Methods

We propose a Weight Agnostic randomly weighted Network method for MRI reconstruction (termed WAN-MRI) which does not require updating the weights of the neural network but rather chooses the most appropriate connections of the network to reconstruct the data from undersampled k-space measurements. The network architecture has three components, i.e. (1) Dimensionality Reduction Layers comprising of 3d convolutions, ReLu, and batch norm; (2) Reshaping Layer is Fully Connected layer; and (3) Upsampling Layers that resembles the ConvDecoder architecture. The proposed methodology is validated on fastMRI knee and brain datasets.

Results

The proposed method provides a significant boost in performance for structural similarity index measure (SSIM) and root mean squared error (RMSE) scores on fastMRI knee and brain datasets at an undersampling factor of R=4 and R=8 while trained on fractal and natural images, and fine-tuned with only 20 samples from the fastMRI training k-space dataset. Qualitatively, we see that classical methods such as GRAPPA and SENSE fail to capture the subtle details that are clinically relevant. We either outperform or show comparable performance with several existing deep learning techniques (that require extensive training) like GrappaNET, VariationNET, J-MoDL, and RAKI.

Conclusion

The proposed algorithm (WAN-MRI) is agnostic to reconstructing images of different body organs or MRI modalities and provides excellent scores in terms of SSIM, PSNR, and RMSE metrics and generalizes better to out-of-distribution examples. The methodology does not require ground truth data and can be trained using very few undersampled multi-coil k-space training samples.
Atlas ofPlasmodium falciparumintraerythrocytic development using expansion microscopy
Authors: Liffner Benjamin , Cepeda Diaz Ana Karla , Blauwkamp James , Anaguano David , Frölich Sonja , Muralidharan Vasant , Wilson Danny W. , Dvorin Jeffrey , Absalon Sabrina
Published: March 2023

Apicomplexan parasites exhibit tremendous diversity in much of their fundamental cell biology, but study of these organisms using light microscopy is often hindered by their small size. Ultrastructural expansion microscopy (U-ExM) is a microscopy preparation method that physically expands the sample ∼4.5x. Here, we apply U-ExM to the human malaria parasitePlasmodium falciparumduring the asexual blood stage of its lifecycle to understand how this parasite is organized in three-dimensions. Using a combination of dye-conjugated reagents and immunostaining, we have catalogued 13 differentP. falciparumstructures or organelles across the intraerythrocytic development of this parasite and made multiple observations about fundamental parasite cell biology. We describe that the outer centriolar plaque and its associated proteins anchor the nucleus to the parasite plasma membrane during mitosis. Furthermore, the rhoptries, Golgi, basal complex, and inner membrane complex, which form around this anchoring site while nuclei are still dividing, are concurrently segregated and maintain an association to the outer centriolar plaque until the start of segmentation. We also show that the mitochondrion and apicoplast undergo sequential fission events while maintaining an association with the outer centriolar plaque during cytokinesis. Collectively, this study represents the most detailed ultrastructural analysis ofP. falciparumduring its intraerythrocytic development to date, and sheds light on multiple poorly understood aspects of its organelle biogenesis and fundamental cell biology.

IMPACT STATEMENT

Using ultrastructure-expansion microscopy we explore the fundamental cell biology of malaria parasites, providing new insights into processes including establishment of cell polarity and organelle fission.
Latent transcriptional programs reveal histology-encoded tumor features spanning tissue origins
Authors: Hieromnimon Hanna M. , Dolezal James , Doytcheva Kristina , Howard Frederick M. , Kochanny Sara , Zhang Zhenyu , Grossman Robert L. , Tanager Kevin , Wang Cindy , Kather Jakob Nikolas , Izumchenko Evgeny , Cipriani Nicole A , Fertig Elana J. , Pearson Alexander T , Riesenfeld Samantha J
Published: March 2023

Precision medicine in cancer treatment depends on deciphering tumor phenotypes to reveal the underlying biological processes. Molecular profiles, including transcriptomics, provide an information-rich tumor view, but their high-dimensional features and assay costs can be prohibitive for clinical translation at scale. Recent studies have suggested jointly leveraging histology and genomics as a strategy for developing practical clinical biomarkers. Here, we use machine learning techniques to identifyde novolatent transcriptional processes in squamous cell carcinomas (SCCs) and to accurately predict their activity levels directly from tumor histology images. In contrast to analyses focusing on pre-specified, individual genes or sample groups, our latent space analysis reveals sets of genes associated with both histologically detectable features and clinically relevant processes, including immune response, collagen remodeling, and fibrosis. The results demonstrate an approach for discovering clinically interpretable histological features that indicate complex, potentially treatment-informing biological processes.
Active dendrites enable robust spiking computations despite timing jitter
Authors: Burger Thomas SJ , Rule Michael E , O’Leary Timothy
Published: March 2023

Dendritic action potentials exhibit long plateaus of many tens of milliseconds, outliving axonal spikes by an order of magnitude. The computational role of these slow events seems at odds with the need to rapidly integrate and relay information throughout large nervous systems. We propose that the timescale of dendritic potentials allows for reliable integration of asynchronous inputs. We develop a physiologically grounded model in which the extended duration of dendritic spikes equips each dendrite with a resettable memory of incoming signals. This provides a tractable model for capturing dendritic nonlinearities observed in experiments and in more complex, detailed models. Using this model, we show that long-lived, nonlinear dendritic plateau potentials allow neurons to spike reliably when confronted with asynchronous input spikes. We demonstrate this model supports non-trivial computations in a network solving an association/discrimination task using sparse spiking that is subject to timing jitter. This demonstrates a computational role for the specific time-course of dendritic potentials in situations where decisions occur quickly, reliably, and with a low number of spikes. Our results provide empirically testable hypotheses for the role of dendritic action potentials in cortical function as well as a potential bio-inspired means of realising neuromorphic spiking computations in analog hardware.